Background Despite promising progress in targeted breast cancer therapy, drug resistance remains challenging. The monoclonal antibody drugs trastuzumab and pertuzumab as well as the small molecule inhibitor erlotinib were designed to prevent ErbB-2 and ErbB-1 receptor induced deregulated protein signalling, contributing to tumour progression. The oncogenic potential of ErbB receptors unfolds in case of overexpression or mutations. Dimerisation with other receptors allows to bypass pathway blockades. Our intention is to reconstruct the ErbB network to reveal resistance mechanisms. We used longitudinal proteomic data of ErbB receptors and downstream targets in the ErbB-2 amplified breast cancer cell lines BT474, SKBR3 and HCC1954 treated with erlotinib, trastuzumab or pertuzumab, alone or combined, up to 60 minutes and 30 hours, respectively. In a Boolean modelling approach, signalling networks were reconstructed based on these data in a cell line and time course specific manner, including prior literature knowledge. Finally, we simulated network response to inhibitor combinations to detect signalling nodes reflecting growth inhibition. Results The networks pointed to cell line specific activation patterns of the MAPK and PI3K pathway. In BT474, the PI3K signal route was favoured, while in SKBR3, novel edges highlighted MAPK signalling. In HCC1954, the inferred edges stimulated both pathways. For example, we uncovered feedback loops amplifying PI3K signalling, in line with the known trastuzumab resistance of this cell line. In the perturbation simulations on the short-term networks, we analysed ERK1/2, AKT and p70S6K. The results indicated a pathway specific drug response, driven by the type of growth factor stimulus. HCC1954 revealed an edgetic type of PIK3CA-mutation, contributing to trastuzumab inefficacy. Drug impact on the AKT and ERK1/2 signalling axes is mirrored by effects on RB and RPS6, relating to phenotypic events like cell growth or proliferation. Therefore, we additionally analysed RB and RPS6 in the long-term networks. Conclusions We derived protein interaction models for three breast cancer cell lines. Changes compared to the common reference network hint towards individual characteristics and potential drug resistance mechanisms. Simulation of perturbations were consistent with the experimental data, confirming our combined reverse and forward engineering approach as valuable for drug discovery and personalised medicine. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2015-02-17T13:38:17Z 2016-01-22T07:08:46Z

Drug pertuzumab

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Stimulatory node for the models from the paper [1].

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Drug erlotinib

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Drug trastuzumab

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<div>\r\n \r\n \r\n \r\n <div class="page" title="Page 3">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">BAX represents BAX (or BAK) activation by insertion into\r\nthe outer membrane of mitochondria and oligomerization [1].&nbsp;</font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">BCL2-associated X protein [</span><em style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">&nbsp;(human)]</span></font></div><font face="Georgia" size="2" style="font-size: 10pt; font-family: Arial, Verdana;">Uniprot ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q07812" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q07812</a></font><div style="font-size: 10pt; font-family: Arial, Verdana;"><font face="Georgia" size="2">Gene Name:&nbsp;<a href="http://www.ncbi.nlm.nih.gov/gene/581" ref="ordinalpos=1&amp;ncbi_uid=581&amp;link_uid=581" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">BAX</span></a></font></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><font face="Georgia" size="2">NCBI Gene ID: 581</font></div>

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<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"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID:&nbsp;</span>P00533</font></div><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID:&nbsp;</span><span style="line-height: 18.8888893127441px;">1956</span></font></div>

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<div>G2/mitotic-specific cyclin-B1</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P14635" 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);">P14635</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene Name:&nbsp;<a href="http://www.ncbi.nlm.nih.gov/gene/891" ref="ordinalpos=1&amp;ncbi_uid=891&amp;link_uid=891" style="color: rgb(100, 42, 143); font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17.9998016357422px; white-space: nowrap; background-color: rgb(213, 222, 227);">CCNB1</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene ID:&nbsp;<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);">891</span></div>

