Cellular decisions are determined by complex molecular interaction networks. Large-scale signaling networks are currently being reconstructed, but the kinetic parameters and quantitative data that would allow for dynamic modeling are still scarce. Therefore, computational studies based upon the structure of these networks are of great interest. Here, a methodology relying on a logical formalism is applied to the functional analysis of the complex signaling network governing the activation of T cells via the T cell receptor, the CD4/CD8 co-receptors, and the accessory signaling receptor CD28. Our large-scale Boolean model, which comprises 94 nodes and 123 interactions and is based upon well-established qualitative knowledge from primary T cells, reveals important structural features (e.g., feedback loops and network-wide dependencies) and recapitulates the global behavior of this network for an array of published data on T cell activation in wild-type and knock-out conditions. More importantly, the model predicted unexpected signaling events after antibody-mediated perturbation of CD28 and after genetic knockout of the kinase Fyn that were subsequently experimentally validated. Finally, we show that the logical model reveals key elements and potential failure modes in network functioning and provides candidates for missing links. In summary, our large-scale logical model for T cell activation proved to be a promising in silico tool, and it inspires immunologists to ask new questions. We think that it holds valuable potential in foreseeing the effects of drugs and network modifications. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-24T02:02:56Z 2019-08-09T15:06:11Z

External node of the T Cell Receptor Signaling (2007) paper.

2017-05-18T11:45:31Z

External node of the T Cell Receptor Signaling (2007) paper.

2015-11-15T18:15:43Z

<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);">External node of the T Cell Receptor Signaling (2007) paper.</span>

2015-11-15T18:15:43Z

2019-08-09T15:06:11Z

External node of the T Cell Receptor Signaling (2007) paper.

2019-08-09T15:04:50Z

2015-11-15T18:15:43Z

MAPK8 = mitogen-activated protein kinase 8<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P45983" 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);">P45983</a></div><div>Gene Name: MAPK8</div><div>Gene ID: 5599</div><div> </div><div>MAPK9 = mitogen-activated protein kinase 9 </div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/P45984" 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);">P45984</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK9</div><div style="font-size: 13.3333330154419px;">Gene ID: 5601</div></div><div style="font-size: 13.3333330154419px;"><br/></div><div style="font-size: 13.3333330154419px;">MAPK10 = mitogen-activated protein kinase 10 </div><div style="font-size: 13.3333330154419px;"><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/P53779" 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);">P53779</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK10 </div><div style="font-size: 13.3333330154419px;">Gene ID:v5602</div></div>

2015-11-15T18:15:43Z

<font face="Georgia"><span class="RECOMMENDED" style="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;">E3 ubiquitin-protein ligase CBL</span></span><br style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"/><acronym class="names EC" title="Enzyme Commission number." style="border: none; cursor: pointer; padding-left: 1.5em; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">EC=</acronym><span class="EC_NAME" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><a href="http://enzyme.expasy.org/EC/6.3.2.-" style="text-decoration: none;">6.3.2.-</a></span></font><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><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">Casitas B-lineage lymphoma proto-oncogene</span></font></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia"><br/></font></span></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal; font-size: 16px;">P22681</span></font></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span style="line-height: normal; font-size: 16px;"><br/></span></font></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span style="line-height: normal; font-size: 16px;">In this model, ccblp2 indicates a pool of </span></font><span style="font-family: NimbusSanL; font-size: 11pt; line-height: normal;">Fyn-dependent cblp [1]. </span></div>\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'"> <br/></span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2017-05-18T11:48:39Z

<div><span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Bcl2 antagonist of cell death</font></span></div><font face="Georgia" size="2">Uniprot ID: <a href="http://www.uniprot.org/uniprot/Q92934" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q92934</a></font><div><font face="Georgia" size="2">Gene Name: BAD</font></div><div><font face="Georgia" size="2">Gene ID: 572</font></div>

2015-11-15T18:15:43Z

<table border="0" cellpadding="0" cellspacing="0" width="964" style="border-collapse:\r\n collapse;width:723pt"><tbody><tr height="20" style="height:15.0pt">\r\n <td height="20" class="xl65" width="964" style="height:15.0pt;width:723pt">c-src\r\n tyrosine kinase<br/>UniProt ID: <a href="http://www.uniprot.org/uniprot/P41240" 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);">P41240</a><br/>Gene Name: CSK<br/>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);">1445</span></td></tr></tbody></table>

2017-05-18T11:45:31Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">RAS guanyl-releasing protein 1</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">O95267</span></font></div>

2015-11-15T18:15:43Z

<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>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Calcineurin-binding protein cabin-1</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q9Y6J0</span></font></div>

2016-03-29T10:35:56Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">GRB2-associated-binding protein 2</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q9UQC2</span></font></div>

2015-11-15T18:15:43Z

<span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Growth arrest and DNA damage-inducible protein GADD45 alpha</span><div><span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">P24522</span></div><div><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><br/></span></div><div><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">From the paper [1]:</span></div><div>GADD45A = growth arrest and DNA-damage-inducible, alpha</div><div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P24522" 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);">P24522</a></div><div>Gene Name: GADD45A</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);">1647</span></div><div><br/></div><div>GADD45B = growth arrest and DNA-damage-inducible, beta</div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/O75293" 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);">O75293</a></div><div style="font-size: 13.3333330154419px;">Gene Name: GADD45B</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);">4616</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div style="font-size: 13.3333330154419px;">GADD45G = growth arrest and DNA-damage-inducible, gamma</div><div style="font-size: 13.3333330154419px;"><span style="font-size: 13.3333330154419px;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O75293" 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);">O75293</a></div><div style="font-size: 13.3333330154419px;">Gene Name: GADD45G</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);">10912</span></div>

2015-11-15T18:15:43Z

<div><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Represents kinase subunits alpha and beta:</font></span></div><font face="Georgia"></font><ul><li><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Inhibitor of nuclear factor kappa-B kinase subunit alpha, UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">O15111</span></li><li><span style="background-color: rgb(255, 255, 255); font-size: small; line-height: 16px;">Inhibitor of nuclear factor kappa-B kinase subunit beta, UniProt ID: O14920</span></li></ul>

2015-11-15T18:15:43Z

<span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Caspase recruitment domain-containing protein 11</span><div><span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">Q9BXL7</span></div>

2015-11-15T18:15:43Z

<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"><font face="Calibri">zeta-chain\r\n (TCR) associated protein kinase 70kDa<span style="mso-spacerun: yes;"> </span></font></font></td>\r\n\r\n </tr>\r\n</tbody></table><p> </p><p>UniProt ID: <a href="http://www.uniprot.org/uniprot/P43403">P43403</a></p><p>Gene Name: ZAP70</p><p>Gene ID: 7535</p>

2017-05-18T11:48:39Z

<div><strong style="color: rgb(68, 68, 68); font-family: Verdana, Arial, sans-serif; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">AP-1 complex subunit gamma-1</strong></div>UniProt ID: <a href="http://www.uniprot.org/uniprot/O43747" style="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(255, 255, 255);">O43747</a><div>Gene Name: JUN</div><div>Gene ID: 3725</div>

2015-11-15T18:15:43Z

<div><table border="0" cellpadding="0" cellspacing="0" width="964" style="border-collapse:\r\n collapse;width:723pt"><tbody><tr height="20" style="height:15.0pt">\r\n <td height="20" class="xl65" width="964" style="height:15.0pt;width:723pt">Glycogen\r\n synthase kinase 3</td></tr></tbody></table></div><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Either:</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></p><ul><li><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);">Glycogen synthase kinase 3 alpha, UniProt ID: P49840, Gene Name: <span class="highlight" style="line-height: 18.88888931274414px; white-space: nowrap;"><a href="http://www.ncbi.nlm.nih.gov/gene/2931" ref="ordinalpos=1&ncbi_uid=2931&link_uid=2931" style="line-height: 18.88888931274414px; white-space: nowrap;">GSK3A</a>, Gene ID: 2931</span></font></li><li><font face="Georgia" size="2" style="background-color: rgb(255, 255, 255);"><span style="line-height: 16px;">Glycogen synthase kinase-3 beta, UniProt ID: </span>P49841, Gene Name: <span class="highlight" style="line-height: 18.88888931274414px; white-space: nowrap;"><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;">GSK3B</a>, Gene ID 2932 (in EGFR_ErbB Signaling models, this node represents GSK3B exclusively [1]). </span></font></li></ul><p style="font-family: Arial, Verdana; font-size: 10pt;"></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div></div>

