The epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential; however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-12-19T18:12:48Z 2018-04-15T09:15:58Z

<font face="Georgia" size="2">A chimeric protein produced when the <span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">first five N-terminal residues of EGF are replaced by first five N-terminal residues of Neu differentiation factor; binds and activates EGF and NDF receptors [1,2]. </span></font><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><br/></font></span></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Pro-neuregulin-1, membrane-bound isoform (Cleaved into active Neuroreglin-1) </font></span></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q02297</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: NRG1</font></span></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3084</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"><font face="Georgia" size="2"><br/></font></span></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Pro-epidermal growth factor</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P01133</span></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: EGF</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">1950</span></font></div>

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\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font size="2" face="Georgia">Epidermal growth factor receptor kinase substrate 8</font></span></p><p><font size="2" face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q12929</span></font></p><p><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font size="2" face="Georgia">Gene Name: EPS8</font></span></p><p><font size="2" face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">2059</span></font></p><p style="font-family: Arial, Verdana; font-size: 10pt; font-weight: normal;"><span style="font-family: sans-serif; font-size: small; font-weight: bold; line-height: 16px; background-color: rgb(255, 255, 255);"><br/></span></p>\r\n </div>\r\n </div>\r\n </div>

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<font face="Georgia" size="2">Reservoir of phosphatidylinositol-3-kinase [1]. </font><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">phosphoinositide-3-kinase</font><div><font size="2" face="Georgia"><br/></font><div><font size="2" face="Georgia">catalytic, alpha polypeptide (PIK3CA)</font></div><div><font size="2" face="Georgia">UniProt Accession ID: P42336</font></div><div><font size="2" face="Georgia"><br/></font></div><div><div><font size="2" face="Georgia">catalytic, beta polypeptide (PIK3CB)</font></div><div><font size="2" face="Georgia">UniProt Accession ID: Q6PJ60</font></div><div><font size="2" face="Georgia"><br/></font></div><div><div><font size="2" face="Georgia">catalytic, gamma polypeptide (PIK3CG)</font></div><div><font size="2" face="Georgia">UniProt Accession ID: P48736</font></div></div><div><font size="2" face="Georgia"><br/></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Phosphoinositide 3-kinase regulatory subunit 6</font></span></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/Q5UE93" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q5UE93</a></font></div><div><font face="Georgia" size="2"><br/></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta</font></span></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/O00750" style="text-decoration: none; background-color: rgb(255, 255, 255);">O00750</a></font></div><div><font face="Georgia" size="2"><br/></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha</font></span></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/O00443" style="text-decoration: none; background-color: rgb(255, 255, 255);">O00443</a></font></div></div></div></div>

2015-11-15T19:36:51Z

<div><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><span style="font-weight: normal;"><font face="Georgia" size="2"><span class="gn">SRC</span> v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog</font></span></h1><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><span style="font-weight: normal;"><font face="Georgia" size="2">Protein Product Name: Proto-oncogene tyrosine-protein kinase Src</font></span></h1><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><span style="font-weight: normal;"><font face="Georgia" size="2">UniProt ID: P12931</font></span></h1><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><span style="font-weight: normal;"><font face="Georgia" size="2">Gene Name: SRC</font></span></h1></div><div><font face="Georgia" size="2">Gene ID: 6714</font></div>

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<font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits [10]. </span><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules [10]. </span></font><div><font face="Georgia" size="2">Catalytic subunit: </font></div><div><span style="line-height: 19.49652862548828px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">protein phosphatase 2, catalytic subunit, alpha isozyme</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 19.49652862548828px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P67775</span></font></div><div><span style="line-height: 19.49652862548828px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: PPP2CA</font></span></div><div><font size="2" face="Georgia"><span style="line-height: 19.488636016845703px;">NCBI Gene ID: 5515</span></font></div><div><div style="font-weight: normal; font-family: Arial, Verdana; font-size: 10pt; line-height: normal;"><span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><br/></span></div></div>

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<font face="Georgia">Reservoir of son of sevenless homolog [1]. </font><div><div style="font-family: Arial, Verdana;"><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q07889</span><span style="background-color: rgb(255, 255, 255);"> </span></font></div><div style="font-family: Arial, Verdana;"><font face="Georgia" size="2">Gene Name: SOS1</font></div><div style="font-family: Arial, Verdana;"><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6654</span></font></div></div>

2015-11-15T19:36:51Z

<span style="font-family: Arial, Verdana; font-size: 10pt; line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Neuregulin 1 alpha</font></span><div><font face="Georgia" size="2"><span style="line-height: 18.875px;">An isoform derived from Pro-neuregulin 1.</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.875px;">Pro-neuregulin-1<br/></span></font><div style="font-family: Arial, Verdana; font-size: 10pt; line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q02297" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q02297</a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt; line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/3084" ref="ordinalpos=1&ncbi_uid=3084&link_uid=3084" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">NRG1</span></a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt; line-height: normal;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 3084</font></span></div></div>

2015-11-15T19:36:51Z

<span style="font-size: 10pt; line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Neuregulin 1 beta</font></span><div style="font-family: Times; font-size: medium;"><font face="Georgia" size="2"><span style="line-height: 18.875px;">An isoform derived from Pro-neuregulin 1.</span></font></div><div style="font-family: Times; font-size: medium;"><font face="Georgia" size="2"><span style="line-height: 18.875px;">Pro-neuregulin-1<br/></span></font><div style="font-family: Arial, Verdana; font-size: 10pt;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q02297" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q02297</a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/3084" ref="ordinalpos=1&ncbi_uid=3084&link_uid=3084" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">NRG1</span></a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 3084</font></span></div></div>

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<font face="Georgia" size="2">Neuregulin-3</font><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P56975" style="text-decoration: none; background-color: rgb(255, 255, 255);">P56975</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/10718" ref="ordinalpos=1&ncbi_uid=10718&link_uid=10718" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NRG3</a></font></div><div><font face="Georgia" size="2">Gene ID: 10718</font></div>

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<font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Dual</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> </span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">specificity </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"></span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">phosphatase</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> 1 </span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P28562" style="text-decoration: none; background-color: rgb(255, 255, 255);">P28562</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1843" ref="ordinalpos=2&ncbi_uid=1843&link_uid=1843" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">DUSP1</a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 1843</font></span></div>

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<p style="orphans: 3; widows: 3; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-size: 12px; background-color: rgb(255, 255, 255);"><font face="Georgia">Protein Phosphatase 2B</font></p><p style="orphans: 3; widows: 3; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-size: 12px; background-color: rgb(255, 255, 255);"><font face="Georgia">Also known as: Calcineurin</font></p><p style="font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><font face="Georgia" style="line-height: normal;">Heterodimer composed of one catalytic subunit and one regulatory subunit. </font></span></p><div style="font-family: Arial, sans-serif; line-height: 18px; font-size: 12px; color: rgb(79, 79, 79); background-color: rgb(255, 255, 255);"><font face="Georgia"><span style="line-height: normal;">There are three isoforms of the catalytic subunit:</span><font style="line-height: normal;"><br/></font></font><div style="line-height: normal;"><ul style="list-style-type: square; line-height: 1.5em; list-style-image: url(data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAUAAAANCAMAAABW4lS6AAAAGXRFWHRTb2Z0d2FyZQBBZG9iZSBJbWFnZVJlYWR5ccllPAAAAAZQTFRFAFKM////QIUK9QAAAAJ0Uk5T/wDltzBKAAAAGklEQVR42mJgBAEGokgGBjBGBxBxsBqAAAMACHwALd5r8ygAAAAASUVORK5CYII=); margin: 0.3em 0px 0px 1.5em; padding: 0px;"><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="background-color: rgb(249, 249, 249); line-height: 16.890625px; text-align: center;"><span style="line-height: 16px; text-align: start; background-color: rgb(255, 255, 255);">Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform</span>, UniProt ID: </span>Q08209</font></li><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="line-height: 16.890625px; text-align: center; background-color: rgb(249, 249, 249);"><span style="line-height: 16px; text-align: start; background-color: rgb(255, 255, 255);">Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform</span>, UnitProt ID:</span>P16298</font></li><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="line-height: 16px;">Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform, UniProt ID: </span>P48454</font></li></ul><div><font face="Georgia">There are two isoforms of the regulatory subunit:</font></div></div><div><ul style="list-style-type: square; line-height: 1.5em; list-style-image: url(data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAUAAAANCAMAAABW4lS6AAAAGXRFWHRTb2Z0d2FyZQBBZG9iZSBJbWFnZVJlYWR5ccllPAAAAAZQTFRFAFKM////QIUK9QAAAAJ0Uk5T/wDltzBKAAAAGklEQVR42mJgBAEGokgGBjBGBxBxsBqAAAMACHwALd5r8ygAAAAASUVORK5CYII=); margin: 0.3em 0px 0px 1.5em; padding: 0px;"><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="line-height: 16px;">Calcineurin subunit B type 1, UniProt ID: </span>P63098</font></li><li style="margin-bottom: 0.1em;"><font face="Georgia"><span style="line-height: 16px;">Calcineurin subunit B type 2, UniProt ID: </span>Q96LZ3</font></li></ul></div></div>

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<font size="2" face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Epiregulin</span></font><div style="font-style: normal;"><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">O14944</span></font></div><div style="font-style: normal;"><font face="Georgia" size="2">Gene Name: EREG</font></div><div style="font-style: normal;"><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255);">O14944</span></font></div>

2015-11-15T19:36:51Z

<div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">3-phosphoinositide-dependent protein kinase 1</font></span></div><font face="Georgia">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q15118">Q15118</a></font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5170" ref="ordinalpos=1&ncbi_uid=5170&link_uid=5170" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">PDPK1</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 5170</font></div>

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mammalian target of rapamycin

rreservoir of mtor

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<font face="Georgia">Neuregulin 2 alpha</font><div><font face="Georgia" size="2">Derived from pro-neuregulin 2</font></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/O14511" style="text-decoration: none; background-color: rgb(255, 255, 255);">O14511</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/9542" ref="ordinalpos=1&ncbi_uid=9542&link_uid=9542" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NRG2</a></font></div><div><font face="Georgia" size="2">Gene ID: 9542</font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Inositol polyphosphate phosphatase-like 1</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">O15357</span></font></div><div><font face="Georgia" size="2">Gene Name: <span style="background-color: rgb(255, 255, 255); line-height: 19.49652862548828px;">INPPL1</span></font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3636</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Neuregulin-4</font><div><font face="Georgia" size="2">Derived from Pro-neruregulin-4. <br/></font><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q8WWG1" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q8WWG1</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/145957" ref="ordinalpos=1&ncbi_uid=145957&link_uid=145957" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NRG4</a></font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">145957</span></font></div></div>

2015-11-15T19:36:51Z

<font size="2" face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><em>Epidermal growth factor</em></span></font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P01133</span></font></div><div><font face="Georgia" size="2">Gene Name: EGF</font></div><div><font face="Georgia" size="2">Gene ID: 1950</font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Transforming Growth Factor alpha</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P01135</span></font></div><div><font face="Georgia" size="2">Gene Name: TGFA</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">7039</span></font></div>

2015-11-15T19:36:51Z

<div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);">\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-erb-b2 erythroblastic\r\nleukemia viral oncogene\r\nhomolog 3 (avian) </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Neuregulin 2 alpha</font><div><font face="Georgia" size="2">Derived from pro-neuregulin 2</font></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/O14511" style="text-decoration: none; background-color: rgb(255, 255, 255);">O14511</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/9542" ref="ordinalpos=1&ncbi_uid=9542&link_uid=9542" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NRG2</a></font></div><div><font face="Georgia" size="2">Gene ID: 9542</font></div>

2015-11-15T19:36:51Z

<div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px;">\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-erb-a erythroblastic\r\nleukemia viral oncogene\r\nhomolog 4 (avian) </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px;"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-4</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px;"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">Q15303</span></font></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px;"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB4</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px;"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2066</span></font></div>

2018-04-15T08:54:57Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P00533</span></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">1956</span></font></div>

2018-04-15T08:58:35Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Amphiregulin</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P15514</span></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: AREG</font></span></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 374</font></span></div>

2015-11-15T19:36:51Z

<div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);">\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-erb-b2 erythroblastic\r\nleukemia viral oncogene\r\nhomolog 2,\r\nneuro/glioblastoma derived\r\noncogene homolog (avian) </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-2</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="color: rgb(79, 79, 79); line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div>