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<table style="width: 723pt; border-collapse: collapse;" border="0" cellSpacing="0" cellPadding="0" width="964">\r\n <colgroup><col style="width: 723pt; mso-width-source: userset; mso-width-alt: 30848;" width="964">\r\n <tbody><tr style="height: 15pt;" height="20">\r\n\r\n <td style="border: 0px black; width: 723pt; height: 15pt; background-color: transparent;" class="xl65" height="20" width="964"><font size="3" face="Calibri">nuclear\r\n factor of kappa light polypeptide gene enhancer in B-cells 1 &amp; RELA</font></td>\r\n\r\n </tr>\r\n</tbody></table><p>UniProt ID: <a href="http://www.uniprot.org/uniprot/P19838">P19838</a></p><p>Gene Name: RELA</p><p>Gene ID: 5970</p>

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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><font face="Georgia" size="2">v-jun sarcoma virus 17\r\noncogene homolog</font></p><p><span style="font-family: Georgia; font-size: small;">UniProt ID:&nbsp;</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P05412</span></p><p><font face="Georgia" size="2">Gene Name: JUN</font></p><p><font face="Georgia" size="2">Gene ID:&nbsp;<span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3725</span></font></p>\r\n </div>\r\n </div>\r\n </div>

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PTEN = phosphatase and tensin homolog<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P60484" 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(222, 239, 245);">P60484</a></div><div>Gene Name: PTEN</div><div>Gene ID:&nbsp;<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);">5728</span></div>

 2015-11-15T20:56:21Z

FoxO1 mutant 3a<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q12778" 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(222, 239, 245);">Q12778</a><br/><div>Gene Name: FoxO1</div><div>Gene ID:&nbsp;<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);">2308</span></div></div>

 2015-11-15T20:56:21Z

Proline-rich AKT1 substrate 1<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q96B36" 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);">Q96B36</a></div><div>Gene Name:&nbsp;<a href="http://www.ncbi.nlm.nih.gov/gene/84335" ref="ordinalpos=1&amp;ncbi_uid=84335&amp;link_uid=84335" style="color: rgb(100, 42, 143); font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17.9998016357422px; white-space: nowrap; background-color: rgb(213, 222, 227);">AKT1S1</a></div><div>Gene ID:&nbsp;<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);">84335</span></div>

 2015-11-15T20:56:21Z

Mitogen-activated protein kinase 3 (ERK1)<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P27361" 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(222, 239, 245);">P27361</a><br/>Gene Name: MAPK1</div><div>Gene ID:&nbsp;<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);">5594</span></div><div><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);"><br/></span></div><div>Mitogen-activated protein kinase 1 (ERK2)</div><div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P28482" 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(222, 239, 245);">P28482</a></div><div>Gene Name: MAPK1&nbsp;</div><div>Gene ID:&nbsp;<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);">5594</span></div>

 2015-11-15T20:56:21Z

Retinoblastoma 1<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P06400" 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);">P06400</a></div><div>Gene Name: RB1</div><div>Gene ID:&nbsp;<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);">5925</span></div>

 2015-11-15T20:56:21Z

<font face="Georgia"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Ribosomal protein S6 kinase, 70kDa, polypeptide 1</span><br/></font><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID:&nbsp;</span><span style="background-color: rgb(255, 255, 255);">P23443</span><span style="background-color: rgb(255, 255, 255);">&nbsp;</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene Name:&nbsp;</span><a href="http://www.ncbi.nlm.nih.gov/gene/6198" ref="ordinalpos=2&amp;ncbi_uid=6198&amp;link_uid=6198" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">RPS6KB1</a></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID:&nbsp;</span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">6198</span></font></div>