2015-11-15T18:15:43Z

RPS6KA1 = ribosomal protein S6 kinase, 90kDa, polypeptide 1 <div>UniProt ID: <a href="http://www.uniprot.org/uniprot/Q15418" 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);">Q15418</a></div><div>Gene Name: RPS6KA1</div><div>Gene ID: 6195</div><div><br/><div>RPS6KA2 = ribosomal protein S6 kinase, 90kDa, polypeptide 2 </div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q15349" 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);">Q15349</a></div><div style="font-size: 13.3333330154419px;">Gene Name: <span style="font-size: 13.3333330154419px;">RPS6KA2</span></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);">6196</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>RPS6KA3 = ribosomal protein S6 kinase, 90kDa, polypeptide 3 </div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/P51812" 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);">P51812</a></div><div style="font-size: 13.3333330154419px;">Gene Name: <span style="font-size: 13.3333330154419px;">RPS6KA3</span></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);">6197</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>RPS6KA6 = ribosomal protein S6 kinase, 90kDa, polypeptide 6 </div></div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q9UK32" 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);">Q9UK32</a></div><div style="font-size: 13.3333330154419px;">Gene Name: <span style="font-size: 13.3333330154419px;">RPS6KA6</span></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);">27330</span></div></div>

2015-11-15T18:15:43Z

Linker for Activation\r\nof T-cells<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/O43561" 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);">O43561</a><br/>Gene Name: LAT</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);">27040</span></div>

2015-11-15T18:15:43Z

<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; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><font face="Georgia"><span class="RECOMMENDED" style="line-height: 16px;"><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;">E3 ubiquitin-protein ligase CBL</span></span><br style="line-height: 16px;"/><acronym class="names EC" title="Enzyme Commission number." style="border: none; cursor: pointer; padding-left: 1.5em; line-height: 16px;">EC=</acronym><span class="EC_NAME" style="line-height: 16px;"><a href="http://enzyme.expasy.org/EC/6.3.2.-" style="outline: none; color: rgb(79, 79, 79); text-decoration: none;">6.3.2.-</a></span></font></span></p><div class="alternatives" style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><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">Casitas B-lineage lymphoma proto-oncogene</span></font></div><div class="alternatives" style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia"><br/></font></span></div><div class="alternatives" style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal;">P22681</span></font></div><div class="alternatives" style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span style="line-height: normal;"><br/></span></font></div><div class="alternatives" style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span style="line-height: normal;">In this model, ccblp2 indicates a pool of ZAP70-dependent</span></font><span style="font-family: NimbusSanL; line-height: normal;"> cblp [1]. </span></div>

2015-11-15T18:15:43Z 2016-03-29T10:35:56Z

<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"><p><font size="3" face="Calibri">phosphoprotein\r\n associated with glycosphingolipid microdomains</font></p><p><font size="3" face="Calibri">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q9NWQ8">Q9NWQ8</a></font></p><p><font size="3" face="Calibri">Gene Name: PAG1</font></p><p><font size="3" face="Calibri">Gene ID: 55824</font></p><p> </p></td>\r\n\r\n </tr>\r\n</tbody></table>

2015-11-15T18:15:43Z

GTPase-activating protein 1 (GAP1) [fruit fly]<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P48423" 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);">P48423</a></div><div>Gene Name: gap1</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);">2540440</span></div>

2015-11-15T18:15:43Z 2015-11-15T18:15:43Z

<span style="font-family: Arial, Verdana; font-size: small; font-style: normal; font-variant: normal; font-weight: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">E3 ubiquitin-protein ligase CBL-B</font></span><div>UniProt ID: Q13191</div><div>Gene Name: CBLB</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);">868</span></div>

2015-11-15T18:15:43Z

MAPK11 = mitogen-activated protein kinase 11 <div>UniProt ID: <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: <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);"> </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 </div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <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: <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 </div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <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: <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>

2015-11-15T18:15:43Z

<font face="Georgia"><span class="RECOMMENDED" style="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;">NF-kappa-B essential modulator</span></span><br style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"/><acronym class="names SHORT" title="Abbreviation of the full name or an acronym." style="border: none; cursor: pointer; padding-left: 1.5em; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Short name=</acronym><span class="SHORT_NAME" style="font-size: smaller; background-color: rgb(255, 255, 255);">NEMO</span></font><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><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">Inhibitor of nuclear factor kappa-B kinase subunit gamma</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;">IKKG</span><br/></font></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia"><br/></font></span></div><div class="alternatives" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal; font-size: 16px;">Q9Y6K9</span><span style="line-height: normal; font-size: 16px;"> </span></font></div>

2015-11-15T18:15:43Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1</font></span><div><font face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P19174</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="font-weight: normal; background-color: rgb(255, 255, 255);">In this model, represents </span>Active form of\r\nPLC?1, PLC-\r\ngamma-1 [1]. </font></div>\r\n \r\n \r\n \r\n <div class="page" title="Page 4" style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'"> <br/></span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T18:15:43Z

<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">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>

2016-03-29T10:35:56Z

<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>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Calcium/calmodulin-dependent protein kinase type IV</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q16566</span></font></div>

2015-11-15T18:15:43Z

<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>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Cyclin-dependent kinase inhibitor 1B</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P46527</span></font></div>

2015-11-15T18:15:43Z

<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>

2017-05-15T17:22:19Z

<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"><p><font size="3" face="Calibri">nuclear\r\n factor of activated T-cells, cytoplasmic, calcineurin-dependent</font></p><p><font size="3" face="Calibri">(NFAT homolog)</font></p><p><font size="3" face="Calibri">Gene Name: NFAT</font></p><p><font size="3" face="Calibri">Gene ID: 32321</font></p><p> </p></td>\r\n\r\n </tr>\r\n</tbody></table>

2015-11-15T18:15:43Z

<table border="0" cellpadding="0" cellspacing="0" width="964" style="border-collapse:\r\n collapse;width:723pt"><tbody><tr height="20" style="height:15.0pt">\r\n <td height="20" class="xl66" width="964" style="height:15.0pt;width:723pt">cell\r\n division cycle 42 (GTP binding protein, 25kDa)<br/>UniProt ID: <a href="http://www.uniprot.org/uniprot/Q9NRR8" 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);">Q9NRR8</a><br/>Gene Name: CDC42<br/>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);">998</span></td></tr></tbody></table>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Cytochrome c1, heme protein, mitochondrial</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P08574</span></font></div>

2015-11-15T18:15:43Z

<span style="background-color: rgb(255, 255, 255); line-height: 16px;"><font face="Georgia">Ras-related C3 botulinum toxin substrate 1</font></span><div><font face="Georgia"><span class="FULL" style="padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P63000</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="background-color: rgb(255, 255, 255);">In this model, rac1p1 represents a </span>Vav-1 dependent pool of rac1 [1]. </font></div>

2015-11-15T18:15:43Z

Uniprot ID: P31749

2015-11-15T18:15:43Z

<div><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">This node indicates a </font></span><span style="font-family: NimbusSanL; font-size: 11pt;">CD4-dependent pool of lck. [1]</span></div><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Tyrosine-protein kinase Lck</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P06239</span></font></div>

2017-05-15T17:22:19Z 2017-05-18T11:48:39Z

<span style="font-family: Arial, Verdana; font-size: small; font-style: normal; font-variant: normal; font-weight: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Transcription factor AP-1, </font></span><font face="Arial, Verdana"><span style="font-size: 10pt;">jun proto-oncogene</span></font><div>UniProt ID: P05412</div><div>Gene Name: JUN</div><div>Gene ID: 3725</div>

2015-11-15T18:15:43Z

<font face="Georgia" size="2"><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: </span><span style="font-weight: normal; background-color: rgb(255, 255, 255);">P23443</span><span style="background-color: rgb(255, 255, 255);"> </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/6198" ref="ordinalpos=2&ncbi_uid=6198&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: </span><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">6198</span></font></div>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Cyclin-dependent kinase inhibitor 1</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P38936</span></font></div>

2015-11-15T18:15:43Z

<div style="font-size: 10pt;">mitogen-activated protein kinase <span style="font-size: 10pt;">kinase 1</span></div><div style="font-size: 10pt;"><span style="font-size: 10pt;"><br/></span></div><div style="font-size: 10pt;">MAP2K5:</div><div style="font-size: 10pt;">UniProt Accession ID: Q13163</div><div style="font-size: 10pt;"><br/></div><div style="font-size: 10pt;">MAP2K6:</div><div style="font-size: 10pt;">UniProt Accession ID: P52564 </div><div style="font-size: 10pt;"><br/></div><div style="font-size: 10pt;">MAP2K3:</div><div style="font-size: 10pt;">UniProt Accession ID: P46734 </div><div style="font-size: 10pt;"><br/></div><div style="font-size: 10pt;">MAP2K1:</div><div style="font-size: 10pt;">UniProt Accession ID: Q02750</div><div style="font-size: 10pt;"><br/></div><div><font size="2">MAP2K2:</font></div><div><font size="2">UniProt Accession ID: P36507</font></div>

2015-11-15T18:15:43Z

<div style="font-family: Times;"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">This node indicates a </font></span><span style="font-family: NimbusSanL; font-size: 11pt;">reservoir pool of lck. </span><span style="font-family: NimbusSanL; font-size: 11pt;">In the case where two\r\npools of a molecule were considered, a?reservoir? was included which was required for\r\nboth pools. This allows to perform a simultaneous knock-out of both pools. [1].</span></div><span style="font-size: small; font-family: Times; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Tyrosine-protein kinase Lck</font></span><div style="font-family: Times;"><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P06239</span></font></div>

2017-05-15T17:22:19Z

<div style="font-family: Times;"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">This node indicates a </font></span><span style="font-family: NimbusSanL; font-size: 11pt;">CD28/TCR-dependent pool of lck [1].</span></div><span style="font-family: Times; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Tyrosine-protein kinase Lck</font></span><div style="font-family: Times;"><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P06239</span></font></div>

2015-11-15T18:15:43Z

Yet unidentified kinase known to be activated by cdc28 and to activate vav1 [1]. 