2018-04-14T21:52:37Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Probetacellulin</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P35070</span></font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: BTC</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">685</span></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">Heparin-binding EGF-like growth factor </font></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q99075">Q99075</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/1839" ref="ordinalpos=1&ncbi_uid=1839&link_uid=1839"><span class="highlight">HBEGF</span></a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: 1839</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal; font-size: 10pt; font-family: Arial, Verdana;"><br/></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Phosphatase</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> and </span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">tensin </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"></span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">homolog</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P60484" style="text-decoration: none; background-color: rgb(255, 255, 255);">P60484</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/5728" ref="ordinalpos=1&ncbi_uid=5728&link_uid=5728" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">PTEN</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;"> </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5728</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase kinase 3 [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">(human)]</span><br/></font><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P46734" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">P46734</a></font></div><div><font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5606" ref="ordinalpos=4&ncbi_uid=5606&link_uid=5606" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K3</a></font></div><div><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia">Gene ID: 5606</font></span></div>

2015-11-15T19:36:51Z

<div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase kinase 4</font></span></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q9Y6R4">Q9Y6R4</a></font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/4216" ref="ordinalpos=1&ncbi_uid=4216&link_uid=4216" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP3K4</a> </font></div><div><font face="Georgia" size="2">Gene ID: 4216<br/><br/>Also known as Mekk4</font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">ELK1, member of ETS oncogene family [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P19419" style="text-decoration: none; background-color: rgb(255, 255, 255);">P19419</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2002" ref="ordinalpos=1&ncbi_uid=2002&link_uid=2002" style="color: rgb(100, 42, 143); line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">ELK1</a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 2002</font></span></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P40763">P40763</a></font></div><div><font face="Georgia" size="2">Gene Name: STAT3</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6774</span></font></div><div><font face="Georgia" size="2"><br/></font></div><div><div><font face="Georgia" size="2">signal transducer and activator of transcription 1, 91kDa (STAT1)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P42224" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42224</a></font></div></div><div><font face="Georgia" size="2"><br/></font></div><div><div><font face="Georgia" size="2">signal transducer and activator of transcription 5A (STAT5A)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P42229" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42229</a></font></div></div><div><font face="Georgia" size="2"><br/></font></div><div><div><font face="Georgia" size="2">signal transducer and activator of transcription 5B (STAT5B)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P51692" style="text-decoration: none; background-color: rgb(255, 255, 255);">P51692</a></font></div></div>

2015-11-15T19:36:51Z

<div><span style="font-size: 13.3333330154419px;">Signal transducer and activator of transcription 5</span></div><div><div style="font-size: 13.3333330154419px;">Gene Name: STAT5</div><div style="font-size: 13.3333330154419px;">Gene ID: <span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">100135887</span></div></div><font face="Georgia" size="2"></font><div><font face="Georgia" size="2"><br/></font></div>The term "stat5" is typically inclusive of the two highly related, structurally and functionally, transcription factors [1]:<div><font face="Georgia" size="2">Stat5A</font></div><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P42229</span></font></div><div><font face="Georgia" size="2">Gene Name: STAT5A</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6776</span></font></div><div><font face="Georgia" size="2">Stat5B</font></div><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P51692</span><span style="background-color: rgb(255, 255, 255);"> </span></font></div><div><font face="Georgia" size="2">Gene Name: STAT5B</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6777</span></font></div><div><br/></div>

2015-11-15T19:36:51Z

<div><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;"><font face="Georgia" size="2">Phosphatidylinositol Triphosphate</font></span></span></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><span style="line-height: 17px;">PubChem ID:</span></span><span style="line-height: 19px; background-color: rgb(255, 255, 255);"> </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=53480352[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);">53480352<br/></a><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Formula:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> C</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">47</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">H</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">86</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">O</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">22</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">P</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">4</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">   </span><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">Molecular Weight:</span><span style="line-height: 17px; background-color: rgb(255, 255, 255);"> 1127.067588 </span></font></div><div style="font-weight: normal; font-size: 10pt; font-family: Arial, Verdana;"><span style="color: rgb(85, 85, 85); font-family: Arial, Verdana, sans-serif; font-size: 13px; line-height: 17px; background-color: rgb(255, 255, 255);"><br/></span></div>

2017-07-17T15:54:04Z

Name: protein kinase B

Gene Name: AKT1

UNIPROT ID: P31749

Gene ID: 207

2015-11-15T19:36:51Z

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Full Name: actin reorganization</font></p><p><font face="Georgia" size="2">Symbolizes actin reorganizing effects\r\ninitiated by LIMK1 [1]. </font><br/>\r\n</p><p style="font-size: 10pt; font-family: Arial, Verdana;"><span style="font-size: 10.000000pt; font-family: 'Helvetica'"><br/></span></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase kinase 11</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q16584</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4296" ref="ordinalpos=2&ncbi_uid=4296&link_uid=4296" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP3K11</a></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: 4296</span></font></div>

2015-11-15T19:36:51Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Dual specificity mitogen-activated protein kinase kinase 4</font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P45985" style="text-decoration: none; background-color: rgb(255, 255, 255);">P45985</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/6416" ref="ordinalpos=6&ncbi_uid=6416&link_uid=6416" style="line-height: 18.88888931274414px; white-space: nowrap;">MAP2K4</a></font></div><div><font face="Georgia" size="2">Gene ID: 6416</font></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Symbolizes endocytosis/degradation\r\nof the receptors [1]. </font><br/>\r\n</p>\r\n </div>\r\n </div>\r\n </div>

2018-04-15T09:15:58Z

<font face="Georgia" size="2">Combined dummy species for p90Rsk and Erk1/2 [1]. </font><div><div><font face="Georgia" size="2" style="line-height: 14.390625px; background-color: rgb(255, 255, 255);">Ribosomal protein </font><font face="Georgia" size="2" style="line-height: 14.390625px; background-color: rgb(255, 255, 255);">S6 kinase, 90kDa polypeptide 1</font></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q9UK32" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q9UK32</a></font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/6195" ref="ordinalpos=1&ncbi_uid=6195&link_uid=6195" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">RPS6KA1</a></font></div><div><font face="Georgia" size="2">Gene ID: 6195</font></div></div><div><font face="Georgia" style="background-color: rgb(255, 255, 255);" size="2">For this model, erk 1 is not differentiated from erk2. This node therefore represents either erk 1 or erk 2 [1]. </font><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase 3</font></span></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID: <a href="http://www.uniprot.org/uniprot/P27361" style="text-decoration: none;">P27361</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5595" ref="ordinalpos=4&ncbi_uid=5595&link_uid=5595" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK3</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5595</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 1</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID:<a href="http://www.uniprot.org/uniprot/P28482" style="text-decoration: none;">P28482</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5594" ref="ordinalpos=1&ncbi_uid=5594&link_uid=5594" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK1</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5594</font></div></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><br/></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2" style="line-height: 14.390625px; background-color: rgb(255, 255, 255);">Ribosomal protein </font><font face="Georgia" size="2" style="line-height: 14.390625px; background-color: rgb(255, 255, 255);">S6 kinase, 90kDa polypeptide 1</font></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q9UK32" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q9UK32</a></font><div><font face="Georgia" size="2">Gene Name: </font><a href="http://www.ncbi.nlm.nih.gov/gene/6195" ref="ordinalpos=1&ncbi_uid=6195&link_uid=6195" style="color: rgb(100, 42, 143); font-family: arial, helvetica, clean, sans-serif; font-size: 13.333333969116211px; line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">RPS6KA1</a></div><div><font face="Georgia" size="2">Gene ID: 6195</font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">BCL2-associated agonist of cell death [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q92934" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q92934</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/572" ref="ordinalpos=1&ncbi_uid=572&link_uid=572" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">BAD</span></a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 572</font></span></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Complex of mTOR and RICTOR [1]. </font><div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mechanistic target of rapamycin (serine/threonine kinase)</font></span></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P42345" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42345</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/2475" ref="ordinalpos=1&ncbi_uid=2475&link_uid=2475" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">MTOR</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 2475</font></div></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Regulatory associated protein of MTOR, complex 1</font></span></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q6R327" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q6R327</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/253260" ref="ordinalpos=1&ncbi_uid=253260&link_uid=253260" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">RICTOR</span></a></font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">253260</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">A phosphorylated dimer of ERK1/2,\r\nlocated in the nucleus [1]. </font><div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 3 (Erk1)</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID: <a href="http://www.uniprot.org/uniprot/P27361" style="text-decoration: none;">P27361</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5595" ref="ordinalpos=4&ncbi_uid=5595&link_uid=5595" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK3</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5595</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><br/></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 1 (Erk2)</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID:<a href="http://www.uniprot.org/uniprot/P28482" style="text-decoration: none;">P28482</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5594" ref="ordinalpos=1&ncbi_uid=5594&link_uid=5594" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK1</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5594</font></div></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><br/></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2"><span class="RECOMMENDED" style="line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer;">Dummy species of shp1 [1]. </acronym></span></font></div><font face="Georgia" size="2" style="font-style: normal;"><span class="RECOMMENDED" style="line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer; font-style: italic;">Recommended name:</acronym><br/><span class="FULL" style="padding-left: 1em;">Tyrosine-protein phosphatase non-receptor type 6</span></span><br/><span class="EC_NAME" style="background-color: rgb(255, 255, 255); line-height: 16px;"></span></font><div class="alternatives" style="font-style: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><acronym class="ALTERNATIVE" title="A synonym of the recommended name." style="border: none; cursor: pointer; font-style: italic;">Alternative name(s):</acronym><br/><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym><span class="FULL_NAME">Protein-tyrosine phosphatase SHP-1</span></font></div><div class="alternatives" style="font-style: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia" size="2"><br/></font></span></div><div class="alternatives" style="font-style: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal;">P29350</span></font></div><div class="alternatives" style="font-style: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: normal;">Gene Name: </span><span style="line-height: 19.49652862548828px;">PTPN6</span></font></div><div class="alternatives" style="font-style: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: normal;">Gene ID:5777</span></font></div>

2018-04-15T09:15:58Z

Sub unit of homo- or heterodimer protein: Ap1<div><br/><div>UniProt ID: <span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">P05412</span></div><div><span class="RECOMMENDED" style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer; font-style: italic;">Recommended name:</acronym><br/><span class="FULL" style="padding-left: 1em;">Transcription factor AP-1</span></span><div class="alternatives" style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="ALTERNATIVE" title="A synonym of the recommended name." style="border: none; cursor: pointer; font-style: italic;">Alternative name(s):</acronym><br/><span style="padding-left: 1em;"><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym></span><span class="FULL_NAME">Activator protein 1</span><br/><acronym class="names SHORT" title="Abbreviation of the full name or an acronym." style="border: none; cursor: pointer; padding-left: 2em; font-size: smaller;">Short name=</acronym><span class="SHORT_NAME" style="font-size: smaller;">AP1</span><br/><span style="padding-left: 1em;"><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym></span><span class="FULL_NAME">Proto-oncogene c-Jun</span></div></div></div>

2015-11-15T19:36:51Z

<div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">\r\n \r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">Phosphorylation of several S/T residues (S404,\r\nS411, S418, S424, T421) in the C-terminal\r\nautoinhibitory domain of p70s6 leads to a\r\nconformational change that enables the\r\nphosphorylation of the catalytic sites T389 and\r\nS229 [3]. Both JNK and\r\nERK1/2 are able to phosphorylate the autoinhibitory\r\nsites [2]</span><span style="font-size: 10pt;"> ? however, the\r\nmechanism of activation of these sites is not well\r\nunderstood and additional kinases are probably\r\ninvolved in this step [1,3].  </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Phosphorylated at auto-inhibitory sites [1]. </font></div><font face="Georgia" size="2" style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Ribosomal protein </font><font face="Georgia" size="2" style="font-family: Arial, Verdana;">S6 kinase, 70kDa polypeptide 1</font><div style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P23443" style="text-decoration: none; background-color: rgb(255, 255, 255);">P23443</a></font></div><div style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/6198" ref="ordinalpos=1&ncbi_uid=6198&link_uid=6198" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">RPS6KB1</a></font></div><div style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Gene ID: 6198</font></div><div style="font-family: Arial, Verdana; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal; font-size: 10pt;"><br/></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Both MEK1 and MEK2 catalyze\r\nthe same reactions; this node represents both [1].<br/>\r\n</font></p><p><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">mitogen-activated protein kinase kinase 1</font></span></p><p><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q02750" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q02750</a></font></p><p><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5604" ref="ordinalpos=1&ncbi_uid=5604&link_uid=5604" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K1</a></font></p><p><font face="Georgia" size="2">Gene ID: 5604</font></p><p><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">mitogen-activated protein kinase kinase 2</font></span></p><p><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P36507" style="text-decoration: none; background-color: rgb(255, 255, 255);">P36507</a></font></p><p><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5605" ref="ordinalpos=1&ncbi_uid=5605&link_uid=5605" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K2</a></font></p><p><font face="Georgia" size="2">Gene ID: 5605</font></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Cell division control protein 42 homolog </font></span><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Also known as: </span><span style="background-color: rgb(255, 255, 255); line-height: 16px;">G25K GTP-binding protein</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 16px;">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P60953</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 16px;"><font face="Georgia" size="2">Gene Name: CDC42</font></span></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 16px;">Gene ID: </span><span style="background-color: rgb(255, 255, 255); color: rgb(87, 87, 87); line-height: 16.78819465637207px; white-space: nowrap;">998</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Src homology 2 domain containing transforming protein 1</font><div><font face="Georgia" size="2">UniProt ID:<span style="background-color: rgb(255, 255, 255);">P29353</span></font></div><div><font face="Georgia" size="2">Gene Name: SHC1</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6464</span></font></div>