 2015-11-15T20:56:21Z

MAPK11 = mitogen-activated protein kinase 11&nbsp;<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q15759" 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);">Q15759</a></div><div>Gene Name: MAPK11</div><div>Gene ID:&nbsp;<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);">&nbsp;</span><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);">5600</span></div><div><br/><div>MAPK12 = mitogen-activated protein kinase 12&nbsp;</div><div><div style="font-size: 13.3333330154419px;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P53778" 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(222, 239, 245);">P53778</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK12</div><div style="font-size: 13.3333330154419px;">Gene ID:&nbsp;<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);">6300</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>MAPK13 = mitogen-activated protein kinase 13&nbsp;</div><div><div style="font-size: 13.3333330154419px;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/O15264" 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);">O15264</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK13</div><div style="font-size: 13.3333330154419px;">Gene ID:&nbsp;<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);">5603</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>MAPK14 = mitogen-activated protein kinase 14</div></div><div><div style="font-size: 13.3333330154419px;">UniProt ID:</div><div style="font-size: 13.3333330154419px;">Gene Name:</div><div style="font-size: 13.3333330154419px;">Gene ID:</div></div>

 2015-11-15T20:56:21Z

40S ribosomal protein S6<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P62753" 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);">P62753</a></div><div>Gene Name: RPS6</div><div>Gene ID:&nbsp;<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);">6194</span></div><br><br>null

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<font face="Georgia" style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">v-</span><span class="highlight" style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">akt</span><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">&nbsp;murine thymoma viral oncogene homolog 1 [</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 style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">UniProt ID:&nbsp;</span><a href="http://www.uniprot.org/uniprot/P31749" style="text-decoration: none; background-color: rgb(255, 255, 255);">P31749</a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);">Gene Name:&nbsp;</span><a href="http://www.ncbi.nlm.nih.gov/gene/207" ref="ordinalpos=1&amp;ncbi_uid=207&amp;link_uid=207" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">AKT1</a></font></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Gene ID: 207</font></span></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><br/></font></span></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="line-height: 18.88888931274414px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Additions from the MAPK Network:</font></span></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"></font></span><div><br/></div><div><span style="line-height: 18.8888893127441px;">AKT2 = v-akt murine thymoma viral oncogene homolog 2</span></div><div><div><span style="line-height: 18.8888893127441px;">UniProt ID:&nbsp;</span><a href="http://www.uniprot.org/uniprot/P31751" style="font-size: 13px; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; line-height: 20.081974029541px;">P31751</a></div><div><span style="line-height: 18.8888893127441px;">Gene Name: AKT2</span></div><div><span style="line-height: 18.8888893127441px;">Gene ID: 208</span></div></div><div><span style="line-height: 18.8888893127441px;"><br/></span></div><div><span style="line-height: 18.8888893127441px;">AKT3 = v-akt murine thymoma viral oncogene homolog 3</span></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: 18.8888893127441px;"><div style="font-family: Georgia; font-size: small; line-height: normal;"><span style="line-height: 18.8888893127441px;">UniProt ID:&nbsp;</span><a href="http://www.uniprot.org/uniprot/Q9Y243" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">Q9Y243</a></div><div style="font-family: Georgia; font-size: small; line-height: normal;"><span style="line-height: 18.8888893127441px;">Gene Name: AKT3</span></div><div style="font-family: Georgia; font-size: small; line-height: normal;"><span style="line-height: 18.8888893127441px;">Gene ID: 10000</span></div></div></div>

 2015-11-15T20:56:21Z

<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)&nbsp;</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:&nbsp;</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:&nbsp;</span><span style="line-height: 18.88888931274414px;">2064</span></font></div>

 2015-11-15T20:56:21Z

<div>RAF proto-oncogene serine/threonine-protein kinase aka&nbsp;proto-oncogene c-RAF</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P04049" 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(222, 239, 245);">P04049</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene Name: RAF1</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene ID:&nbsp;<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);">5894</span></div>

 2015-11-15T20:56:21Z

<p style="margin: 0.4em 0px 0.5em;"><span id="parentSpecies:viewSpeciesDescription">Glycogen synthase kinase-3 beta</span></p><div>UniProt ID:&nbsp;P49841</div><div><br/></div><div>Glycogen synthase kinase-3 alpha</div><div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P49840" 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(222, 239, 245);">P49840</a></div>

 2015-11-15T20:56:21Z

<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)&nbsp;</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:&nbsp;</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:&nbsp;</span><span style="line-height: 16.78819465637207px; white-space: nowrap;">2065</span></font></div>

 2015-11-15T20:56:21Z

TP53 = tumor protein p53<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P04637" 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(222, 239, 245);">P04637</a></div><div>Gene Name: TP53</div><div>Gene ID:&nbsp;<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);">7157</span></div>

 2015-11-15T20:56:21Z

BAX activates itself [1].