2015-11-15T18:15:43Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Mitogen-activated protein kinase kinase kinase 1</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);">Q13233</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/4214" ref="ordinalpos=1&ncbi_uid=4214&link_uid=4214" style="line-height: 18.88888931274414px; white-space: nowrap; background-color: rgb(255, 255, 255);">MAP3K1</a></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: 4214</span></font></div>

2015-11-15T18:15:43Z

<span style="background-color: rgb(255, 255, 255); line-height: 16px;"><font face="Georgia">Ras-related C3 botulinum toxin substrate 1</font></span><div><font face="Georgia"><span class="FULL" style="padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P63000</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="background-color: rgb(255, 255, 255);">In this model, rac1pr represents a </span>reservoir of rac1 [1]. </font></div>

2015-11-15T18:15:43Z

<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>

2015-11-15T18:15:43Z

<span style="font-family: Arial, Verdana; font-size: small; font-style: normal; font-variant: normal; font-weight: normal; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">T-cell-specific surface glycoprotein CD28</font></span><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P10747</span></font></div><div>Gene Name: CD28</div><div>Gene ID: 12487</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"><span style="font-size: 16px; background-color: rgb(255, 255, 255);"><br/></span></font></div>

2015-11-15T18:15:43Z

<span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Calcium/calmodulin-dependent protein kinase type II subunit beta</span><div><span style="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">Q13554</span></div>

2015-11-15T18:15:43Z

From the paper [1]:<div><br/><div>MAPK1 = mitogen-activated protein kinase 1</div><div>UniProt ID: <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</div><div>Gene ID: 5594</div><div><br/></div><div>MAPK3 = mitogen-activated protein kinase 3</div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <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(255, 255, 255);">P27361</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK3</div><div style="font-size: 13.3333330154419px;">Gene ID: 5595</div></div></div>

2015-11-15T18:15:43Z

Scaffolding protein <font color="#444444" face="Verdana, Arial, sans-serif"><span style="font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">GRB2-related adapter protein 2</span></font> (GADS)<div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="font-size: 10pt;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O75791" 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);">O75791</a><div>Gene Name: Grap2</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);">17444</span></div></div>

2015-11-15T18:15:43Z

<span style="font: 10pt/normal Arial, Verdana;">Raspberry</span> Ras-like protein 2<font face="Arial, Verdana"><span style="font-size: 10pt;"> (RAS)</span></font><div style="font: 10pt/normal Arial, Verdana;">UniProt ID: <a style="color: rgb(64, 148, 180); line-height: 20.08px; font-family: Verdana, Arial, sans-serif; font-size: 13.05px; text-decoration: none; border-bottom-width: 0px; cursor: pointer; background-color: rgb(255, 255, 255);" href="http://www.uniprot.org/uniprot/P04388">P04388</a></div><div style="font: 10pt/normal Arial, Verdana;">Gene Name: ras</div><div style="font: 10pt/normal Arial, Verdana;">Gene ID: <span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);">43873</span></div><div style="font: 10pt/normal Arial, Verdana;"><span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);"></span> </div><div style="font: 10pt/normal Arial, Verdana;"><span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);"></span> </div><div style="font: 10pt/normal Arial, Verdana;"><span style="color: rgb(87, 87, 87); line-height: 16.19px; font-family: arial, helvetica, clean, sans-serif; font-size: 11.69px; background-color: rgb(213, 222, 227);"><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"><p><font color="#000000" size="3" face="Calibri"><font color="#575757" face="Arial">In [1]:</font></font></p><p><font color="#000000" size="3" face="Calibri">rat\r\n sarcoma viral oncogene homolog</font></p><p><font color="#000000" size="3" face="Calibri">Protein family</font><font color="#000000" size="3" face="Calibri"> </font></p></td>\r\n\r\n </tr>\r\n</tbody></table></span></div>

2015-11-15T18:15:43Z

<div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><table border="0" cellpadding="0" cellspacing="0" width="964" style="border-collapse:\r\n collapse;width:723pt"><tbody><tr height="20" style="height:15.0pt">\r\n <td height="20" class="xl65" width="964" style="height:15.0pt;width:723pt">IL2-inducible\r\n T-cell kinase </td></tr></tbody></table></div><span style="font-family: Arial, Verdana; font-size: 10pt;">Tyrosine-protein kinase ITK/TSK</span><div>UniProt ID: Q08881</div><div>Gene Name: ITK</div><div>Gene ID: 3702</div>

2017-05-18T11:48:39Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Protein kinase C theta type</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q04759</span></font></div><div><font face="Georgia"><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Gene Name: PKC</span></font></div><div><font face="Georgia"><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Gene ID: </span></font><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);">100152637</span></div>

2015-11-15T18:15:43Z

<table border="0" cellpadding="0" cellspacing="0" width="964" style="border-collapse:\r\n collapse;width:723pt"><tbody><tr height="20" style="height:15.0pt">\r\n <td height="20" class="xl64" width="964" style="height:15.0pt;width:723pt">c-abl\r\n oncogene 1, non-receptor tyrosine kinase<br/>UniProt ID: <a href="http://www.uniprot.org/uniprot/P00519" 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);">P00519</a><br/>Gene Name: ABL1 <br/>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);">25</span></td></tr></tbody></table>

2015-11-15T18:15:43Z

\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 style="font-family: Arial, Verdana;"><font face="Georgia" size="2"><u>Ligand of T cell receptor (peptide-MHC\r\ncomplex or antibody)</u></font></p><p style="font-family: Arial, Verdana;"><font face="Georgia" size="2">There are multiple ligands that bind to the various T cells. </font></p><p style="font-family: Arial, Verdana;"><font face="Georgia" size="2">Class I peptide-MHC complexes display to and are recognized by CD8+ T cells. Class II peptide MHC complexes are recognized by CD4+ T cells. </font><font face="Georgia" size="2">Class I MHC protein complexes are generated from three genes: HLA-A, HLA-B and HLC-C. The class I molecule consists of two non-covalently linked polypeptide chains: an alpha chain and a beta chain. </font><span style="background-color: rgb(255, 255, 255); font-family: Georgia; font-size: small; line-height: 15.989583969116211px;">Class II MHC protein complexes are a heterodimer held together by non-covalent interactions. These peptides are encoded by three genes.</span></p><p style="font-family: Arial, Verdana;"><font face="Georgia" size="2">Genes encoding MHC class I:</font></p><font face="Arial, Verdana" size="2"></font><ul><li><font face="Georgia"></font><dt class="desig" style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important;">Major histocompatibility complex, class I, A. Official Symbol: </dt><dd class="desig" style="margin: 0px; display: inline; padding: 0px;">HLA-A, NCBI Gene ID: 3105</dd></li><li><font face="Georgia"></font><dt class="desig" style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Major histocompatibility complex, class I, B. Official Symbol: </dt><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-B, NCBI Gene ID: 3106</dd></li><li><font face="Georgia"></font><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);"><span style="line-height: normal;">Major histocompatibility complex, class I, C. </span></dd><dt class="desig" style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-C, NCBI Gene ID: 3107</dd><span style="background-color: rgb(255, 255, 255); line-height: 16px;"> </span></li></ul></div><div class="column" style="font-family: Arial, Verdana;"><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);"><span style="font-family: Georgia; font-size: small; line-height: normal;">Genes encoding MHC class II:</span></dd></div><div class="column" style="font-family: Arial, Verdana;"><ul><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DP, alpha 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DPA1. NCBI Gene ID:3113</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DP, beta 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DPB1. NCBI Gene ID:3115</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DQ, alpha 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DQA1. NCBI Gene ID:3117</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DQ, beta 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DQB1. NCBI Gene ID: 3119</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DR, alpha 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DRA. NCBI Gene ID: 3122</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DR, beta 1. </span><dt class="desig" style="font-family: Georgia; font-size: small; display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; background-color: rgb(255, 255, 255); margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);">HLA-DRB1. NCBI Gene ID: 3123</dd></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DR, beta 3. </span><dd class="desig" style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255); line-height: 16px; margin: 0px; display: inline; padding: 0px;"></dd><dt class="desig" style="display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px;">HLA-DRB3</dd> NCBI Gene ID: 3125</li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DR, beta 4. </span><dd class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); margin: 0px; display: inline; padding: 0px;"></dd><dt class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); margin: 0px; display: inline; padding: 0px;">HLA-DRB4</dd><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"> NCBI Gene ID: 3126</span></li><li><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">Major histocompatibility complex, class II, DR, beta 5. </span><dd class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); margin: 0px; display: inline; padding: 0px;"></dd><dt class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); display: inline; padding: 0px; margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px !important;">Official Symbol: </dt><dd class="desig" style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255); margin: 0px; display: inline; padding: 0px;">HLA-DRB5</dd><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"> NCBI Gene ID: 3127</span></li></ul></div><div class="column" style="font-family: Arial, Verdana;"><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px; background-color: rgb(255, 255, 255);"></dd><dd class="desig" style="margin: 0px; display: inline; padding: 0px; line-height: 16px;"><font face="Georgia" size="2"><br/></font></dd></div><div class="column" style="font-family: Arial, Verdana;"><dd class="desig" style="margin: 0px; display: inline; padding: 0px; font-family: arial, helvetica, clean, sans-serif; font-size: 12px; line-height: 16px; background-color: rgb(255, 255, 255);"></dd><dd class="desig" style="margin: 0px; display: inline; padding: 0px; font-size: 12px; line-height: 16px;"><br/></dd></div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T18:15:43Z