2015-11-15T19:36:51Z

<div style="font-size: 12px; font-family: Arial, sans-serif; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Phosphorylated at the catalytic T389 and S229 [1]. </font></div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Ribosomal protein </font><font face="Georgia" size="2" style="line-height: 14.390625px; background-color: rgb(255, 255, 255);">S6 kinase, 70kDa polypeptide 1</font><div style="font-size: 12px; font-family: Arial, sans-serif; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P23443" style="outline: none; text-decoration: none;">P23443</a></font></div><div style="font-size: 12px; font-family: Arial, sans-serif; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/6198" ref="ordinalpos=1&ncbi_uid=6198&link_uid=6198" style="outline: none; line-height: 18.88888931274414px; white-space: nowrap;">RPS6KB1</a></font></div><div style="font-size: 12px; font-family: Arial, sans-serif; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 6198</font></div>

2015-11-15T19:36:51Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription">Calcium Ion</span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.390625px; background-color: rgb(255, 255, 255);">PubChem ID: <a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=271[uid]" style="outline: 0px; color: rgb(0, 153, 78); border: 0px; font-family: Arial, Verdana, sans-serif; font-size: 14px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none;">271</a></div>

2015-11-15T19:36:51Z

<span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Protein tyrosine phosphatase, non-receptor type 11</font></span><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q06124" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q06124</a><span style="line-height: 19.999780654907227px;"><br/></span></font><div style="line-height: normal;"><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5781" ref="ordinalpos=1&ncbi_uid=5781&link_uid=5781" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">PTPN11</a></font></div><div style="line-height: normal;"><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">5781</span></font></div></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 8 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P45983" style="text-decoration: none; background-color: rgb(255, 255, 255);">P45983</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5599" ref="ordinalpos=5&ncbi_uid=5599&link_uid=5599" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAPK8</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5599</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">v-Raf-1 murine leukemia viral oncogene homolog 1</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P04049</span></font></div><div><font face="Georgia" size="2">Gene Name: RAF1</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">5894</span></font></div>

2015-11-15T19:36:51Z

<div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Guanine nucleotide exchange factor VAV2</font></span></div><font face="Georgia" size="2">Uniprot ID: P52735</font><div><font face="Georgia" size="2">Gene Name: VAV2</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); color: rgb(87, 87, 87); line-height: 16.78819465637207px; white-space: nowrap;">7410</span></font></div>

2015-11-15T19:36:51Z

<font style="line-height: normal; background-color: rgb(255, 255, 255);" face="Georgia" size="2"><span style="border: 0px; outline: 0px; font-style: inherit; font-variant: inherit; line-height: inherit; vertical-align: baseline; margin: 0px; padding: 0px;">Diacylglycerol </span></font><div><font face="Georgia" size="2">PubChem ID: <span style="line-height: 19px; background-color: rgb(255, 255, 255);">6026790</span></font></div><div><font face="Georgia" size="2"><span style="line-height: inherit; font-style: inherit; font-variant: inherit; border: 0px; outline: 0px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Formula:</span><span style="background-color: rgb(255, 255, 255); line-height: inherit;"> </span><span style="background-color: rgb(255, 255, 255); line-height: inherit;">C</span><sub style="font-style: inherit; font-variant: inherit; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">37</sub><span style="background-color: rgb(255, 255, 255); line-height: inherit;">H</span><sub style="font-style: inherit; font-variant: inherit; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">70</sub><span style="background-color: rgb(255, 255, 255); line-height: inherit;">O</span><sub style="font-style: inherit; font-variant: inherit; border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px;">5</sub><span style="background-color: rgb(255, 255, 255); line-height: inherit;">   </span><span style="line-height: inherit; font-style: inherit; font-variant: inherit; border: 0px; outline: 0px; vertical-align: baseline; margin: 0px; padding: 0px;">Molecular Weight:</span><span style="background-color: rgb(255, 255, 255); line-height: inherit;"> </span><span style="background-color: rgb(255, 255, 255); line-height: inherit;">594.9487  </span></font></div>

2015-11-15T19:36:51Z

<span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase 7</font></span><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O14733" style="text-decoration: none; background-color: rgb(255, 255, 255);">O14733</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5609" ref="ordinalpos=3&ncbi_uid=5609&link_uid=5609" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K7</a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 5609</font></span></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Heterodimer composed of ErbB1-and\r\nErbB2-receptor [1]: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P00533</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">1956</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-2</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div><p style="font-size: 10pt; font-family: Arial, Verdana;"><span style="font-size: 10.000000pt; font-family: 'Helvetica'"><br/></span></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB4-receptor [1]: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P00533</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">1956</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-4</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">Q15303</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB4</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2066</span></font></div>

2017-07-17T15:54:04Z

<h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;">\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font size="2" style="font-weight: normal;" face="Georgia">Homodimer composed of two ErbB1-\r\nreceptors [1]:<br/>\r\n</font></p>\r\n </div>\r\n </div>\r\n </div></h1><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><font size="2" style="font-weight: normal;" face="Georgia"><span class="gn">EGFR</span> epidermal growth factor receptor</font></h1><h1 class="title" style="margin: 1em 0px 0.5em; padding: 0px;"><font size="2" style="font-weight: normal;" face="Georgia">UniProt ID: P00533</font></h1><div><font size="2" face="Georgia">Gene Name: EGFR</font></div><div><font size="2" face="Georgia">Gene ID: 1956</font></div>

2018-04-15T09:15:58Z

<div><span style="border: 0px; outline: 0px; line-height: 24px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Phosphoinositide-3,4-bisphosphate</font></span></div><font face="Georgia" size="2"><span style="line-height: 19px; background-color: rgb(255, 255, 255);">PubChem ID: </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=643960[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);">643960</a></font>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">Heat Shock Protein 27</font></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P04792" style="text-decoration: none; background-color: rgb(255, 255, 255);">P04792</a></font>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">RAS p21 protein activator</font><div><font face="Georgia" size="2"><em>also known as:</em> Ras GTPase-activating protein 1</font></div><div style="font-style: normal;"><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P20936</span></font></div><div style="font-style: normal;"><font face="Georgia" size="2">Gene Name: RASA1</font></div><div style="font-style: normal;"><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">5921</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase-activated protein kinase 2 [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 18.88607406616211px;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P49137" style="text-decoration: none; background-color: rgb(255, 255, 255);">P49137</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88607406616211px;">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/9261" ref="ordinalpos=2&ncbi_uid=9261&link_uid=9261" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAPKAPK2</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88607406616211px;">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">9261</span></font></div>

2015-11-15T19:36:51Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Signal transducer and activator of transcription 1</font></span><div><font face="Georgia" size="2"><span style="line-height: 15.989583969116211px;">Uniport ID: </span><a href="http://www.uniprot.org/uniprot/P42224">P42224</a><span style="line-height: 15.989583969116211px;"><br/></span></font><div><div style="line-height: normal;"><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: STAT1 </font></span></div></div></div><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">6772</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Ras homolog enriched in brain</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q15382</span><span style="background-color: rgb(255, 255, 255);"> </span></font></div><div><font face="Georgia" size="2">Gene Name: RHEB</font></div><div><font face="Georgia" size="2">Gene ID: 6009</font></div>

2015-11-15T19:36:51Z

<span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase kinase 1, E3 ubiquitin protein ligase</font></span><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q13233" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q13233</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/4214" ref="ordinalpos=4&ncbi_uid=4214&link_uid=4214" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP3K1</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">4214</span></font></div>

2015-11-15T19:36:51Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Heterodimer composed of ErbB2-and ErbB4-receptor [1]: </font></p><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-2</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div><div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-4</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">Q15303</span></font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB4</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2066</span></font></div></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 14 </span><br/></font><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q16539</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/1432" ref="ordinalpos=1&ncbi_uid=1432&link_uid=1432" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAPK14</a></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">1432</span></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">cAMP responsive element binding protein 1</font></div><div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Cyclic AMP-responsive element-binding protein 1</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P16220</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene Name: CREB1</font></span></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">1385</span></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">LIM Domain Kinase 1</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P53667" style="text-decoration: none; background-color: rgb(255, 255, 255);">P53667</a></font></div><div><font face="Georgia" size="2">Gene Name: <span class="highlight" style="color: rgb(100, 42, 143); line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><a href="http://www.ncbi.nlm.nih.gov/gene/3984" ref="ordinalpos=1&ncbi_uid=3984&link_uid=3984" style="color: rgb(100, 42, 143); line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">LIMK1</a></span></font></div><div><font face="Georgia" size="2">Gene ID: 3984</font></div>

2015-11-15T19:36:51Z

<div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase 6 </font></span></div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P52564" style="text-decoration: none; background-color: rgb(255, 255, 255);">P52564</a></font><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5608" ref="ordinalpos=2&ncbi_uid=5608&link_uid=5608" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP2K6</a></font></div><div><font face="Georgia" size="2">Gene ID: 5608</font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span class="RECOMMENDED" style="line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer; font-style: italic;">Recommended name:</acronym><br/><span class="FULL" style="padding-left: 1em;">Tyrosine-protein phosphatase non-receptor type 6</span></span><br/><span class="EC_NAME" style="background-color: rgb(255, 255, 255); line-height: 16px;"></span></font><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><acronym class="ALTERNATIVE" title="A synonym of the recommended name." style="border: none; cursor: pointer; font-style: italic;">Alternative name(s):</acronym><br/><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym><span class="FULL_NAME">Protein-tyrosine phosphatase SHP-1</span></font></div><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia" size="2"><br/></font></span></div><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal;">P29350</span></font></div><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: normal;">Gene Name: </span><span style="line-height: 19.49652862548828px;">PTPN6</span></font></div><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: normal;">Gene ID:5777</span></font></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Cas-Br-M (murine) ecotropic\r\nretroviral transforming\r\nsequence<br/>\r\n</font></p><p><font face="Georgia" size="2">Protein Product Name: <span style="background-color: rgb(255, 255, 255); line-height: 16px;">Kynurenine--oxoglutarate transaminase 1</span></font></p><p><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q16773</span></font></p><p><font face="Georgia" size="2">Gene Name: CBL</font></p><p><span style="font-family: Georgia; font-size: small;">Gene ID: </span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">867</span></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Related to the N terminus of tre </font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q92738</span></font></div><div><font face="Georgia" size="2">Gene Name: <span style="background-color: rgb(255, 255, 255); line-height: 19.49652862548828px;">USP6NL</span></font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">9712</span></font></div>

2015-11-15T19:36:51Z

<div><span class="RECOMMENDED" style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer;">UniProt ID: </acronym></span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">P05412<br/></span><span class="RECOMMENDED" style="font-size: small; font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer; font-style: italic;">Recommended name:</acronym></span></div><span class="RECOMMENDED" style="font-style: normal; font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL" style="padding-left: 1em;">Transcription factor AP-1</span></span><div class="alternatives" style="font-style: normal; font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><acronym class="ALTERNATIVE" title="A synonym of the recommended name." style="border: none; cursor: pointer; font-style: italic;">Alternative name(s):</acronym><br/><span style="padding-left: 1em;"><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym></span><span class="FULL_NAME">Activator protein 1</span><br/><acronym class="names SHORT" title="Abbreviation of the full name or an acronym." style="border: none; cursor: pointer; padding-left: 2em; font-size: smaller;">Short name=</acronym><span class="SHORT_NAME" style="font-size: smaller;">AP1</span></div>