<span style="font-size: 13.3333330154419px;">BAX activates itself [1].</span>

 S_2 1

AKT activates CyclinD1 [1, 2, 3].&nbsp;<span style="font-size: 13.3333330154419px;">ERK1_2 activates CyclinD1 [1, 4]. Cyclin D self-regulates [1]. GSKa_b activates CyclinD1 [1, 3]. RPS6 activates CyclinD1 [1]</span>

<span style="font-size: 13.3333330154419px;">Cyclin D self-regulates [1]</span>

GSK3a_b activates CyclinD1 [1, 3]

ERK1_2 positively regulates CyclinD1 [1, 4]

AKT activates CyclinD1 [1, 2, 3]

RPS6 activation of CyclinD1 is inferred [1]

 S_18 1 S_22 1 S_3 1 S_22 1 S_19 1 S_22 1 S_14 1 S_22 1

ERBB1 positively regulates itself [1]. Stimulus activates ERBB1 [1]. Erlotinib inhibits ERBB1 [1, 2]. Pertuzumab inhibits ERBB1 [1, 3, 4].

ERBB1 self regulates [1]

the drug erlotinib inhibits ERBB1 [1, 2]

Stimulus activates ErbB-1 [1]

The drug pertuzumab inhibits ERBB1 [1, 3, 4]

 S_5 1 S_1 1 S_8 1 S_4 1 S_1 1 S_8 1

CyclinB1 activates itself [1]. ERBB1 positively regulates CyclinB1 [1].&nbsp;<span style="font-size: 13.3333330154419px;">ERBB3 positively regulates CyclinB1 [1]. p53 inhibits CyclinB1 [1, 2].</span>

<span style="font-size: 13.3333330154419px;">ErbB-1 and ErbB-3 drive activation of Cyclin B1 [1]</span>

Cyclin B1 self-activates [1]

<span style="font-size: 13.3333330154419px;">ErbB-1 and ErbB-3 drive activation of Cyclin B1 [1]</span>

p53 inhibits CyclinB1 [1, 2]

 S_4 1 S_24 1 S_23 1 S_24 1 S_6 1 S_24 1

TSC2 positively regulates itself [1].&nbsp;<span style="orphans: 3; widows: 3;">GSK3a_b inhibits TSC2 [1, 2].</span>&nbsp;<span style="orphans: 3; widows: 3;">AKT inhibits TSC2 [1, 2, 3].&nbsp;</span><span style="orphans: 3; widows: 3;">ERK1_2 inhibits TSC2 [1, 4]</span>

GSK3a_b inhibits TSC2 [1, 2]

ERK1_2 inhibits TSC2 [1, 4]

AKT inhibits TSC2 [1, 2, 3].

TSC2 positively regulates itself [1].

 S_7 1 S_19 1 S_22 1 S_14 1

Nfkb positively regulates itself [1].

<span style="font-size: 13.3333330154419px;">Nfkb positively regulates itself [1].</span>

 S_9 1

<span style="font-size: 13.3333330154419px;">cJUN activates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">GSK3a_b inhibits cJUN [1, 2]</span>

GSK3a_b inhibits cJUN [1, 2]

cJUN activates itself [1].

 S_10 1 S_22 1

PTEN positively regulates itself [1]. GSK3a_b inhibits PTEN [1, 2].