<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 & 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>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Mucosa-associated lymphoid tissue lymphoma translocation protein 1</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q9UDY8</span></font></div>

2015-11-15T18:15:43Z

Bcl-2-like protein 1 (BCL2L1)<div>UniProt Accession ID: Q07817</div><div><br/></div><div>B-cell CLL/lymphoma2 (BCL2)</div><div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P10415" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P10415</a></div>

2015-11-15T18:15:43Z

<font face="Georgia">This is an ambiguous node representing a T cell receptor bound to its ligand [1]. </font>

2015-11-15T18:15:43Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11pt;"><font face="Georgia">Complex of CARD11, CARMA1, and\r\nBCL10, which is their fully active form </font></span></p><p><ul><li><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Caspase recruitment domain-containing protein 11, UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q9BXL7</span></font></li><li><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">B-cell lymphoma/leukemia 10, UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">O95999</span></font></li></ul></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T18:15:43Z 2015-11-15T18:15:43Z

Growth factor receptor-bound protein 2 <div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P62993" 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);">P62993</a></div><div>Gene Name: GRB2</div><div>Gene ID: 2885</div>

2015-11-15T18:15:43Z

<font face="Arial, Verdana" size="2" style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">FYN oncogene related to SRC, FGR, YES</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Arial, Verdana" size="2"><br/></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="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Tyrosine-protein kinase Fyn</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="font-family: sans-serif; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt Accession ID: P06241</span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"> </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="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><br/></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="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);">For more info:</span></div><div><span style="background-color: rgb(255, 255, 255);"><font face="sans-serif">http://www.ncbi.nlm.nih.gov/mesh/68051076</font></span></div>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Mitogen-activated protein kinase kinase kinase kinase 1</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">Q92918</span></font></div>

2015-11-15T18:15:43Z

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Represents a T-cell Receptor phosphorylated [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2015-11-15T18:15:43Z

<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"><font face="Georgia"><span class="RECOMMENDED" style="font-size: small; line-height: 16px;"><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;">E3 ubiquitin-protein ligase CBL</span></span><br style="font-size: small; line-height: 16px;"/><acronym class="names EC" title="Enzyme Commission number." style="border: none; cursor: pointer; padding-left: 1.5em; font-size: small; line-height: 16px;">EC=</acronym><span class="EC_NAME" style="font-size: small; line-height: 16px;"><a href="http://enzyme.expasy.org/EC/6.3.2.-" style="outline: none; color: rgb(79, 79, 79); text-decoration: none;">6.3.2.-</a></span></font></span></p><div class="alternatives" style="font-size: small; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><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">Casitas B-lineage lymphoma proto-oncogene</span></font></div><div class="alternatives" style="font-size: small; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><span class="FULL_NAME"><font face="Georgia"><br/></font></span></div><div class="alternatives" style="font-size: small; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><span class="FULL_NAME">UniProt ID: </span><span style="line-height: normal; font-size: 16px;">P22681</span></font></div><div class="alternatives" style="font-size: small; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);"><br/></div>

2015-11-15T18:15:43Z

<span class="RECOMMENDED" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><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;">Lymphocyte cytosolic protein 2</span></font></span><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">SH2 domain-containing leukocyte protein of 76 kDa</span><br/><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em;"></acronym><span class="FULL_NAME">SLP-76 tyrosine phosphoprotein</span><br/><acronym class="names SHORT" title="Abbreviation of the full name or an acronym." style="border: none; cursor: pointer; padding-left: 2em;">Short name=</acronym><span class="SHORT_NAME">SLP76</span></font></div><div class="alternatives" style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span class="SHORT_NAME">UniProt ID: </span><span style="line-height: normal;">Q13094</span></font></div>

2017-05-18T11:48:39Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Proto-oncogene vav</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);">P15498</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/7409" ref="ordinalpos=2&ncbi_uid=7409&link_uid=7409" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">VAV1</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;">7409</span></font></div>

2017-05-18T11:48:39Z

<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"><p><font size="3" face="Calibri">SH3-domain\r\n binding protein 2</font></p><p> </p></td>\r\n\r\n </tr>\r\n</tbody></table><p>UniProt ID: <a href="http://www.uniprot.org/uniprot/P78314">P78314</a></p><p>Gene Name: SH3BP2</p><p>Gene ID: 6452</p>

2015-11-15T18:15:43Z 2015-11-15T18:15:43Z

<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>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Serum response factor</font></span><div><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P1183</span></font></div>

2015-11-15T18:15:43Z

FBJ murine osteosarcoma viral oncogene homolog <br/><div>UniProt ID: P01100</div><div>Gene Name: FOS</div><div>Gene ID: 2353</div>

2015-11-15T18:15:43Z

<span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">Tyrosine-protein kinase TXK</font></span><div><font face="Georgia"><acronym class="ALTERNATIVE" title="A synonym of the recommended name." style="border: none; cursor: pointer; font-style: italic; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Alternative name(s):</acronym><br style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"/><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"></acronym><span class="FULL_NAME" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Protein-tyrosine kinase 4</span><br style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"/><acronym class="names FULL" style="border: none; cursor: pointer; padding-left: 1em; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);"></acronym><span class="FULL_NAME" style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Resting lymphocyte kinase</span><font size="2"><span style="line-height: 16px;"><br/></span></font></font><div style="font-size: 10pt; line-height: normal;"><font face="Georgia"><span style="font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-size: 16px; background-color: rgb(255, 255, 255);">P42681</span></font></div></div>

2015-11-15T18:15:43Z

<div>Protein Tyrosine Phosphatase, receptor <span style="font-size: 10pt;">type, C</span></div><div><span style="font-size: 10pt;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P08575" 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);">P08575</a></div><div><span style="font-size: 10pt;">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/5788" ref="ordinalpos=1&ncbi_uid=5788&link_uid=5788" 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);">PTPRC</a></div><div><span style="font-size: 10pt;">Gene ID: </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);">5788</span></div><div><br/></div>

2017-05-15T17:22:19Z

2015-11-15T18:15:43Z

\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">Phosphatidylinositol (3,4,5)-trisphosphate</font></p><p><font face="Georgia"><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);">41</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);">103</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">N</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">7</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);"> 1170.185268</span></font></p><p><font face="Georgia">PubChem ID:  <span style="line-height: 19px; background-color: rgb(255, 255, 255);">CID </span><font><span style="line-height: 19px; background-color: rgb(255, 255, 255);"><a href="http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16760614&loc=ec_rcs">16760614</a></span></font></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

2017-05-15T17:30:37Z

<font face="Georgia">Can occur in the cytosol or the mitochondria. </font><div><ul><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Branched-chain-amino-acid aminotransferase, cytosolic, UniProt ID: </span><span style="font-family: Georgia; font-size: 16px; background-color: rgb(255, 255, 255);">P54687</span></li><li><span style="font-family: Georgia; font-size: small; line-height: 16px; background-color: rgb(255, 255, 255);">Branched-chain-amino-acid aminotransferase, mitochondrial. UniProt ID: </span><span style="font-family: Georgia; font-size: 16px; background-color: rgb(255, 255, 255);">O15382</span></li></ul></div>