2015-11-15T19:36:51Z

<div><font size="2" face="Georgia">phospholipase C, gamma 1 (PLCG1)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <span style="background-color: rgb(255, 255, 255);">P19174</span></font></div><div><font size="2" face="Georgia">Gene Name: PLCG1</font></div><div><font size="2" face="Georgia">NCBI Gene ID: 5535</font></div>

2015-11-15T19:36:51Z

<span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">GRB2-associated binding protein 1 </font></span><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/Q13480" style="text-decoration: none;">Q13480</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 18.88888931274414px;">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2549" ref="ordinalpos=1&ncbi_uid=2549&link_uid=2549" style="line-height: 18.88888931274414px; white-space: nowrap;"><span class="highlight">GAB1</span></a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 2549</font></span></div>

2015-11-15T19:36:51Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB2-receptor [1]: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><span style="font-family: Georgia; font-size: small; line-height: 16px;">Receptor tyrosine-protein kinase erbB-2</span></p><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P04626</font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB2</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">2064</span></font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><div><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px;"><br/></span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">There are three forms of IP3:</font><div><ul><li><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Inositol-trisphosphate 3-kinase A, UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P23677 (activated by calmodulin [3]). </span></font></li><li><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Inositol-trisphosphate 3-kinase B, </span><span style="background-color: rgb(255, 255, 255); line-height: 16px;">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P27987</span><span style="background-color: rgb(255, 255, 255); line-height: 16px;">  (more sensitive, by 8-fold, to calmodulin than isoform A [4])</span></font></li><li><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Inositol-trisphosphate 3-kinase C, UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">Q96DU7 (activated by calmodulin like IP3A [2], but localized and expressed h</span><span style="background-color: rgb(255, 255, 255); line-height: 16px;">ighly in pancreas, skeletal muscle, liver, placenta and weakly in kidney and brain [2].</span><span style="background-color: rgb(255, 255, 255);"> </span><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Shuttles actively between nucleus and cytoplasm with both nuclear import and nuclear export activity. [1])</span></font></li></ul></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">In EGFR ErbB Signaling  and IL-6 models, this node represents the molecule i</span>nositol-1,4,5-triphosphate (PubChem ID:<span style="color: rgb(85, 85, 85); line-height: 19px; background-color: rgb(255, 255, 255);"> </span><a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=439456[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; color: rgb(0, 86, 204); background-color: rgb(255, 255, 255);">439456</a>) and not the kinase [5,6]. </font></div>\r\n \r\n \r\n \r\n <div class="page" title="Page 2">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Helvetica'"> <br/></span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Phosphatidylinositol</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">-4,5-bisphosphate 3-kinase, catalytic subunit alpha [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P42336" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42336</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5290" ref="ordinalpos=1&ncbi_uid=5290&link_uid=5290" style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px; white-space: nowrap;">PIK3CA</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">5290</span></font></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2">The protein kinase c family consists of 15 isozymes in humans [49]. </font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">Protein Kinase C alpha</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P17252">P17252</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCA</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5578</span></font></div><div><div><font face="Georgia" size="2">Protein Kinase C beta</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P05771" style="text-decoration: none; background-color: rgb(255, 255, 255);">P05771</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCB</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5579</span></font></div></div><div><div><div><font face="Georgia" size="2">Protein Kinase C gamma</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P05129" style="text-decoration: none; background-color: rgb(255, 255, 255);">P05129</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCG</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5582</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C delta</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q05655" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q05655</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCD</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5580</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C epsilon</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q02156" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q02156</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCE</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5581</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C eta</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P24723" style="text-decoration: none; background-color: rgb(255, 255, 255);">P24723</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCH</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5583</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C theta</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q04759" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q04759</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCQ</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5588</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C iota</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/P41743" style="text-decoration: none; background-color: rgb(255, 255, 255);">P41743</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCI</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5584</span></font></div></div><div><div><font face="Georgia" size="2">Protein Kinase C zeta</font></div><div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q05513">Q05513</a></font></div><div><font face="Georgia" size="2">Gene Name: PRKCZ</font></div><div><font face="Georgia" size="2">Gene ID:<span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5590</span></font></div></div></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">For this model, erk 1 is not differentiated from erk2. This node therefore represents either erk 1 or erk 2 [1]. </font><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><br/></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 3</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID: <a href="http://www.uniprot.org/uniprot/P27361" style="text-decoration: none;">P27361</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5595" ref="ordinalpos=4&ncbi_uid=5595&link_uid=5595" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK3</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5595</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><br/></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase 1</font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">UniProt ID:<a href="http://www.uniprot.org/uniprot/P28482" style="text-decoration: none;">P28482</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5594" ref="ordinalpos=1&ncbi_uid=5594&link_uid=5594" style="line-height: 18.88888931274414px; white-space: nowrap;">MAPK1</a></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene ID: 5594</font></div><div style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;"><font face="Georgia" size="2"><br/></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Glycogen synthase kinase 3</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> [</span><em style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">(human)]</span></font><div><font face="Georgia" size="2">?/? (species refers to both currently known isoforms) <br/></font><div><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Glycogen synthase kinase 3 </span>?</font></div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P49841" style="text-decoration: none; background-color: rgb(255, 255, 255);">P49841</a></font><div><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2932" ref="ordinalpos=1&ncbi_uid=2932&link_uid=2932" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">GSK3B</a></font></div><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">2932</span></font></div></div></div></div><div style="line-height: normal;"><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Glycogen synthase kinase 3</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> </span>?</font></div><div style="line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P49840" style="text-decoration: none; background-color: rgb(255, 255, 255);">P49840</a></font><div><div><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2931" ref="ordinalpos=4&ncbi_uid=2931&link_uid=2931" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">GSK3A</a></font></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 2931</font></span></div></div></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Complex of mTOR and RPTOR [1]. </font><div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mechanistic target of rapamycin (serine/threonine kinase)</font></span></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P42345" style="text-decoration: none; background-color: rgb(255, 255, 255);">P42345</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/2475" ref="ordinalpos=1&ncbi_uid=2475&link_uid=2475" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">MTOR</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 2475</font></div></div><div><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Regulatory associated protein of MTOR, complex 1</font></span></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q8N122" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q8N122</a></font></div><div><font face="Georgia" size="2">Gene Name: <span class="highlight" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);"><a href="http://www.ncbi.nlm.nih.gov/gene/57521" ref="ordinalpos=1&ncbi_uid=57521&link_uid=57521" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">RPTOR</a></span> </font></div><div><font face="Georgia" size="2">Gene ID: 57521</font></div>

2015-11-15T19:36:51Z

<span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">v-myc avian myelocytomatosis viral oncogene homolog</font></span><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">UniProt ID:</span><a href="http://www.uniprot.org/uniprot/P01106" style="text-decoration: none; background-color: rgb(255, 255, 255);">P01106</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/4609" ref="ordinalpos=1&ncbi_uid=4609&link_uid=4609" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">MYC</a></font></div><div><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 4609</font></span></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Son of sevenless homolog 1</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q07889</span><span style="background-color: rgb(255, 255, 255);"> </span></font></div><div><font face="Georgia" size="2">Gene Name: SOS1</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">6654</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Dummy species for Phosphatase and tensin homolog [1]:</font><div><font size="2" face="Georgia">Also known as: <span style="background-color: rgb(255, 255, 255); line-height: 16px;">Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN</span></font></div><div><font size="2" face="Georgia"><span style="background-color: rgb(255, 255, 255); line-height: 16px;">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P60484</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 16px;"><font size="2" face="Georgia">Gene Name: PTEN</font></span></div><div><font size="2" face="Georgia"><span style="background-color: rgb(255, 255, 255); line-height: 16px;">NCBI Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">5728</span></font></div>

2015-11-15T19:36:51Z

<font size="2" style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal; background-color: rgb(255, 255, 255);" face="Georgia">Growth factor receptor-bound protein 2</font><div><font face="Georgia" style="background-color: rgb(255, 255, 255);"><font size="2" style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Uniprot Accession ID: </font><font size="2">Q60631</font></font></div><div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/2885" ref="ordinalpos=1&ncbi_uid=2885&link_uid=2885" style="line-height: 18.88888931274414px; white-space: nowrap;"><span class="highlight">GRB2</span></a></font></div><div><font size="2" face="Georgia" style="background-color: rgb(255, 255, 255);">Gene ID: 2885</font></div>

2015-11-15T19:36:51Z

<div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Ras-like Protein</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P0CQ42">P0CQ42</a></font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2"><br/></font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS)</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Rat:</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">UniProt Accession ID: P20171</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font size="2" face="Georgia">Human:</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font size="2" face="Georgia">UniProt Accession ID: P01112</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font size="2" face="Georgia">Gene Name: HRAS</font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); color: rgb(87, 87, 87); line-height: 16.78819465637207px; white-space: nowrap;">3265</span></font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2"><br/></font></div><div><span style="font-weight: normal;"><font face="Georgia" size="2">Kirsten rat sarcoma viral oncogene homolog (KRAS)</font></span></div><div><font face="Georgia" size="2"><span style="font-weight: normal;">UniProt ID: </span><strong style="background-color: rgb(255, 255, 255);">P01116</strong></font></div><div><span style="font-weight: normal;"><font face="Georgia" size="2">Gene Name: KRAS</font></span></div><div><font face="Georgia" size="2"><span style="font-weight: normal;">Gene ID: </span><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3845</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;"><br/></span></font></div><div>NRAS = neuroblastoma RAS viral (v-ras) oncogene homolog </div><div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P01111" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">P01111</a></div><div>Gene Name: NRAS</div><div>Gene ID: <span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">4893</span></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Ras-related protein Rab-5A</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P20339</span><span style="background-color: rgb(255, 255, 255);"> </span></font></div><div><font face="Georgia" size="2">Gene Name: RAB5A</font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 16.78819465637207px; white-space: nowrap;">5868</span></font></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Dummy species for akt [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">RAS and RAB interactor 1</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q13671</span></font></div><div><font face="Georgia" size="2">Gene Name: RIN1</font></div><div><font face="Georgia" size="2">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">9610</span></font></div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">P21/cdc42/Rac-1 activated kinase</font><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q13153" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q13153</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5058" ref="ordinalpos=1&ncbi_uid=5058&link_uid=5058" style="line-height: 18.88888931274414px; white-space: nowrap;"><span class="highlight">PAK1</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 5058</font></div>

2015-11-15T19:36:51Z

<p><font face="Georgia" size="2">Heterodimer composed of ErbB1-and ErbB3-receptor [1]: </font></p><p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span>P00533</font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 18.88888931274414px;">1956</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div style="line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div><div style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px;"><br/></span></font></div>