<span style="font-size: 13.3333330154419px;">PTEN positively regulates itself [1].</span>

GSK3a_b inhibits PTEN [1, 2]

 S_11 1 S_22 1

<span style="font-size: 13.3333330154419px;">FoxO1_3a self-regulates [1]. AKT inhibits FoxO1_3a [1, 2, 3].</span>

FoxO1_3a self-regulates [1].

AKT inhibits FoxO1_3a [1, 2, 3]

 S_12 1 S_19 1

PRAS positively regulates itself [1]. AKT inhibits PRAS [1, 2]

<span style="font-size: 13.3333330154419px;">PRAS positively regulates itself [1].</span>

AKT inhibits PRAS [1, 2]

 S_13 1 S_19 1

ERK1_2 positively regulates itself [1]. cRAF positively regulates ERK1_2 [1, 2, 3].

ERK1_2 self-regulates [1]

cRAF positively activates ERK1_2 [1, 2, 3]

 S_21 1 S_14 1

<span style="font-size: 13.3333330154419px;">RB activates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3;">Nfkb activates Rb [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3;">CyclinD1 inhibits Rb [1, 2]</span>

Nfkb activates Rb [1].

CyclinD1 inhibits Rb [1, 2]

<span style="font-size: 13.3333330154419px;">RB activates itself [1].</span>

 S_15 1 S_3 1 S_9 1 S_3 1

<span style="font-size: 13.3333330154419px;">ERK1_2 activates p70s6k [1, 2].</span><span style="font-size: 13.3333330154419px;">&nbsp;p70s6k activates itself [1].&nbsp;</span><span style="font-size: 13.3333330154419px;">Nfkb inhibits p70s6k [1].&nbsp;</span><span style="font-size: 13.3333330154419px;">PRAS inhibits p70s6k [1, 3, 4].&nbsp;</span><span style="font-size: 13.3333330154419px;">TSC2 inhibits p70s6k [1, 5].</span>

Nfkb inhibits p70s6k [1]

PRAS inhibits p70s6k [1, 3, 4]

p70s6k regulates itself [1]

ERK1_2 positively regulates p70s6k [1, 2]

TSC2 inhibits p70s6k [1, 5]

 S_14 1 S_13 1 S_9 1 S_7 1 S_16 1 S_13 1 S_9 1 S_7 1

<span style="font-size: 13.3333330154419px;">p38 positively regulates itself [1]</span>. AKT positively regulates p38 [1, 2].

<span style="font-size: 13.3333330154419px;">p38 positively regulates itself [1]</span>

AKT activates p38 [1, 2]

 S_17 1 S_19 1

<span style="font-size: 13.3333330154419px;">RPS6 activates itself [1].&nbsp;</span><span style="font-size: 13.3333330154419px;">p70s6k activates RPS6 [1, 2].</span>

p70s6k positively regulates RPS6 [1, 2].

RPS6 activates itself [1].

 S_18 1 S_16 1

AKT activates AKT [1].&nbsp;<span style="font-size: 13.3333330154419px;">ERBB1 activates AKT [1, 2, 3]. ERBB2&nbsp;</span><span style="font-size: 13.3333330154419px;">activates AKT [1, 4, 5, 6, 7]. ERBB3</span><span style="font-size: 13.3333330154419px;">&nbsp;activates AKT [1, 6, 7, 8, 9]. PTEN</span><span style="font-size: 13.3333330154419px;">&nbsp;inhibits AKT [1, 10].</span>

PTEN inhibits AKT [1, 10]

ERBB dimers predominantly activate key regulators, AKT or ERK1_2 [1, 2, 3]

ERBB dimers predominantly activate key regulators, AKT or ERK1_2 [1, 4, 5, 6, 7]

ERBB dimers predominantly activate key regulators, AKT or ERK1_2 [1, 6, 7, 8, 9]

AKT self-activates itself [1]