2015-11-15T18:15:43Z

PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/P42336" 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);">P42336</a></div><div>Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/5290" ref="ordinalpos=1&ncbi_uid=5290&link_uid=5290" style="font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17.9998016357422px; white-space: nowrap; color: rgb(100, 42, 143);">PIK3CA</a></div><div>Gene ID: <span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 12px;">5290</span></div>

2015-11-15T18:15:43Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia">1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1</font></span><div><font face="Georgia"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P19174</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="background-color: rgb(255, 255, 255);">In this model, represents </span><span style="font-size: 11pt;">PLCG1, PLC-\r\n</span><span style="font-size: 12pt;">?</span><span style="font-size: 11pt;">-1 bound to\r\nLAT (but not\r\nactive, see\r\nplcga)</span> [1]. </font></div><div class="page" title="Page 4" style="font-size: 10pt;"><div class="section"><div class="layoutArea"><div class="column"><p><span style="font-size: 11pt;"><font face="Georgia"> </font></span></p></div></div></div></div>

2017-05-18T11:48:39Z

SOS1 = son of sevenless homolog 1 (Drosophila) <div>UniProt ID: <a href="http://www.uniprot.org/uniprot/Q07889" 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);">Q07889</a></div><div>Gene Name: SOS1</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);">6654</span><br/><div><br/></div><div>SOS2 = son of sevenless homolog 2 (Drosophila)</div></div><div><div style="font-size: 13.3333330154419px;">UniProt ID: <a href="http://www.uniprot.org/uniprot/Q07890" 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);">Q07890</a></div><div style="font-size: 13.3333330154419px;">Gene Name: SOS2</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);">6655</span></div></div>

2015-11-15T18:15:43Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Forkhead box protein O1</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);">Q12778</span></font></div><div><font size="2" face="Georgia"><span style="background-color: rgb(255, 255, 255);">Gene Name:</span><a href="http://www.ncbi.nlm.nih.gov/gene/2308" ref="ordinalpos=1&ncbi_uid=2308&link_uid=2308" style="background-color: rgb(255, 255, 255); line-height: 19.999780654907227px; white-space: nowrap; color: rgb(100, 42, 143);">FOXO1</a></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene ID: 2308</span></font></div>

2015-11-15T18:15:43Z

<span style="line-height: 16px; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">Guanine nucleotide exchange factor VAV3</span><div><span style="line-height: 16px; font-family: sans-serif; font-size: small; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><font size="2">Q9UKW4</font></span></div><div><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><font size="2">Gene Name: VAV3</font></span></div><div><span style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><font size="2">Gene ID:</font> <font size="2">10451</font></span></div>

2015-11-15T18:15:43Z

<div><font face="Georgia" size="2">Represents the inhibitor of nuclear factor kappa-B. </font></div><div><font face="Georgia" size="2"><span style="line-height: 16px; background-color: rgb(255, 255, 255);">Inhibitor of nuclear factor kappa-B kinase subunit beta </span></font></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);">O14920</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/4793" ref="ordinalpos=7&ncbi_uid=4793&link_uid=4793" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">NFKBIB</a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">4793</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;"><font face="Georgia" size="2"><br/></font></span></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><span style="font-size: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div style="font-size: 10pt; font-family: Arial, Verdana; font-weight: normal;"><strong style="font-family: sans-serif; font-size: 16px; background-color: rgb(255, 255, 255);"><br/></strong></div>

2015-11-15T18:15:43Z

Transcription factor cAMP response elements (CRE)<div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div>

2015-11-15T18:15:43Z

<font size="2">There are several different individual d<span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">iacylglycerol kinases. </span></font><div><ul><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase alpha, UniProt ID: </span><span style="font-family: sans-serif; background-color: rgb(255, 255, 255);">P23743</span></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase beta, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">Q9Y6T7</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase gamma, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">P49619</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase delta, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">Q16760</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase epsilon, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">P52429</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase zeta, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">Q13574</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase eta, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">Q86XP1</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase theta, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">P52824</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase iota, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">O75912</span></font></font></li><li><font size="2"><span style="font-family: sans-serif; line-height: 16px; background-color: rgb(255, 255, 255);">Diacylglycerol kinase kappa, UniProt ID: </span><font face="sans-serif"><span style="background-color: rgb(255, 255, 255);">Q5KSL6</span></font></font></li></ul></div>

2015-11-15T18:15:43Z

PTEN = phosphatase and tensin homolog<div>UniProt ID: <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: <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>

2017-05-15T17:30:37Z

PDK1\r\n= pyruvate dehydrogenase kinase, isozyme\r\n1<div>UniProt ID: <a href="http://www.uniprot.org/uniprot/O15530" 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);">O15530</a></div><div>Gene Name: PDK1</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);">5163</span></div>

2015-11-15T18:15:43Z 2015-11-15T18:15:43Z

<span style="background-color: rgb(255, 255, 255); line-height: 16px;"><font face="Georgia">Ras-related C3 botulinum toxin substrate 1</font></span><div><font face="Georgia"><span class="FULL" style="padding-left: 1em; line-height: 16px; background-color: rgb(255, 255, 255);">UniProt ID: </span><span style="background-color: rgb(255, 255, 255);">P63000</span></font></div><div><span style="background-color: rgb(255, 255, 255);"><font face="Georgia"><br/></font></span></div><div><font face="Georgia"><span style="background-color: rgb(255, 255, 255);">In this model, rac1p2 represents a </span>Vav-3 dependent pool of rac1 [1]. </font></div>

2015-11-15T18:15:43Z

<span style="line-height: 16px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">Tyrosine-protein phosphatase non-receptor type 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);">Q06124</span></font></div><div><font face="Georgia" size="2"><span style="background-color: rgb(255, 255, 255);">Gene Name: </span><span style="background-color: rgb(255, 255, 255); line-height: 19.49652862548828px;">PTPN11</span></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: 18.88888931274414px;">5781</span></font></div>

2015-11-15T18:15:43Z

<font face="Georgia">Mekk1 and mkk4 each activate jnk [1].</font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">active mekk1 leads to JNK activation[1, 2, 3, 4]. </span></p>\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'"> <br/></span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_53 1 S_7 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Upon Fyn phosphorylation, ccbl can inhibit plcg[30].\r\nThis is one out of 2 mechanisms ccbl is involved in,\r\nand we call it ccblp2 (pool 2, see legend). Since ccbl\r\nmediated inhibition is slower than the early events,\r\n</span><span style="font-size: 12.000000pt; font-family: 'StandardSymL'">t</span><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">=2. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Upon Fyn phosphorylation, </span><span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ccbl can inhibit plcg and activate ccblp2 [1,2]. </span>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: NimbusSanL; font-size: 15px; background-color: rgb(255, 255, 255);">Upon Fyn phosphorylation, </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-family: NimbusSanL; font-size: 15px; background-color: rgb(255, 255, 255);">ccbl can inhibit plcg and activate ccblp2 [1,2]. </span>

S_76 1 S_73 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 14.44444465637207px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">pkb inhibits bad [1,2].  </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">pkb inhibits bad [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_43 1

pag activates csk [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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Phosphorylation of pag allows csk to bind it and become activated [1,2,3].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_23 1

<font face="Georgia">dag activates rasgrp [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">dag causes the cytoplasmic rasgrp1 to move to\r\nthe golgi, where it can act on Golgi associated-\r\nras[1, 2, 3]. Even though pkcth phosphorylates ras-\r\ngrp at t184,[1, 4] we did not include connection pkcth\r\n</span><span style="font-size: 12.000000pt; font-family: 'CMSY10'">! </span><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">rasgrp1 since this effect is not specific to pkcth,\r\nbut general to other pkcs (less well-characterized in\r\nT cells and therefore not included in the model); in-\r\nclusion of this effect would make this step strictly de-\r\npendent on pkcth, which is not the case [1].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_81 1

Mekk1 or mlk3 activate mkk4 [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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">mlk3 phosphorylates and activates mkk4 [1,3].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">mekk1 is able to phosphorylate MKK4 leading to its\r\nactivation[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_55 1 S_53 1

<font face="Georgia">camk4 deactivates cabin1 [1,2].</font>

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">camk4 regulates via phosphorylation nuclear export\r\nof Cabin1; phosphorylation deactivates camk4 [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_35 1

\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"><p><span style="font-family: NimbusSanL; font-size: 15px;">zap70 activates gab2 upon binding to lat and grb2 or gads [1,2,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">zap70 phosphorylates and activates gab2 upon binding to lat and grb2 or gads [1, 2, 3]. </span><span style="font-size: 11pt; font-family: NimbusSanL;">This process must take place after the early events to allow signal propagation, thus </span><span style="font-size: 12pt; font-family: StandardSymL;">t</span><span style="font-size: 11pt; font-family: NimbusSanL;">=2. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">zap70 phosphorylates and activates gab2 upon binding to lat and gads [1, 2, 3]. </span><span style="font-size: 11pt; font-family: NimbusSanL;">This process must take place after the early events to allow signal propagation, thus </span><span style="font-size: 12pt; font-family: StandardSymL;">t</span><span style="font-size: 11pt; font-family: NimbusSanL;">=2. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">zap70 phosphorylates and activates gab2 upon binding to lat and\r\ngrb2 [1, 2, 3]. </span><span style="font-size: 11pt; font-family: NimbusSanL;">This process must take place after the early events to allow signal propagation, thus </span><span style="font-size: 12pt; font-family: StandardSymL;">t</span><span style="font-size: 11pt; font-family: NimbusSanL;">=2. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_59 1 S_16 1 S_20 1 S_72 1 S_16 1 S_20 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of gadd45 is not clear, thus we set an external input to it. Default value is 1. [1].  </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Regulation of gadd45 is not clear, thus we set an\r\nexternal input to it. Default value is 1. [1].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_15 1

ikkg and camk2 activate ikkab [1,2,3,4]. 