2017-07-17T14:47:06Z

\r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Represents a complex of SOS1, Eps8 and E3b1 [1]. </font></p><p><font face="Georgia" size="2">Son of sevenless homolog 1</font></p><p><font face="Georgia" size="2">UniProt ID: Q07889 </font></p><div><font face="Georgia" size="2">Gene Name: SOS1</font></div><div><font face="Georgia" size="2">Gene ID: 6654</font></div><div><font face="Georgia" size="2"><br/></font></div><div><p style="margin: 0.4em 0px 0.5em;"><font face="Georgia" size="2">Epidermal growth factor receptor kinase substrate 8</font></p><p style="margin: 0.4em 0px 0.5em;"><font face="Georgia" size="2">UniProt ID: Q12929</font></p><p style="margin: 0.4em 0px 0.5em;"><font face="Georgia" size="2">Gene Name: EPS8</font></p><p style="margin: 0.4em 0px 0.5em;"><font face="Georgia" size="2">Gene ID: 2059</font></p></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">Abl interactor 1</font></div><div><font face="Georgia" size="2">UniProt ID: Q8IZP0</font></div><div><font face="Georgia" size="2">Gene Name: ABI1</font></div><div><font face="Georgia" size="2">Gene ID: 10006</font></div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 11.818181991577148px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Heterodimer composed of ErbB3-and ErbB4-receptor [1]: </font></p><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-3</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">P21860</span></font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB3</font></span></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div><div style="font-size: 11.818181991577148px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.389204025268555px; background-color: rgb(255, 255, 255);"><div><span style="line-height: 16px;"><font face="Georgia" size="2">Receptor tyrosine-protein kinase erbB-4</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID: </span><span style="line-height: normal;">Q15303</span></font></div><div><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: ERBB4</font></span></div><div><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID: </span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2066</span></font></div></div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2"><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">NCK</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"> adaptor protein 1</span></font></div><div><font face="Georgia" size="2">UniProt ID: <a href="http://www.uniprot.org/uniprot/P16333" style="text-decoration: none; background-color: rgb(255, 255, 255);">P16333</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/4690" ref="ordinalpos=2&ncbi_uid=4690&link_uid=4690" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">NCK1</a></font></div><div><font face="Georgia" size="2">Gene ID: 4690</font></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Symbolizes the pro-apoptotic effect of\r\nBAD [1].</font><br/>\r\n</p>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<div><font face="Georgia" size="2"><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="border: none; cursor: pointer; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID:</acronym><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="font-style: italic; border: none; cursor: pointer; line-height: 16px; background-color: rgb(255, 255, 255);"> </acronym><span style="font-style: normal; background-color: rgb(255, 255, 255);">P01100<br/></span><acronym class="RECOMMENDED" title="The name recommended by the UniProt consortium." style="font-style: italic; border: none; cursor: pointer; line-height: 16px; background-color: rgb(255, 255, 255);">Recommended name:</acronym></font></div><span class="FULL" style="font-style: normal; padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Proto-oncogene c-Fos</font></span><div><font face="Georgia" size="2"><span class="FULL" style="font-style: normal; padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/2353" ref="ordinalpos=5&ncbi_uid=2353&link_uid=2353" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">FOS</a><span style="background-color: rgb(255, 255, 255); line-height: 16px;"> </span></font></div><div><span class="FULL" style="font-style: normal; padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 2353</font></span></div>

2015-11-15T19:36:51Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 4">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Represents Tuberous sclerosis complex 1\r\nand 2 [1]: </font></p><p><font face="Georgia" size="2">Hamatin</font></p><p><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">Q92574</span></font></p><p><font face="Georgia" size="2">Gene Name: <span style="background-color: rgb(255, 255, 255); line-height: 17.77777862548828px;">TSC1</span></font></p><p><font face="Georgia" size="2">Gene ID: 7248</font></p><p><font face="Georgia" size="2">Tuberin</font></p><p><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">P49815</span><span style="background-color: rgb(255, 255, 255);"> </span></font></p><p><font face="Georgia" size="2">Gene Name: TSC2</font></p><p><font face="Georgia" size="2">Gene ID: 7249</font></p><p style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;"><span style="font-family: Helvetica; font-size: 10pt;"> </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T19:36:51Z

<font face="Georgia" size="2">Dummy species for ship2 [1]:</font><div><font face="Georgia" size="2">Inositol polyphosphate phosphatase-like 1</font><div><font face="Georgia" size="2">UniProt ID: <span style="background-color: rgb(255, 255, 255);">O15357</span></font></div><div><font face="Georgia" size="2">Gene Name: <span style="background-color: rgb(255, 255, 255); line-height: 19.49652862548828px;">INPPL1</span></font></div><div><font face="Georgia" size="2"><font size="2">Gene ID: </font><span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3636</span></font></div></div>

2017-07-17T15:54:04Z

<font face="Georgia" size="2">Mlk3 activates mkk3 [1]. </font>

S_11 1

<font face="Georgia" size="2">Raccdc42 activates mekk4 [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MEKK4 contains a Cdc42/Rac interactive binding\r\nmotif and is activated after binding to Cdc42/Rac.\r\nThis binding is independent of the nucleotide bound\r\nto Cdc42/Rac, thus MEKK4 can be activated by the\r\nGDP-and GTP-bound protein [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_32 1

\r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Nucerk12 activates ELK1, while pp2b deactivates ELK1 and is dominant over nucerk12 [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">PP2B dephosphorylates Elk1 and deactivates it [1,3]. </font></span>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1/2 phosphorylates Elk1 at S383 and S389 [1,2]</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">. </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">However, for phosphorylating transcription factors translocation to the nucleus is necessary, which is stimulated in the case of JNK by UV-irradiation [1,2]. </span></font>

S_22 1 S_29 1

<span style="font-family: Georgia; font-size: small;">ErbB11 dimer can activate Stat3 when cSrc is active [1]. </span>

<span style="font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Src is recruited to the activated receptor and phosphorylates receptor bound STATs on the consensus C-terminal Y-residue [1,2,3]</span><span style="font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span>

<span style="font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">STAT1, 3 and 5 can be activated through ErbB1- homodimers whereas ErbB1 heterodimers do not seem to contribute to STAT activation [1,3].</span>

S_48 1 S_14 1

\r\n \r\n \r\n <div class="page" title="Page 10">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Stat5 has to routes of activation: ErbB11 dimer can activate Stat5 when cSrc is active, or ErbB24 dimer can activate Stat5 when cSrc is active [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Src is recruited to the activated receptor and phosphorylates receptor bound STATs on the consensus C-terminal Y-residue [1,2,3]</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span></font>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Neuregulin, which cannot activate ErbB1 dimers, induces activation of STAT5 through ErbB2 [1,3]. </font></span>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">STAT1, 3 and 5 can be activated through ErbB1- homodimers whereas ErbB1 heterodimers do not seem to contribute to STAT activation [1,3].</font></span>

S_48 1 S_14 1 S_56 1 S_14 1

\r\n \r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Helvetica'">PI3K phosphorylates PI(4,5)P2 at the D3 position\r\nand thus generates PIP3 (Vanhaesebroeck </span><span style="font-size: 10.000000pt; font-family: 'Helvetica'; font-style: oblique">et al</span><span style="font-size: 10.000000pt; font-family: 'Helvetica'">,\r\n1997). Since PI(4,5)P2 is one of the major\r\nphosphorylated forms of PtdIns (Tolias & Cantley,\r\n1999) we assume that it is always present in the\r\ncell and do not consider its regulation. PTEN\r\ndephosphorylates PIP3 at the D3 position\r\n(generating PI(4,5)P2), SHIP catalyzes the\r\ndephosphorylation at D5 (Scheid & Woodgett,\r\n2003) and thus the synthesis of PI(3,4)P2. We\r\nassume that PTEN and SHIP2 do not compete for\r\ndephosphorylating PIP3, otherwise we would have\r\nto know which of the two reactions is preferred. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_74 1 S_104 1 S_82 1

\r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia">Pip34p2 and pip3 are positive regulators that depend upon the presence of pdk1 and mtor_ric to activate Akt. The negative regulation of pp2a is dominant over all positive regulators. [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">At the membrane, the HM region of Akt is phosphorylated at S473, probably by the Rictor-mTOR complex [1,2]. </font></span>

<span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">PIP3 or PI(3,4)P2 recruit Akt and PDK1 to the plasma membrane. [1,2].  </font></span>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">The phosphorylated HM region of PKB stabilizes PDK1 so that PDK1 can phosphorylate T308 of PKB [1,3]. </font></span>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">PP2A dephosphorylates Akt [1,4]. </font></span>

S_49 1 S_21 1 S_40 1 S_15 1 S_40 1 S_21 1 S_7 1 S_15 1

<font face="Georgia" size="2">Limk activates actinreorg [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">LIMK1 phosphorylates cofilin, thereby leading to\r\naccumulation of actin filaments and aggregates [1,2].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_60 1

<font face="Georgia" size="2">Raccdc42 activates mlk3 [1]. </font>

S_32 1

<font face="Georgia" size="2">Mekk1, mekk4, and mlk3 each activate mkk4 [1]. </font>

<font face="Georgia" size="2">MKK4 is phosphorylated and activated by MLK3 [1,2]. </font>

<font face="Georgia" size="2">MKK4 is phosphorylated and activated by MEKK4 [1,3].</font>

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MKK4 is phosphorylated and activated by MEKK1 [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_2 1 S_11 1 S_55 1

\r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Rab5a and ccbl are both required for endocyt_degrad [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">c-Cbl and Rab5a are both involved in the endocytic trafficking of ErbB receptors. </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Rab5a controls the formation and fusion of endocytic vesicles</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> [1,2]. </span></font>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">c-Cbl and Rab5a are both involved in the endocytic trafficking of ErbB receptors. c-Cbl is necessary for degradation of the receptors [1,2]. </font></span>

S_64 1 S_90 1

<font face="Georgia" size="2">Erk12 and p90Rsk must be present for activation of p90rskerk12d [1]. </font>

<span style="font-family: Georgia; font-size: small;">Reaction that is introduced for modeling the time delay p90RSK and ERK1/2 phosphorylate and thus inhibit SOS1 with [1]. </span>

\r\n \r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Reaction that is introduced for modeling the time\r\ndelay p90RSK and ERK1/2 phosphorylate and thus\r\ninhibit SOS1 with [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_19 1 S_76 1

<font face="Georgia" size="2">Both erk12 and pdk1 are required for activation of p90rsk [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">ERK1/2 and PDK1 activate p90RSK by\r\nphosphorylation. ERK1/2 activates the C-terminal\r\ndomain, PDK1 the N-terminal domain (Ser227),\r\nwhereas the first is necessary for the latter [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small;">ERK1/2 and PDK1 activate p90RSK by phosphorylation. ERK1/2 activates the C-terminal domain, PDK1 the N-terminal domain (Ser227), whereas the first is necessary for the latter [1,2]</span><span style="font-family: Georgia; font-size: small;">. </span>

S_76 1 S_40 1

\r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-family: Georgia; font-size: small;">Akt is a negative regulator of BAD in the presence of pak1 [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2">PAK1 phosphorylates Bad on S112 and S136, independently of PI3K [1,2]. I</font><span style="font-family: Georgia; font-size: small;">n some cell types (e. g. Il-3 dependent hematopoietic cells) Bad must be phosphorylated on S136 and S112 by pak1 [1,2,3]. </span>

<font face="Georgia" size="2">Akt phosphorylates Bad on S136. In some cell types (e. g. cerebellar granule cells) this suffices for inhibiting apoptosis.[1,2,3]. </font>

S_93 1 S_8 1

<font face="Georgia" size="2">mtorr activates mtor_ric [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">As the molecular mechanism of the regulation of\r\nthe mTOR-rictor complex is unknown (Sarbassov <span style="font-style: oblique;">et\r\nal</span>, 2005a), here it is assumed that it is only activated by its\r\nreservoir and therefore always active [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_41 1

<font face="Georgia" size="2">Erk12 activates nucerk12 while mkp deactivates nucerk12 and is dominant over erk12 [1]. </font>

<font face="Georgia" size="2">Accumulation of erk12 allows it to be phosphorylated and sent to the nucleus [1,2]. </font>

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MKP dephosphorylates ERK1/2 and thus inhibits\r\nphosphorylation of transcription factors like Elk1 in\r\nthe nucleus [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_76 1 S_26 1

<font face="Georgia" size="2">Shp1 activates shp1d [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">SHP1 dephosphorylates the ErbB1 dimers\r\n(negative feedback; see e.g. reaction 8). We\r\nassume this dephosphorylation to be a late event\r\nand therefore have to include a dummy species [1].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_63 1

<font face="Georgia" size="2">Jnk activates cJun [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">JNK phosphorylates c-Jun. Unphosphorylated c-\r\nJun is ubiquitinated and degraded. Phosphorylation\r\nby JNK also increases the transriptional activity of\r\nc-Jun [1,2]. Regulation of transcription\r\nof c-Jun is not considered here, this could be\r\nincluded in a model regarding multi-level activation [1].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_39 1

<font face="Georgia" size="2">Erk12 and jnk each activate p70s6_1 [1]. </font>

<font face="Georgia" size="2">Both JNK and ERK1/2 are able to phosphorylate the auto-inhibitory sites ? however, the mechanism of activation of these sites is not well understood and additional kinases are probably involved in this step [1,2].</font>

\r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n \r\n <div class="layoutArea">\r\n <div class="column"><p><span style="font-family: Georgia; font-size: small;">Both JNK and ERK1/2 are able to phosphorylate the auto-inhibitory sites ? however, the mechanism of activation of these sites is not well understood and additional kinases are probably involved in this step [1,2].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_39 1 S_76 1

<font face="Georgia" size="2">Mekk1 and raf1 each activate mek12 [1]. </font>

<span style="font-family: Georgia; font-size: small;">MEKK1 and Raf1 both phosphorylate MEK1 and MEK2 [1,2,3]</span><span style="font-family: Georgia; font-size: small;">. </span>