 S_20 1 S_11 1 S_19 1 S_11 1 S_4 1 S_11 1 S_23 1 S_11 1

ERBB2 positively regulates itself [1]. Stimulus positively regulates ERBB2 [1]. Erlotinib inhibits ERBB2 [1, 2, 3]. Pertuzumab inhibits ERBB2 [1, 4]. Trastuzumab inhibits ERBB2 [1, 4].&nbsp;

<table class="ui-datagrid-data" style="width: 747px;"><tbody><tr class="ui-datagrid-row"><td class="ui-datagrid-column" style="padding: 3px; vertical-align: top;"><p style="orphans: 3; widows: 3; margin: 0.4em 0px 0.5em;">The drug erlotinib inhibits ERBB2 [1, 2, 3]</p></td></tr></tbody></table>

ERBB2 positively regulates itself [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Stimulus activates ErbB-2 [1]</span>

<span style="font-size: 13.3333330154419px;">The drug pertuzumab inhibits ERBB2 [1, 4]</span>

The drug trastuzumab inhibits ERBB2 [1, 4]

 S_20 1 S_8 1 S_25 1 S_1 1 S_5 1 S_8 1 S_25 1 S_1 1

cRAF activates itself [1].&nbsp;<span style="orphans: 3; widows: 3;">ERBB1 activates cRAF [1, 3, 4].&nbsp;</span><span style="orphans: 3; widows: 3;">ERBB2 activates cRAF [1, 3, 4, 5].&nbsp;</span><span style="orphans: 3; widows: 3;">ERK1_2 inhibits cRAF [1, 2].</span>

ERBB1 activates cRAF [1, 3, 4]

ERBB2 activates cRAF [1, 3, 4, 5]

ERK1_2 inhibits cRAF [1, 2]

cRAF activates itself [1]

 S_20 1 S_14 1 S_4 1 S_14 1 S_21 1 S_14 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">GSK3a_b self-regulates [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CyclinD1 activates GSK3a_b [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p53 activates GSK3a_b [1, 2]</span>

CyclinD1 activates GSK3a_b [1]

GSK3a_b self-regulates [1]

p53 activates GSK3a_b [1, 2]

 S_3 1 S_24 1 S_22 1

ERBB3 positively regulates itself [1]. Stimulus positively regulates ERBB3 [1].&nbsp;<span style="font-size: 13.3333330154419px;">RPS6 positively regulates ERBB3 [1]. Erlotinib inhibits ERBB3 [1, 2, 3].&nbsp;</span><span style="font-size: 13.3333330154419px;">Pertuzumab inhibits ERBB3 [1, 4].&nbsp;</span><span style="font-size: 13.3333330154419px;">PTEN inhibits ERBB3 [1].&nbsp;</span>

PTEN inhibits ERBB3 [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug erlotinib inhibits ERBB3 [1, 2, 3]</span>

Stimulus results in the activation of ErbB-3 [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug pertuzumab inhibits ERBB3 [1, 2, 4]</span>

ERBB3 positively regulates itself [1]

RPS6 activates ERBB3 [1]

 S_23 1 S_11 1 S_1 1 S_8 1 S_18 1 S_11 1 S_1 1 S_8 1 S_5 1 S_11 1 S_1 1 S_8 1

CyclinB1 activates p53 [1, 2].&nbsp;<span style="font-size: 13.3333330154419px;">p38activates p53 [1, 3].&nbsp;</span><span style="font-size: 13.3333330154419px;">p53 activates itself [1].&nbsp;</span><span style="font-size: 13.3333330154419px;">PTEN activates p53 [1, 4].&nbsp;</span><span style="font-size: 13.3333330154419px;">RB activates p53 [1, 5]. Stimulus activates p53 [1].</span>

PTEN activates p53 [1, 4]

<span style="font-size: 13.3333330154419px;">Stimulus activates p53 [1]</span>

p38 activates p53 [1, 3]

Cyclin B1 positively regulates p53 [1, 2]

RB activates p53 [1, 5]

p53 activates itself [1]

 S_11 1 S_17 1 S_5 1 S_15 1 S_6 1 S_24 1