\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: 11.000000pt; font-family: 'NimbusSanL'">Phosphorylation by camk2 is required\r\nfor the activation of the kinase subunits ikkalpha and\r\nbeta (ikkab)[1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </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: 11.000000pt; font-family: 'NimbusSanL'">The regulatory molecule ikkg is required\r\nfor the activation of the kinase subunits ikkalpha and\r\nbeta (ikkab) [1, 2, 3, 4].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_29 1 S_57 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Plcga activates ip3 [1]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Active plcga splits pip2 into active ip3 and diacylglycerol [1, 2,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_31 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of card11 is not clear, thus we set an external input to it. Default value is 1. [1].  </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Regulation of card11 is not clear, thus we set an external input to it. Default value is 1. [1].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_15 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="NimbusSanL"><span style="font-size: 15px;">Abl and tcrp activate zap70, while ccblp1 deactivates zap70 and is dominant over the positive regulators [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Active ccbl can degrade zap70 [1]. </span>

<font face="Georgia">zap70 must be bound to tcr to be activated [1,2]. </font>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">abl phosphorylates and thus activates zap70 [1,2]. </span>

S_75 1 S_63 1 S_21 1

<span style="font-family: NimbusSanL; font-size: 15px;">Binding of jun with fos leads to the formation of ap1[1, 2, 3]. </span>

S_83 1 S_46 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">pkb inhibits p27k [1,2,3]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">pkb inhibits p27k [1,2,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_43 1

<span style="font-family: NimbusSanL; font-size: 15px;">erk activates rsk via phosphorylation[1, 2]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">erk activates rsk via phosphorylation[1, 2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_58 1

ZAP70 activates lat [1]. 

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">zap70 phosphorylates lat at different sites and activates it [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_16 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">ccbl binds to activated (and thus phosphorylated)\r\nzap70, leading to the ubiquination and subsequent\r\ndegradation of zap70 and tcr[31]. This is one out\r\nof 2 mechanisms ccbl is involved in, and we call it\r\nccblp1 (pool 1, see legend). Since ccbl mediated\r\ndegradation has to be slower than the early events,\r\n</span><span style="font-size: 12.000000pt; font-family: 'StandardSymL'">t</span><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">=2. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ccbl binds to activated (and thus phosphorylated) zap70. This leads to ubiquination of ZAP70 and tcr, which activates ccblp1 [1,2]. </span>

S_76 1 S_16 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of calpr1 is not clear, thus we set an external input to it. Default value is 0. [1]. </span>

An unknown regulator activates calpr1, and other species in the model. Here this unknown node is represented as unknown_input2 [1]. 

S_66 1

\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: 11.000000pt; font-family: 'NimbusSanL'">Pag is activated by fyn and deactivated by tcrb [1]. Tcrb is dominant over fyn activation [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">upon ligand binding to the tcr, pag is dephosphorylated by an unidentified phosphatase (probably cd45) [1,2]. This deactivates pag [1,2]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">fyn phosphorylates pag [1,3], leading to the binding of\r\ncsk. This process takes place 3-5 min after tcr activation, and thus it belongs to the time scale </span><span style="font-size: 12.000000pt; font-family: 'StandardSymL'">t</span><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">=2[44] [1]. This activates pag [1,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_73 1 S_69 1

<span style="font-family: NimbusSanL; font-size: 15px;">GTP activating proteins (gaps) are important regulators of ras activation but their own regulation is not clear[2]; they are included in the model with an external input. [1].  </span>

An unknown regulator activates gap in the model. Here this unknown node is represented as unknown_input3 [1]. 

S_33 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Regulation of akap79 is not clear, thus we set an external input to it. Default value is 0. [1].  </span>

An unknown input activates this node [1]. 

S_66 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="NimbusSanL"><span style="font-size: 15px;">Cblb is deactivated by cd28 [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-size: 11pt; font-family: NimbusSanL;">cd28 induces cblb ubiquitination and degradation[2] after the early events thus, </span><span style="font-size: 12pt; font-family: StandardSymL;">?</span><span style="font-size: 11pt; font-family: NimbusSanL;">=2. [1]. </span>

S_56 1

\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: 11.000000pt; font-family: 'NimbusSanL'">gadd45 inhibits the zap70 mediated activation of\r\np38[24]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">gadd45 inhibits the zap70 mediated activation of p38 [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">zap70 mediates the activation of p38 [1,2]. </span>

S_16 1 S_11 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">card11a and pkcth activate ikg [1, 2, 3, 4, 5].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The complex card11+bcl10 +malt1 is required for ikkg activation [1, 2, 3, 4]. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Phosphorylation by pkcth is required for activation [1,5]. </span>

S_70 1 S_62 1

<font face="Georgia">Plcga can be activates by itk and plgb and slp76 and vav1 and zap 70, OR plgb and rlk and slp76 and vav1 and zap 70. Plcga has on dominant negative regulator: ccblp2 [1].  </font>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Once bound to phosphorylated lat, plcgb is activated by the combined action of vav and itk (or rlk) [1,2].</span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Once bound to phosphorylated lat, plcgb is activated by the combined action of vav and itk (or rlk) [1,2].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">Once bound to phosphorylated lat, plcgb is activated by the combined action of vav and itk [1,2].</span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Additionally, binding to slp76\r\n(phosphorylated by zap70) is required to establish\r\nand stabilize the complex [1,3].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">Additionally, binding to slp76 (phosphorylated by zap70) is required to establish and stabilize the complex [1,3]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Activated ccbl degrades\r\nplcga [1,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_90 1 S_78 1 S_61 1 S_77 1 S_16 1 S_2 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">cam binds to and activates calcineurin (calcin), while\r\ncabin1, calpr1, akap79 inhibit calcin; negative regulators are dominant over cam [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 14.666666984558105px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">cam binds to and activates calcineurin [1, 2, 3, 4].</span>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">cabin1 binds to and inactivates calcin [1,2,3, 4].</span>

<font face="Georgia">akap79 binds to and inactivates calcin [1,2,3, 4].</font>

<span style="color: rgb(79, 79, 79); font-family: Georgia; font-size: 12.222222328186035px; line-height: 17.98611068725586px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">calpr1 binds to and inactivates calcin [1,2,3, 4].</span>

S_86 1 S_8 1 S_25 1 S_22 1

<font face="Georgia">rsk activates creb [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Rsk phosphorylates creb increasing its activity [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_19 1

<span style="font-family: NimbusSanL; font-size: 15px;">camk2 activation is dependent on calmodulin (cam) activation [1,2]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">camk2 activation is dependent on calmodulin\r\n(cam) activation [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_86 1

<font face="Georgia">ip3 activates calcium [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Binding of ip3 to the ip3 receptor in the endoplasmatic reticulum leads to the release of calcium [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_13 1

<span style="font-family: NimbusSanL; font-size: 15px;">pkb inhibits p27k [1, 2, 3]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">pkb inhibits p27k [1, 2, 3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_43 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="NimbusSanL"><span style="font-size: 15px;">lckp1 and not erk activates shp1 [1,2,3]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">erk phosphorylates lck at p59, protecting it from shp1?s effect. This deactivates shp1 [1,2,3]. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">lck phosphorylates shp1 leading to its activation. </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 11pt; font-family: NimbusSanL;">Since shp1 activation comes some time after lck activation, it takes place at </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 12pt; font-family: StandardSymL;">?</span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 11pt; font-family: NimbusSanL;">=2 [1,2,3]. </span>

S_44 1 S_58 1

<span style="font-family: NimbusSanL; font-size: 15px;">calcineurin dephosphorylates nfat leading to nuclear translocation and activation of nfat [1,2, 3, 4]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">calcineurin dephosphorylates nfat leading to nuclear\r\ntranslocation and activation of nfat [1,2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_32 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Regulation of cdc42 is not clear, thus we set an external input to it. Default value is 0. [1]. </span>

An unknown regulator activates cdc42, and other species in the model. Here this unknown node is represented as unknown_input2 [1]. 