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MEKK1 and Raf1 both phosphorylate MEK1 and\r\nMEK2 [1,2,3].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_55 1 S_42 1

\r\n \r\n \r\n <div class="page" title="Page 10">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font size="2" face="Georgia">Both vav2 and sos1esp8e3b1 are activators of raccdc42 [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Both Vav2 and SOS1 (complexed with Eps8 and E3b1) act as GEF for Rac and Cdc42 [1,2,3]. </font></span>

S_95 1 S_43 1

<font face="Georgia" size="2">All ErbB dimers (11,12,13,14,23, 24, 34, 44) activate shc [1]. </font>

<span style="font-family: Georgia; font-size: small;">Shc binds to all types of ErbB-receptors. On ErbB1, the binding sites are pY1148 (via PTB domain) and pY1173 (via PTB and SH2 domain) [1,2]</span><span style="font-family: Georgia; font-size: small;">. </span>

\r\n \r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Shc binds to all types of ErbB-receptors. On ErbB1,\r\nthe binding sites are pY1148 (via PTB domain) and\r\npY1173 (via PTB and SH2 domain) [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_97 1 S_46 1 S_37 1 S_48 1 S_56 1 S_94 1 S_47 1 S_70 1

<font face="Georgia" size="2">mtor_rap, p70s6_1, and pdk1 must all be present to activate p70s6_2 [1]. </font>

<font face="Georgia" size="2">mTOR phosphorylates p70s6 on T389 [1,2].</font>

<span style="font-family: Georgia; font-size: small;">p70s6 is phosphorylated at by PDK1 [1,3,4].</span>

<font face="Georgia" size="2">p70s6 must be present to be differentially phosphorylated [1,2,3,4]. </font>

S_40 1 S_79 1 S_30 1

<font face="Georgia" size="2">Ip3 activates Ca [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Binding of IP<span style="vertical-align: -1pt;">3 </span>to its receptor at the endoplasmatic reticulum leads to Ca release into the cytosol [1,2,3]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_72 1

<font face="Georgia" size="2">Bir, btc, nrg1a, nrg1b, nrg2a, nrg2b, nrg3, nrg4 are all positive regulators of erbb44, yet they all require erbb4 to be present to activate erbb44 [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-1 alpha activates the ErbB 44 dimer [1,2,3,4,5]. </font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n \r\n \r\n \r\n \r\n <p><font face="Georgia" size="2">Betacellulin activates the ErbB 44 dimer [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-1 beta activates the ErbB 44 dimer [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.984375px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Erbb4 must be active to form dimers [1,2]. </span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-2 beta activates the ErbB 44 dimer [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>

S_57 1 S_86 1 S_66 1 S_86 1 S_4 1 S_86 1 S_23 1 S_86 1 S_24 1 S_86 1 S_96 1 S_86 1 S_25 1 S_86 1

<font face="Georgia" size="2">Gab1 activates shp2 [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Phosphorylated Gab1 recruits and activates SHP2 [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_69 1

<font face="Georgia" size="2">Mkk4 and Mkk7 are both required to activate jnk [1]. </font>

<span style="font-family: Georgia; font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">MKK4 and MKK7 cooperate to activate JNK. MKK4 phosphorylates Y185, MKK7 phosphorylates T183 [1,2]. </span>

\r\n \r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MKK4 and MKK7 cooperate to activate JNK. MKK4\r\nphosphorylates Y185, MKK7 phosphorylates T183 [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_45 1 S_13 1

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><font size="2">Both cSrc and pak1 serve as </font><font size="2">activators</font><font size="2"> of raf1 in the presence of ras. Aktd deactivates raf1 and is dominant over all positive regulators [1]. </font></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Src phosphorylates Raf1 on Y341, whereas it seems as if phosphorylation of either S338 or Y341 is sufficient for Raf1 activation [1,2]. </font></span>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font size="2" face="Georgia">Pak1 phosphorylates S338, whereas it seems as if phosphorylation of either S338 or Y341 is sufficient for Raf1 activation [1,2]. </font></span>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Ras recruits Raf1 to the plasma membrane where it is phosphorylated at various sites [1,2]. </font></span>

S_84 1 S_14 1 S_91 1 S_93 1 S_84 1 S_91 1

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Both PIP3 and PI(3,4)P2 mediate the nucleotide exchange activity of Vav2 towards Rac and Cdc42 [1,2]</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">. In Oda </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">(2005), PI3K instead of PIP3/PI(3,4)P2 is depicted to influence the Rac- GEF activity of Vav2 [1,3]. </span>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">The SH2 domain of Vav2 binds to pY992 or pY1148 on ErbB1. The receptor phosphorylates Vav2 on Y142, Y159 and Y172 and activates Vav2 [1,2]. </font></span>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Both PIP3 and PI(3,4)P2 mediate the nucleotide exchange activity of Vav2 towards Rac and Cdc42 [1,2]</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">. In Oda </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">(2005), PI3K instead of PIP3/PI(3,4)P2 is depicted to influence the Rac- GEF activity of Vav2 [1,3]. </span></font>

S_48 1 S_7 1 S_49 1 S_48 1

<font face="Georgia" size="2">Active plcg produces DAG [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PLC? hydrolyzes PI(4,5)P2 to generate DAG and\r\nIP3 [1,2]. At present, we do not\r\nconsider PLC? (as depicted in Oda <span style="font-style: oblique;">et al </span>(2005)),\r\nsince this is part of the G-coupled receptor\r\nsignaling [1,2,3].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_68 1

<font face="Georgia" size="2">Mekk1 activates mkk7 [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MEKK1 phosphorylates and thus activates MKK7 [1,2] (Lu <span style="font-style: oblique;">et al</span>, 1997). </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_55 1

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Bir, btc, egf, epr, hbegf, and tgfa are all activators of erbb12, but each require the presence of erbb1 and erbb2 to activate. Shp1d is a negative regulator of erbb12 and is dominant over all positive regulators [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">As we have not included the detailed endocytosis mechanism in the model so far, we do not distinguish between EGF- bound and TGF</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">? </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">?bound receptors at the moment. Internalized receptors are still capable of activating signaling pathways [3], so we decided to exclude this reaction in the logical analysis [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Betacellulin activates </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">12</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">EGF activates </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">12</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">HB-EGF activates </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">12</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Epiregulin activates </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">12</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Biregulin activates the ErbB </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">12</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2].</span>

S_71 1 S_89 1 S_87 1 S_27 1 S_4 1 S_89 1 S_87 1 S_27 1 S_73 1 S_89 1 S_87 1 S_27 1 S_33 1 S_89 1 S_87 1 S_27 1 S_102 1 S_89 1 S_87 1 S_27 1 S_96 1 S_89 1 S_87 1 S_27 1

<font face="Georgia">Egf, epr, nrg1a, nrg1b, nrg2a, nrg2b, nrg4 and tgfa are all positive regulators of erbb14, however they all require both erbb1 and erbb2 to activate erbb14. Shp1d and erbb2 are negative regulators of erbb14 and are dominant over all positive regulators [1]. </font>

<font face="Georgia"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">TGF alpha</span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;"> </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">activates the ErbB 14 dimer [1,2,3]. </span></font>

<span style="font-size: small; font-family: Georgia;">ErbB2 is the preferred heterodimerization partner of the other ErbBs and therefore the other heterodimers 13, 14 and 34 are only formed in absence of ErbB2</span><span style="font-size: small; color: rgb(79, 79, 79); font-family: Georgia; line-height: 17.984375px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> [1,2]. </span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">In absence of ErbB2, also 13 and 14 can be activated [1,4,5].</span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-1 alpha activates ErbB 14 dimer [1,3,4,5,7]. </font></p>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">NRG-1 beta activates the ErbB </span><span style="color: rgb(79, 79, 79); font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">14 </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">dimer</span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);"> [1,2,4,7]. </span></font>

<font face="Georgia"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">SHP1 binds to ErbB1 at phosphorylated Y1173. </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">SHP1 dephosphorylates the ErbB1 dimers [1,8]. </span></font>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">In absence of ErbB2, also 13 and 14 can be activated by egf [1,4,5].</span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG-2 beta</span><span style="font-size: 10pt;"> </span><span style="font-size: 10pt;">activates the ErbB 14 dimer [1,2,7]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">In Shelly </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">(1998) additionally activation of 13, 14 (high) and 34, 44 (low) is mentioned. </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Here included is activation of 13 and 14 in the model, because these heterodimers are not part of the analysis in Jones </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">(1999) and thus the results in Jones </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">(1999) and Shelly </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">(1998) are not contradictory [1,2,6]. </span>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">NRG-2 alpha activates the ErbB 14 dimer 24 [1,2,7]. </span>

S_66 1 S_86 1 S_87 1 S_27 1 S_89 1 S_24 1 S_86 1 S_87 1 S_27 1 S_89 1 S_73 1 S_86 1 S_87 1 S_27 1 S_89 1 S_71 1 S_86 1 S_87 1 S_27 1 S_89 1 S_33 1 S_86 1 S_87 1 S_27 1 S_89 1 S_57 1 S_86 1 S_87 1 S_27 1 S_89 1 S_85 1 S_86 1 S_87 1 S_27 1 S_89 1 S_23 1 S_86 1 S_87 1 S_27 1 S_89 1

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Ar, bir, btc, egf, epr, hbegf, and tgfa are all positive regulators of erbb11 but all require the presence of erbb1 to activate erbb11. Shp1d and endocyto_degrad are negative regulators of erbb11 and are dominant over all positive regulators [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">As we have not included the detailed endocytosis mechanism in the model so far, we do not distinguish between EGF- bound and TGF</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">? </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">?bound receptors at the moment. Internalized receptors are still capable of activating signaling pathways [11], so we decided to exclude this reaction in the logical analysis [1].</span></font>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Betacellulin activates </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">11</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span></font>

<font face="Georgia" size="2">Ligand that specifically binds ErbB1 and upregulates it [1,2].</font>

<font face="Georgia" size="2">Shp1d is a negative regulator of erbb11 [1,2]. </font>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">EGF activates </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">11</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span></font>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">HB-EGF activates </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">11</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span></font>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Epiregulin activates </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">the ErbB </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">11</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2]. </span></font>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ErbB1-homodimers activated through EGF are endocytosed and subsequently degraded ? in contrast to TGF</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">? </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">-bound receptors [10]</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> and the other ErbB-dimers [1,11].</span></font>

<font face="Georgia" size="2">Erbb1 must be active to form homodimers of itself [1,2]. </font>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Biregulin activates the ErbB </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">11</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> dimer [1,2].  </span></font>

S_73 1 S_17 1 S_87 1 S_27 1 S_88 1 S_87 1 S_17 1 S_27 1 S_102 1 S_87 1 S_17 1 S_27 1 S_33 1 S_17 1 S_87 1 S_27 1 S_87 1 S_17 1 S_27 1 S_17 1 S_4 1 S_17 1 S_87 1 S_27 1 S_96 1 S_87 1 S_17 1 S_27 1 S_71 1 S_87 1 S_17 1 S_27 1 S_73 1 S_96 1 S_88 1 S_27 1 S_71 1 S_102 1 S_33 1 S_17 1 S_87 1 S_4 1

<font face="Georgia" size="2">Pi3k and ship2d are required for activation of pi34p2. Ptend is a negative regulator of pi34p2 and is dominant over both activators [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PTEN\r\ndephosphorylates PIP3 at the D3 position\r\n(generating PI(4,5)P2), SHIP catalyzes the\r\ndephosphorylation at D5 [1,4] and thus the synthesis of PI(3,4)P2 [1,4]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small;">SHIP catalyzes the dephosphorylation at D5 and thus the synthesis of PI(3,4)P2 [1,4]. </span>

\r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">PI3K phosphorylates PI(4,5)P2 at the D3 position\r\nand thus generates PIP3 [2].</span><span style="font-size: 10pt;"> Since PI(4,5)P2 is one of the major\r\nphosphorylated forms of PtdIns [3] here it is assumed that it is always present in the\r\ncell and do not consider its regulation [1].</span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_104 1 S_74 1 S_82 1

<font face="Georgia" size="2">Mk2 activates HSP27 [1]. </font>

S_52 1

<font face="Georgia" size="2">Gab1 activates rasgap, while shp2 deactivates rasgap and is dominant over gab1 [1]. </font>

<font face="Georgia" size="2">Gab1-bound SHP2 dephosphorylates these sites [1,2]. </font>

S_69 1 S_38 1

<font face="Georgia" size="2">p38 is an activator of mk2 [1]. </font>

S_58 1

<span style="font-family: Georgia; font-size: small;">ErbB11 dimer can activate Stat1 when cSrc is active [1]. </span>

S_48 1 S_14 1

<font face="Georgia" size="2">tsc1_tsc2 deactivates rheb [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Akt phosphorylates Tsc2 and thus inhibits the\r\nRheb-GAP activity of the Tsc1/Tsc2 complex. GTP-\r\nbound Rheb activates the mTOR-raptor complex\r\n[1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_101 1

<font face="Georgia" size="2">Raccdc42 activates mekk1 [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MEKK1 binds GTP-bound Cdc42/Rac and is thus\r\nactivated [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_32 1

<font face="Georgia" size="2">Bir, btc, egf, epr, hbegf, nrg1a, nrg1b, nrg2a, nrg2b, nrg3, nrg4, tgfa are all activators or erbb24, however they all require both erbb2 and erbb4 to be active for erbb24 to be activated [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">TGF</span><span style="font-size: 10pt;">?</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG3</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG-2</span><span style="font-size: 10pt;">?</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">HB-EGF</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG-1</span><span style="font-size: 10pt;">?</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2, 3, 4, 5, 6]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG-1</span><span style="font-size: 10pt;">?</span><span style="font-size: small;"> activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG4 </span><span style="font-size: small;">activates the ErbB 24 dimer [1,6]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">NRG-2</span><span style="font-size: 10pt;">? </span><span style="font-size: small;">activates the ErbB 24 dimer [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

S_73 1 S_89 1 S_86 1 S_4 1 S_89 1 S_86 1 S_24 1 S_89 1 S_86 1 S_23 1 S_89 1 S_86 1 S_71 1 S_89 1 S_86 1 S_85 1 S_89 1 S_86 1 S_57 1 S_89 1 S_86 1 S_33 1 S_89 1 S_86 1 S_102 1 S_89 1 S_86 1 S_25 1 S_89 1 S_86 1 S_66 1 S_89 1 S_86 1 S_96 1 S_89 1 S_86 1

<font face="Georgia" size="2">Mkk3, mkk4, and mkk6 each activate p38 [1]. </font>

<span style="font-family: Georgia; font-size: small;">MKK3, MKK4 and MKK6 phosphorylate p38 on threonine and tyrosine residues [1,2].</span>

\r\n \r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font size="2" face="Georgia">MKK3, MKK4 and MKK6 phosphorylate p38 on\r\nthreonine and tyrosine residues [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small;">MKK3, MKK4 and MKK6 phosphorylate p38 on threonine and tyrosine residues [1,2].</span>

S_1 1 S_62 1 S_13 1

<font face="Georgia" size="2">P90rsk and mk2 are activators of CREB [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">p90RSK phosphorylates CREB on S133 and thus\r\nactivates it [1,3]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_19 1 S_52 1

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PAK1 activates LIMK1 [1]. </span>

\r\n \r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PAK1 (activated through Rac/Cdc42)\r\nphosphorylates LIMK1 at T508 [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_93 1

<font face="Georgia" size="2">Mlk3 activates mkk6 [1]. </font>

S_11 1

<font face="Georgia" size="2">Shp1 is activated by erbb11 [1]. </font>

<font face="Georgia" size="2">shp1 is positively regulated by erbb11.  shp1 binds to erbb1 at phosphorylated Y1173 [1,2].</font>

S_48 1

<font face="Georgia" size="2">ErbB11 activates cCbl [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">c-Cbl binds ErbB1 at pY1045, leading to\r\ndegradation of the receptor in the lysosome [1,2].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_48 1

<font face="Georgia" size="2">ErbB11 and esp8r are required for activation of rntre [1]. </font>

<span style="font-family: Georgia; font-size: small;">RN-tre binds to the adaptor protein Eps8 and is phosphorylated in response to EGF stimulation [1,2]. </span>

\r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">RN-tre binds to the adaptor protein Eps8 and is\r\nphosphorylated in response to EGF stimulation [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_10 1 S_48 1

<font face="Georgia" size="2">cfos and cjun must be active to activate AP1 [1]. </font>

<span style="font-family: Georgia; font-size: small;">Ap1 is a collective term referring to dimeric transcription factors composed of jun, fos or ATF subunits, here: heterodimer composed of c-Jun and c-Fos [1]. </span><span style="font-family: Georgia; font-size: small;">c-Jun and c-Fos heterodimerize and form the transcription factor AP-1  [1,2].</span>

<font face="Georgia" size="2">Ap1 is a collective term referring to dimeric transcription factors composed of jun, fos or ATF subunits, here: heterodimer composed of c-Jun and c-Fos [1]. c-Jun and c-Fos heterodimerize and form the\r\ntranscription factor AP-1  [1,2].</font>

S_100 1 S_28 1

<font face="Georgia" size="2">ErbB11 activates plcg [1]. </font>

S_48 1

<font face="Georgia" size="2">ErbB11, grb2 and pip3 are all positive regulators of gab1 [1]. </font>

<span style="font-family: Georgia; font-size: small;">Gab1 can bind directly to ErbB1 receptors or via Grb2 and is phosphorylated on Y-residues by the receptor kinase [1,2].</span>

\r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PIP3 recruits Gab1 molecules to the EGFR and\r\nthus enhances the activity of Gab1 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Gab1 can bind directly to ErbB1 receptors or via\r\nGrb2 and is phosphorylated on Y-residues by the\r\nreceptor kinase [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_7 1 S_48 1 S_83 1

<font face="Georgia" size="2">Bir, btc, epr, nrg1a, nrg1b, nrg2b are all positive regulators of erbb23, however, all positive regulators require the presence of both erbb2 and erbb3 to activate erbb23 [1]. </font>

<span style="line-height: 17.984375px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Erbb2 must be active to form dimers [1,2]. </font></span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-1 alpha activates the following ErbB dimers: 23,\r\n24, 44 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia"><span style="font-size: 10pt;">In\r\nWang </span><span style="font-size: 10pt; font-style: oblique;">et al </span><span style="font-size: 10pt;">(1998) and Graus-Porta </span><span style="font-size: 10pt; font-style: oblique;">et al </span><span style="font-size: 10pt;">(1997)\r\nactivation of 23 is reported, what is contradictory to\r\nJones </span><span style="font-size: 10pt; font-style: oblique;">et al </span><span style="font-size: 10pt;">(1999) and not mentioned in Alroy &\r\nYarden (1997). However, it is in accordance with\r\nthe findings of Beerli & Hynes (1996) that BTC\r\nactivates ErbB3 when all ErbB receptors are\r\npresent and is thus included in the model [1,2,3,4,8]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">NRG-1 beta activates the following ErbB dimers: 23,\r\n24, 44 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small; line-height: 17.984375px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Erbb3 must be active to form dimers [1,2]. </span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">In accordance with Jones <span style="font-style: oblique;">et al </span>(1999), NRG-2?\r\nactivates the following ErbB dimers: 23, 24, 44 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Epiregulin activates the following ErbB-dimers: 11,\r\n12, 23, 24 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Biregulin activates the following ErbB dimers: 11,\r\n12, 23, 24, 44 [1,2].</font></p>\r\n </div>\r\n </div>\r\n \r\n \r\n \r\n \r\n </div>\r\n </div>

S_96 1 S_89 1 S_78 1 S_57 1 S_89 1 S_78 1 S_4 1 S_89 1 S_78 1 S_33 1 S_89 1 S_78 1 S_23 1 S_89 1 S_78 1 S_24 1 S_89 1 S_78 1

<font face="Georgia" size="2">Plcg activates Ip3 [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">PLC? hydrolyzes PI(4,5)P2 to generate DAG and\r\nIP3 [1,2].</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_68 1

<font face="Georgia">Phosphorylated Gab1 recruits and activates PI3K [1,5].</font>

<span style="font-family: Georgia; font-size: small;">In Oda </span><span style="font-family: Georgia; font-size: small; font-style: oblique;">et al </span><span style="font-family: Georgia; font-size: small;">(2005) (second figure) activation of PI3K through all ErbB3- and ErbB4 dimers is considered. Indeed there are binding sites for the p85 subunit of PI3K on both ErbB3 and ErbB4 ? however, there are 6 sites on ErbB3 and only one site on ErbB4, suggesting that ErbB3 is the main activator of PI3K [1,2].</span><span style="font-family: Georgia; font-size: small;"> Furthermore, there are naturally occurring ErbB4 isoforms that do not contain the binding site for PI3K [3]</span><span style="font-family: Georgia; font-size: small;"> ? thus PI3K interaction is shown only with ErbB3 dimers [1].</span>

\r\n \r\n \r\n <div class="page" title="Page 10">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: small; font-family: Georgia;">In Oda </span><span style="font-size: small; font-family: Georgia; font-style: oblique;">et al </span><span style="font-size: small; font-family: Georgia;">(2005) (second figure) activation of PI3K through all ErbB3- and ErbB4 dimers is considered. Indeed there are binding sites for the p85 subunit of PI3K on both ErbB3 and ErbB4 ? however, there are 6 sites on ErbB3 and only one site on ErbB4, suggesting that ErbB3 is the main activator of PI3K [1,2].</span><span style="font-size: small; font-family: Georgia;"> Furthermore, there are naturally occurring ErbB4 isoforms that do not contain the binding site for PI3K [3]</span><span style="font-size: small; font-family: Georgia;"> ? thus PI3K interaction is shown only with ErbB3 dimers [1].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia">GTP-bound Ras activates PI3K [1,4].</font>

<span style="font-size: small; font-family: Georgia;">In Oda </span><span style="font-size: small; font-family: Georgia; font-style: oblique;">et al </span><span style="font-size: small; font-family: Georgia;">(2005) (second figure) activation of PI3K through all ErbB3- and ErbB4 dimers is considered. Indeed there are binding sites for the p85 subunit of PI3K on both ErbB3 and ErbB4 ? however, there are 6 sites on ErbB3 and only one site on ErbB4, suggesting that ErbB3 is the main activator of PI3K [1,2].</span><span style="font-size: small; font-family: Georgia;"> Furthermore, there are naturally occurring ErbB4 isoforms that do not contain the binding site for PI3K [3]</span><span style="font-size: small; font-family: Georgia;"> ? thus PI3K interaction is shown only with ErbB3 dimers [1].</span>

<font face="Georgia"><span style="font-size: 10pt;">Phosphorylated Gab1 recruits and activates PI3K [1,5].</span><span style="font-size: 10pt;"> Gab1-bound SHP2 dephosphorylates the PI3K-binding site of Gab1. However,  the negative influence of SHP2 on PI3K is not included in the model so far, because it seems as if SHP2 indeed downregulates PI3K, but does not completely inhibit PI3K activation through Gab1 [1,5,6].</span></font>

S_84 1 S_12 1 S_12 1 S_69 1 S_70 1 S_12 1 S_97 1 S_12 1 S_94 1 S_12 1

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">A pseudosubstrate is bound to the substrate-binding cavity, which is released after binding of the second messengers Ca</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); vertical-align: 5pt;">2+ </span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">and DAG [1,2]. </span></font>

<span style="font-family: Georgia; font-size: small; color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">A pseudosubstrate is bound to the substrate-binding cavity, which is released after binding of the second messengers Ca</span><span style="font-family: Georgia; font-size: small; color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); vertical-align: 5pt;">2+ </span><span style="font-family: Georgia; font-size: small; color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">and DAG [1,2]. </span>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">PKC is phosphorylated at its activation loop by PDK1. This leads to autophosphorylation and the release of PKC into the cytoplasma [1,2]. </font></span>

S_40 1 S_36 1 S_44 1

<font face="Georgia" size="2">MEK12 activates erk1/2 [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">MEK1 and MEK2 phosphorylate ERK1/2 [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_31 1

<font face="Georgia" size="2">Both akt and p90rsk are negative regulators of gsk3 [1]. </font>

<span style="font-family: Georgia; font-size: small;">Akt also phosphorylates Gsk3 on S9 [1,2].</span>

\r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">p90Rsk phosphorylates Gsk3 on S9 and thus\r\ndeactivates it in response to EGF [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_19 1 S_8 1

<font face="Georgia" size="2">Rheb and mTOR activate the mtor-raptor complex [1]. </font>