S_66 1

\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: 11.000000pt; font-family: 'NimbusSanL'">Gsk3 inhibits cyc1 [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Gsk3 inhibits cyc1 [1,2]. </span>

S_18 1

<span style="font-family: NimbusSanL; font-size: 15px;">Rac1r and vav1 activate rac1p1 [1]. </span>

<span style="font-family: NimbusSanL; font-size: 15px;">Downregulation of Vav1 but not Vav3 affects IL-2 production in T cells[1,2] via the rac1-mediated jnk pathway. Since rac1 mediates this process, we defined a vav1-dependent pool of rac1 [1]. Rac1r and vav1 activate rac1p1 [1]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Downregulation of Vav1 but not Vav3 affects IL-2\r\nproduction in T cells[1,2] via the rac1-mediated jnk\r\npathway. Since rac1 mediates this process, we defined a vav1-dependent pool of rac1 [1]. Rac1r and vav1 activate rac1p1 [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_54 1 S_78 1

pdk1 activates pkb [1]. 

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pdk1 phosphorylates pkb leading to its activation [1,2,3,4].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_98 1

\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="NimbusSanL"><span style="font-size: 15px;">lckp1 is activated when cd45, cd4, and lckr are all active and shp1 and csk are inactive [1,2]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">Activation of lck depends on autophosphorylation of the positive regulatory site, which cd4-bound lck can perform upon cd4 crosslinking. Thus, a resevoir of lck is required for activation of lck [1,2]. </font></span>

<span style="background-color: rgb(255, 255, 255); color: rgb(79, 79, 79); font-size: 15px; line-height: 18px; orphans: 3; widows: 3;"><font face="Georgia">cd45 must dephosphorylate the negative regulatory site of lck to activate lck [1,2]. </font></span>

<span style="color: rgb(79, 79, 79); font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">Activation of lck depends on autophosphorylation of the positive regulatory site, which cd4-bound lck can perform upon cd4 crosslinking. cd4 is required for activation of lck [1,2]. </font></span>

<font face="Georgia">shp1 is a negative regulator of lck [1,2]. </font>

<span style="color: rgb(79, 79, 79); font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);"><font face="Georgia">csk phosphorylates the negative regulatory site of lck and thus is an inhibitor of lck activation [1,2]. </font></span>

S_85 1 S_50 1 S_5 1 S_4 1 S_38 1

S_90 1 S_78 1 S_61 1 S_77 1 S_16 1 S_2 1

<span style="font-family: NimbusSanL; font-size: 15px;">jnk activates jun[1,2]. </span>

S_1 1

pdk1 activates p70s [1]. 

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pkd1 phosphorylates p70s leading to its\r\nactivation[1,2,3]. [69, 70]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_98 1

\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: 11.000000pt; font-family: 'NimbusSanL'">pkb inhibits p21c [1, 2, 3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">pkb inhibits p21c [1, 2, 3]. </span>

S_43 1

<font face="Georgia">Raf activates mek [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Raf phosphorylates mek leading to mek\r\nactivation[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_99 1

<span style="font-family: NimbusSanL; font-size: 15px;">Input to the system (presence of Lck in the cell). Default value is 1. [1].  </span>

lckr_input positively regulates lckr [1]

S_10 1

\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="NimbusSanL"><span style="font-size: 11pt;">The second\r\npool of lck is </span><span style="font-size: 15px;">activated</span><span style="font-size: 11pt;"> by tcrb and lckr [1]. </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 5">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">second\r\npool of lck (lckp2) which can be activated by tcr activation, but there must be a reservoir of lck (lckr) [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The second pool of lck (lckp2) which can be activated by tcr activation[1,2]. </span>

S_50 1 S_69 1

<font face="Georgia">x is activated by cdc28 [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">cd28 activation activates a non-identified kinase, here represented as x [1, 2, 3, 4]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_56 1

Cdc42, Hpk1 and rac1p2 each activate mekk1 [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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">GTP-bound Rac1p2 is able to bind and activate mekk1[1, 2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The GTP bound cdc42 (and rac1, see hyperarc 87)\r\nis able to bind mekk1[1,2]; CD28 activates mekk1 in\r\na cdc42 mediated manner[1,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">hpk1 binds and phosphorylates mekk1, which activates mekk1 [1,4]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_40 1 S_74 1 S_100 1

<span style="font-family: NimbusSanL; font-size: 15px;">Input to the system (presence of rac1 in the cell). Default value is 1. [1].  </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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Input to the system (presence of rac1 in the cell).\r\nDefault value is 1. [1].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_15 1

<font face="Georgia">hpk1 or rac1p1 activate mlk3 [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">hpk1 binds and phosphorylates mlk3[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_42 1 S_74 1

<font face="Georgia">Ligand_antibody is a positive regulator of CD28 [1].</font>

S_30 1

<span style="font-family: NimbusSanL; font-size: 15px;">cam (calmodulin) activates calmodulin-dependent kinase II (camk2) [1,2].  </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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">cam (calmodulin) activates calmodulin-dependent\r\nkinase II (camk2) [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_86 1

mek activates erk [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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">mekk1 is able to phosphorylate erk leading to its\r\nactivation [1,2, 3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_49 1

lat activates gads [1]. 

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">gads can bind to phosphorylated lat and be activated [1,2,3].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_20 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">sos and rasgrp and NOT gap activates ras [1]. </span></p><p><br/></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">Bound to lat via grb2, sos catalyzes the exchange of GTP for GDP in the cellular-membrane-located ras and thereby activates ras [1,3]. </span>

<span style="font-family: NimbusSanL; font-size: 15px;">Rasgrp1 catalyzes the exchange of GTP for GDP in golgi-located ras [1,3]. </span>

<span style="font-family: NimbusSanL; font-size: 15px;">In turn gap catalyzes the conversion GTP to GDP and thus deactivates ras[1,2]. </span>

S_91 1 S_6 1 S_24 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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Itk is activated by pip3 when slp76 and zap70 are also active [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">When phosphorylated, slp76 can bind to itk; additional binding to pip3 and phosphorylation via zap70 activates itk [1, 2, 3, 4]. </span>

S_87 1 S_77 1 S_16 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Activation of pkcth requires binding to dag, phosphorylation by pdk1, and vav1 [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Activation of pkcth requires phosphorylation by pdk1[1, 2].</span>

S_81 1 S_98 1 S_78 1

<font face="Georgia">fyn or lckp1 activate abl [1]. </font>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">abl kinases are activated following tcr stimulation via a Src kinase (lck or fyn, see hyperarc 59)[1,2]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">abl kinases are activated following tcr stimulation via\r\na Src kinase (lck or fyn, see hyperarc 59)[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_44 1 S_73 1

Ligand_antibody is a positive regulator of tcrlig [1].

S_26 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ikb inhibits nfkb [1,2]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">nfkb is retained in the cytoplasm by tight binding to\r\nthe inhibitory protein ikb; ikb inhibits nfkb [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_94 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of malt1 is not clear, thus we set an external input to it. Default value is 1. [1]</span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Regulation of malt1 is not clear, thus we set an external input to it. Default value is 1. [1]</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_15 1

S_3 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Tcrlig activates tcr. Ccblp1 deactivates tcrb and is dominant over tcrlig [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia">Active ccblp1 ubiquinates tcr, leading to tcr degradation [1,2]. </font>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Binding of tcr ligand activates the tcr [1,2]. </span>

S_64 1 S_21 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The binding of malt1 to card11 and bcl10 forms the\r\nactive card11 complex [1].  </span></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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The binding of malt1 to card11 and bcl10 forms the\r\nactive card11 complex [1,2,3,4,5].</span></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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The binding of malt1 to card11 and bcl10 forms the\r\nactive card11 complex </span><span style="font-family: NimbusSanL; font-size: 15px;">[1,2,3,4,5].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_67 1 S_80 1 S_14 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of ship1 is not clear, thus we set an external input. Default value is 0. [1]. </span>

An unknown regulator activates ship1, and other species in the model. Here this unknown node is represented as unknown_input2 [1]. 