<font face="Georgia" size="2">Mtorr must be present to activate the mTOR-raptor complex [1,2]. </font>

S_54 1 S_41 1

\r\n \r\n \r\n <div class="page" title="Page 14">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Nucerk12 is a positive regulator of cMYC. Gsk3 is a negative regulator and is dominant over nucerk12 [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">ERK1/2 phosphorylates c-Myc at S62 and thus stabilizes it [1,2,3].</font></span>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">The phosphorylation of S62 is necessary for the phosphorylation of T58 by GSK3 beta, which leads to ubiquitin dependent degradation of c-Myc [1,2]. </font></span>

S_22 1 S_77 1

\r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Sos1r activates sos1 when grb2 is active. p90rskerk12d is a negative regulator of sos1 [1]. </font></p><div class="page" title="Page 9" style="font-size: 10pt; font-family: Arial, Verdana;"><div class="section"><div class="layoutArea"><div class="column">\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">SOS1 is bound to Grb2. Binding of Grb2 to EGFR, either directly or indirectly through Shc, leads to activation of SOS1 [1,2]. </font></span>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Serine/threonine phosphorylation of SOS1 by p90RSK or ERK1/2 causes dissociation of Grb2-SOS1 from Shc or from the phosphorylated receptor [1,2].</font></span>

S_16 1 S_83 1 S_18 1

<span style="font-family: Georgia; font-size: small;">Pten activates ptend [1]. </span>

<font face="Georgia" size="2">Pten activates ptend [1]. </font>

S_103 1

<font face="Georgia" size="2">Shc and ErbB dimers (11,12,13,14,23,24,34) are all positive regulators of grb2 [1]. </font>

<font face="Georgia">Grb2 can bind to ErbB-dimers via Shc [1,2] or directly via its SH2 domain. As there are binding sites for Grb2 on all ErbB receptors [3], we assume that Grb2 can directly interact with all possible ErbB-dimers [1].</font><span style="font-size: 10pt; font-family: Helvetica;"> </span>

<font face="Georgia">Grb2 can bind to ErbB-dimers via Shc or directly via its SH2 domain [1,2]. </font>

\r\n \r\n \r\n <div class="page" title="Page 8">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Grb2 can bind to ErbB-dimers via Shc [1,2] or directly via its SH2 domain. As there\r\nare binding sites for Grb2 on all ErbB receptors [3], we assume that Grb2 can\r\ndirectly interact with all possible ErbB-dimers [1].</font><span style="font-size: 10pt; font-family: Helvetica;"> </span></p>\r\n </div>\r\n </div>\r\n \r\n \r\n \r\n \r\n \r\n </div>\r\n </div>

S_94 1 S_97 1 S_56 1 S_37 1 S_34 1 S_48 1 S_47 1 S_70 1 S_46 1

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Interaction with SOS1 increases the rate of GDP/GTP exchange of Ras (and thus acts as activating GEF) [1,2]</span><span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span></font>

<span style="color: rgb(79, 79, 79); line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">The GTPase activating protein RasGAP leads to hydrolysis of Ras-bound GTP to GDP [1,3]. </font></span>

S_81 1 S_51 1

\r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Rin1 activates rab5a. Rntre deactivates rab5a and is dominant over rin1 [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Rin1 mediates GDP/GTP exchange for Rab5a thus activating it [1,2]</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">. </span></font>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The GTPase activating protein RN-tre acts on Rab5a and inhibits internalization of the EGFR [1,3]</span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span></font>

S_92 1 S_65 1

\r\n \r\n \r\n <div class="page" title="Page 13">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Reaction that is only included for modeling the time\r\ndelay Akt deactivates Raf1 [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small;">Reaction that is only included for modeling the time delay Akt deactivates Raf1 [1]. </span>

S_8 1

<font face="Georgia" size="2">Ras activates rin1 [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Rab5-GEF activity of Rin1 is potentiated by\r\nactivated Ras [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_84 1

<font face="Georgia" size="2">Grb2 and raccdc42 can activate pak1, or alternately nck and raccdc42 can activate pak1 [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 15">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Pak1 is recruited to the plasma membrane via Grb2 [2] or Nck [3] where it is\r\nactivated through GTP-bound Rac/Cdc42 [1,4]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small;">Pak1 is recruited to the plasma membrane via Grb2 [2]</span><span style="font-family: Georgia; font-size: small;"> or Nck [3]</span><span style="font-family: Georgia; font-size: small;"> where it is activated through GTP-bound Rac/Cdc42 [1,4]. </span>

S_83 1 S_32 1 S_98 1 S_32 1

\r\n \r\n \r\n <div class="page" title="Page 6">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Ar, btc, egf, epr, nrg1a, nrg1b, nrg2a, tgfa are all activators of erbb13, however they all require both erbb1 and erbb3 to be active to activate erbb13. Shp1d is a negative regulator of erbb13 and is dominant over all positive regulators [1].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NRG-1 alpha activates the Erbb 13 dimer [1,4,5,6]. </font></span>

<span style="font-family: Georgia; font-size: small;">ErbB2 is the preferred heterodimerization partner of the other ErbBs and therefore the other heterodimers 13, 14 and 34 are only formed in absence of ErbB2</span><span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: small; line-height: 17.984375px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> [1,2]. </span>

<font face="Georgia"><font size="2"><span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Betacellulin activates the ErbB-dimer</span><span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> 13 [1,4]. </span></font><span style="font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">However, it is in accordance with the findings of Beerli & Hynes (1996) that BTC activates ErbB3 when all ErbB receptors are present and is thus included in the model [1,3]. </span></font>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Amphiregulin binds ErbB1-homodimers and ErbB13\r\n? however, the affinity of AR towards ErbB1 is\r\nsignificantly lower than the affinity of EGF [1,3]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">NRG-1 beta activates the Erbb 13 dimer [1,2,4,8]. </font></span>

\r\n \r\n \r\n <div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n \r\n \r\n \r\n \r\n <p><font face="Georgia" size="2">SHP1 binds to ErbB1 at phosphorylated Y1173. SHP1 dephosphorylates the ErbB1 dimers [1,9]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">In absence of ErbB2, also 13 and 14 can be activated [1,5,6]. </font></span>

\r\n \r\n \r\n \r\n <font face="Georgia" size="2">Epiregulin activates the erbb 13 dimer<span style="line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> 13 [1,2,7].</span></font>

<span style="font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">NRG-2 alpha activates the ErbB dimer 13 [1,2,8]. </font></span>

S_24 1 S_78 1 S_87 1 S_89 1 S_27 1 S_71 1 S_78 1 S_87 1 S_89 1 S_27 1 S_33 1 S_78 1 S_87 1 S_89 1 S_27 1 S_73 1 S_78 1 S_87 1 S_89 1 S_27 1 S_96 1 S_78 1 S_87 1 S_89 1 S_27 1 S_88 1 S_78 1 S_87 1 S_27 1 S_23 1 S_78 1 S_87 1 S_89 1 S_27 1 S_85 1 S_78 1 S_87 1 S_89 1 S_27 1

\r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">All positive regulators (esp8r, pi3kr, pip3, and sos1r) are required for activation of sos1esp8e3b1 complex [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">SOS1, Eps8 and E3b1/Abi1 form a complex which is necessary for the Rac-GEF activity of SOS1 [1,3]. </font></span>

<font face="Georgia" size="2"><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">SOS1, Eps8 and E3b1/Abi1 form a complex which is necessary for the Rac-GEF activity of SOS1. </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Note that this reaction differs from the description in the map of Oda </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">(2005): There, only Ras-activated PI3K influences the GEF- activaty, whereas we assume the inactivated form to mediate this effect. Additionally, the influence of PIP3 is not considered in the map of Oda </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="line-height: 17.99715805053711px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">(2005) [1,2,3]. </span></font>

S_16 1 S_7 1 S_10 1 S_12 1

<font face="Georgia" size="2">Nrg1a, nrg1b, nrg2a, and nrg2b are all positive regulators of erbb34. All positive regulators require the presence of both erbb3 and erbb4. Erbb2 is a negative regulator of erbb34 and is dominant over all positive regulators [1]. </font>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p style="font-size: 10pt; font-family: Arial, Verdana;">\r\n \r\n \r\n \r\n </p><div class="page" title="Page 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">ErbB2 is the preferred heterodimerization partner of the other\r\nErbBs and therefore the other heterodimers 13, 14 and 34 are only formed in absence of ErbB2 [1].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: Georgia; font-size: small; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">NRG-1 alpha activates the ErbB 34 dimer [1,3,4,5,6]. </span>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="color: rgb(79, 79, 79); font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">NRG-1 beta activates the ErbB 3</span><span style="color: rgb(79, 79, 79); font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">4 </span><span style="color: rgb(79, 79, 79); font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">dimer</span><span style="color: rgb(79, 79, 79); font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);"> [1,2,4,6]. </span></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">NRG-2 beta</span><span style="font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;"> </span><span style="font-family: Georgia; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 10pt;">activates the ErbB 14 dimer [1,2,6]. </span></p>\r\n </div>\r\n </div>\r\n </div>

\r\n \r\n \r\n <div class="page" title="Page 7">\r\n <div class="layoutArea">\r\n <div class="column"><p><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255); line-height: 18px; orphans: 3; widows: 3;">NRG-2</span>?<span style="background-color: rgb(255, 255, 255); line-height: 18px; orphans: 3; widows: 3;"> activates the ErbB 14 dimer 34 [1,2,6]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>

S_85 1 S_78 1 S_86 1 S_89 1 S_57 1 S_78 1 S_86 1 S_89 1 S_24 1 S_78 1 S_86 1 S_89 1 S_23 1 S_78 1 S_86 1 S_89 1

<font face="Georgia" size="2">ErbB11, erbB14, and ErbB44 each activate nck [1]. </font>

<span style="font-size: 10pt; font-family: Helvetica;">Nck binds to EGFR.</span><span style="font-size: 10pt; font-family: Helvetica;"> A Nck binding site on ErbB4 is reported [1,2,3]. </span>

<span style="font-size: 10pt; font-family: Helvetica;">Nck binds to EGFR.</span><span style="font-size: 10pt; font-family: Helvetica;"> A Nck binding site on ErbB4 is reported [1,2,3].  </span>

\r\n \r\n \r\n <div class="page" title="Page 9">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 10.000000pt; font-family: 'Helvetica'">Nck binds to EGFR.</span><span style="font-size: 10.000000pt; font-family: 'Helvetica'"> A Nck binding site on ErbB4 is reported [1,2,3].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_37 1 S_48 1 S_47 1

<font face="Georgia" size="2">BAD is a positive regulator of pro_apoptotic [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 12">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Phosphorylation of Bad avoids its proapoptotic\r\nfunction. Bad promotes apoptosis [1,2].  </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_20 1

<font face="Georgia" size="2">P90RSK and ERK 1/2 upregulate cFos when both are present. Jnk is a positive regulator of cFos. Pp2a is a negative regulator and is dominant over all positive regulator [1]. </font>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">JNK phosphorylates c-Fos and thus prevents it from degradation [1,2]. </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Note that this reaction is independent of ERK  [1,2]. </span></font>

<span style="font-family: Georgia; font-size: small; color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1/2 and p90RSK coordinately phosphorylate c- Fos - unphosphorylated c-Fos is rapidly degraded [1,4]</span><span style="font-family: Georgia; font-size: small; color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1/2 and p90RSK coordinately phosphorylate c- Fos - unphosphorylated c-Fos is rapidly degraded [1,4]</span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">.</span></font>

<font face="Georgia" size="2"><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PP2A dephosphorylates c-Fos, whereas PP2B does not [2]</span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"> inconsistent with Oda </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-style: oblique;">et al </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">(2005) [1,2,3]. </span></font>

S_39 1 S_15 1 S_19 1 S_76 1 S_15 1

akt inhibits tsc1_tsc2.

\r\n \r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">Akt phosphorylates Tsc2 and thus inhibits the\r\nRheb-GAP activity of the Tsc1/Tsc2 complex [1,2]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_8 1

<font face="Georgia" size="2">Ship2 activates ship2d [1]. </font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 11">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">"PTEN and SHIP2 both down regulate PIP3\r\nsynthesis. As we could not find any information how\r\nPTEN and SHIP2 are regulated, we included them\r\nas inputs to the model. We suppose that down\r\nregulation of PI3K signaling is time delayed and\r\ntherefore set the activation of PTEN and SHIP2 to\r\ntime scale 2" [1]. </font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_61 1