S_66 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">grb2 activates grb2 [1,2,3]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">grb2 (which in turn binds sos) can bind to phosphorylated lat which activates grb2 [1,2,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_20 1

<font face="Georgia">lckp1 activates fyn when cd45 is active or tcrb activates fyn when lckr is active [1]. </font>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">A fraction of fyn is bound to the tcr, and tcr\r\ncrosslinking leads to fyn autophosphorylation and\r\nactivation[1,3]. Since lck is required in the development for having capable fyn[1,4], lckr (existence of\r\nlck in the cell) is required as well. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">lck activates fyn[1,2], a process where the dephosphorylation of the negative regulatory site of fyn by cd45 is also required. </span>

<span style="font-family: NimbusSanL; font-size: 15px;">lck activates fyn[1,2], a process where the dephosphorylation of the negative regulatory site of fyn by cd45 is also required. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">A fraction of fyn is bound to the tcr, and tcr crosslinking leads to fyn autophosphorylation and activation[1,3]. Since lck is required in the development for having capable fyn[1,4], lckr (existence of lck in the cell) is required as well. </span>

S_44 1 S_85 1 S_69 1 S_50 1

<span style="font-family: NimbusSanL; font-size: 15px;">lat activates hpk1 [1].</span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">hpk1 binds to lat and is recruited to the lipid\r\nraftss [1,2]. This activates hpk1. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_20 1

Fyn and tcrb or lckp1 and tcrb activate tcrp [1]. 

<span style="font-family: NimbusSanL; font-size: 15px;">Upon ligand binding to the tcr, active fyn can phosphorylate the tcr and activates it [1,2]. </span>\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The co-localization of tcr with cd4 mediated by\r\npeptide-MHC or antibody crosslinking results in an\r\nincreased local concentration of lck around the tcr\r\nleading to phosphorylation of ITAMs[1,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">The co-localization of tcr with cd4 mediated by peptide-MHC or antibody crosslinking results in an increased local concentration of lck around the tcr leading to phosphorylation of ITAMs[1,3]. </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Upon ligand binding to the tcr, active fyn can phosphorylate the tcr and activates it [1,2]</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_69 1 S_44 1 S_73 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Input to the system (presence of ccbl in the cell).\r\nDefault value is 1. [1]</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">Input to the system (presence of ccbl in the cell). Default value is 1. [1]</span>

S_15 1

\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="NimbusSanL"><span style="font-size: 11pt;">zap70 and gads are required for </span><span style="font-size: 15px;">activation</span><span style="font-size: 11pt;"> of slp76, while gab2 deactivates slp76 and is dominant over both positive regulators [1,2,3,4,5]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<font face="Georgia">zap70 is required for activation of slp76 [1]. </font>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">slp76 associates with lat via gads; this activates slp76 [1, 2, 3].</span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">gab2 competes for binding, and thus inhibits binding of slp76 to gads; this ihibits slp76 [1,4,5]. </span>

S_16 1 S_59 1 S_9 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Vav1 can be activated by active ZAP70 and sh3bp2 or active kinase x [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">zap70 phosphorylates vav1[1, 6] which together with binding of vav1 to sh3bp2[1, 7], leads to vav1 activation. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CD28 stimulation leads to Vav1 activation[1, 2, 3, 4, 5], a process mediated by a yet unidentified kinase (here called x). </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">zap70 phosphorylates vav1[1, 6] which together with\r\nbinding of vav1 to sh3bp2[1, 7], leads to vav1 activation. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_16 1 S_79 1 S_52 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">sh3bp2 is activated by lat and zap70 [1,2]. </span>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">sh3bp2 binds to phosphorylated lat and is activated upon phosphorylation by zap70 [1,2]. </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">sh3bp2 binds to phosphorylated lat and is activated upon phosphorylation by zap70 [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_16 1 S_20 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Regulation of bcl10 is not clear, thus we set an external input to it. Default value is 1. [1]. </span>

An unknown regulator activates bcl10, and other species in the model. Here this unknown node is represented as unknown_input2 [1]. 

S_66 1

\r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="section">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="NimbusSanL"><span style="font-size: 15px;">Plga and not dgk active dag [1,2,3]. </span></font></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 11pt; font-family: NimbusSanL;">The active form of plc </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 12pt; font-family: StandardSymL;">? </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255); font-size: 11pt; font-family: NimbusSanL;">1 (plcga) splits pip2 into diacylglycerol (dag) and ip3, thus pcga activaes dag [1,2]. </span>

dgk degrades dag into phosphatic acid, deactivating dgk [1,3]. 

S_31 1 S_96 1

Cdc42 or rac1p2 activate sre [1]. 

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Vav3-dependent Rac1 is able to activate Sre via\r\nSRF [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">cdc42 is able to activate Sre via SRF [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_100 1 S_40 1

<font face="Georgia">erk activates fos [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">erk phosphorylates fos, thus activating fos [1, 2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_58 1

<font face="Georgia">lckp1 activates rlk [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">lck phosphorylates rlk leading to its activation [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_44 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of cd45 is not clear, thus we set an external input to it. Default value is 1. [1]. </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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">Regulation of cd45 is not clear, thus we set an external input to it. Default value is 1. [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_15 1

<span style="font-family: NimbusSanL; font-size: 15px;">Calcium binds to calmodulin and activates calmodulin [1,2].  </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">Calcium binds to calmodulin and activates calmodulin [1,2].  </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_36 1

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pi3k leads to the production of pip3, while ship1 and\r\npten inhibit this process[1].</span></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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pten inhibits the production of pip3 [1,2,3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pi3k leads to the production of pip3 [1,2,3].</span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">ship1 inhibits the production of pip3 [1,2,3]. </span>

S_89 1 S_97 1 S_71 1

\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: 11.000000pt; font-family: 'NimbusSanL'">Gsk3 inhibits bcat [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Gsk3 inhibits bcat [1,2]. </span>

S_18 1

<font face="Georgia">cblb and lckp2 are activators of pi3k and x is a negative regulator dominant over both cblb and lckp2 [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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pi3k is also activated upon CD28[1, 4, 5] via an\r\nnon-determined kinase x (see hyperarc 48). Even\r\nthough Lck has been proposed to be involved in this\r\nprocess[1, 6, 7, 8, 9], our experiments show that,\r\nat least for primary human T-cells, PI3K activation\r\nis not strictly Src-kinase dependent (see Fig. S4).\r\nA reasonable candidate would be a Tec kinase, but\r\nsince it is not experimentally verified, we keep an\r\nundetermined x [1]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

<span style="font-family: NimbusSanL; font-size: 15px;">cblb promotes pi3k ubiquination (inactivation) [1,3]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pi3k is dependent on the Src kinase lck for\r\nactivation[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_52 1 S_27 1 S_51 1 S_27 1

<font face="Georgia">plcgb is activated by lat [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">plcgamma binds to lat and is activated [1, 2, 3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_20 1

grb2 activates sos [1]. 

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">sos binds to grb2 and thus get recruited to the membrane via lat and be activated [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_72 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">pkb inhibits fkhr [1,2]. </span>

\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: 11.000000pt; font-family: 'NimbusSanL'">pkb inhibits fkhr [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_43 1

<font face="Georgia">sh3bp2 activates vav3 [1]. </font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">sh3bp2 binds vav3 via an sh2 domain, leading to its\r\nactivation [1,2] </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_79 1

<font face="Georgia">ikkab inhibits ikb [1,2,3]. </font>

\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: 11.000000pt; font-family: 'NimbusSanL'">ikb is phosphorylated by ikkab, leading to its\r\nubiquination and subsequent degradation[1, 2, 3]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_12 1

<font face="Georgia">Creb activates cre [1].</font>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">The creb protein is a transcription factor that binds\r\nto cre, activating the related genes[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_34 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">dgks get activated after tcr activation [1]. </span>

\r\n \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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">dgks get activated after tcr activation in yet an unclear manner, we therefore make it dependent on\r\nactivation of the tcr. Since dag must be produced in\r\nthe early events, we assign it a </span><span style="font-size: 12.000000pt; font-family: 'StandardSymL'">t</span><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">=2 [1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_69 1

<span style="font-family: NimbusSanL; font-size: 15px;">Regulation of pten is not clear, thus we set an external input. Default value is 0. [1].  </span>

An unknown regulator activates pten, and other species in the model. Here this unknown node is represented as unknown_input2 [1]. 

S_66 1

<span style="font-family: NimbusSanL; font-size: 15px;">pip3 is required for pdk1 activation[1,2]. </span>

\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><span style="font-size: 11.000000pt; font-family: 'NimbusSanL'">pip3 is required for pdk1 activation[1,2]. </span></p>\r\n </div>\r\n </div>\r\n </div>\r\n </div>

S_87 1

S_60 1

<span style="font-family: NimbusSanL; font-size: 15px;">Downregulation of Vav3 but not Vav1 affects Sre activity[1,2]. Since rac1 mediates this process, we defined a vav3-dependent pool of rac1 [1].   Vav3 and rac1r activate rac1p2 [1]. </span>

S_54 1 S_93 1

<span style="color: rgb(79, 79, 79); font-family: NimbusSanL; font-size: 15px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Gab2 activates shp2 [1]. </span>

S_9 1