Background Despite promising progress in targeted breast cancer therapy, drug resistance remains challenging. The monoclonal antibody drugs trastuzumab and pertuzumab as well as the small molecule inhibitor erlotinib were designed to prevent ErbB-2 and ErbB-1 receptor induced deregulated protein signalling, contributing to tumour progression. The oncogenic potential of ErbB receptors unfolds in case of overexpression or mutations. Dimerisation with other receptors allows to bypass pathway blockades. Our intention is to reconstruct the ErbB network to reveal resistance mechanisms. We used longitudinal proteomic data of ErbB receptors and downstream targets in the ErbB-2 amplified breast cancer cell lines BT474, SKBR3 and HCC1954 treated with erlotinib, trastuzumab or pertuzumab, alone or combined, up to 60 minutes and 30 hours, respectively. In a Boolean modelling approach, signalling networks were reconstructed based on these data in a cell line and time course specific manner, including prior literature knowledge. Finally, we simulated network response to inhibitor combinations to detect signalling nodes reflecting growth inhibition. Results The networks pointed to cell line specific activation patterns of the MAPK and PI3K pathway. In BT474, the PI3K signal route was favoured, while in SKBR3, novel edges highlighted MAPK signalling. In HCC1954, the inferred edges stimulated both pathways. For example, we uncovered feedback loops amplifying PI3K signalling, in line with the known trastuzumab resistance of this cell line. In the perturbation simulations on the short-term networks, we analysed ERK1/2, AKT and p70S6K. The results indicated a pathway specific drug response, driven by the type of growth factor stimulus. HCC1954 revealed an edgetic type of PIK3CA-mutation, contributing to trastuzumab inefficacy. Drug impact on the AKT and ERK1/2 signalling axes is mirrored by effects on RB and RPS6, relating to phenotypic events like cell growth or proliferation. Therefore, we additionally analysed RB and RPS6 in the long-term networks. Conclusions We derived protein interaction models for three breast cancer cell lines. Changes compared to the common reference network hint towards individual characteristics and potential drug resistance mechanisms. Simulation of perturbations were consistent with the experimental data, confirming our combined reverse and forward engineering approach as valuable for drug discovery and personalised medicine. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2015-02-17T14:00:12Z 2016-01-22T07:08:46Z

Drug pertuzumab

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Drug trastuzumab

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Drug erlotinib

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

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MAPK11 = mitogen-activated protein kinase 11&nbsp;<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q15759" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">Q15759</a></div><div>Gene Name: MAPK11</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">&nbsp;</span><span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5600</span></div><div><br/><div>MAPK12 = mitogen-activated protein kinase 12&nbsp;</div><div><div style="font-size: 13.3333330154419px;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P53778" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P53778</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK12</div><div style="font-size: 13.3333330154419px;">Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">6300</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>MAPK13 = mitogen-activated protein kinase 13&nbsp;</div><div><div style="font-size: 13.3333330154419px;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/O15264" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">O15264</a></div><div style="font-size: 13.3333330154419px;">Gene Name: MAPK13</div><div style="font-size: 13.3333330154419px;">Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5603</span></div></div><div style="font-size: 13.3333330154419px;"><br/></div><div>MAPK14 = mitogen-activated protein kinase 14</div></div><div><div style="font-size: 13.3333330154419px;">UniProt ID:</div><div style="font-size: 13.3333330154419px;">Gene Name:</div><div style="font-size: 13.3333330154419px;">Gene ID:</div></div>

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<div>G2/mitotic-specific cyclin-B1</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P14635" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">P14635</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene Name:&nbsp;<a href="http://www.ncbi.nlm.nih.gov/gene/891" ref="ordinalpos=1&amp;ncbi_uid=891&amp;link_uid=891" style="color: rgb(100, 42, 143); font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17.9998016357422px; white-space: nowrap; background-color: rgb(213, 222, 227);">CCNB1</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">891</span></div>

 2015-11-15T20:56:32Z 2015-11-15T20:56:32Z

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

 2015-11-15T20:56:32Z

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

 2015-11-15T20:56:32Z

Proline-rich AKT1 substrate 1<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q96B36" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">Q96B36</a></div><div>Gene Name:&nbsp;<a href="http://www.ncbi.nlm.nih.gov/gene/84335" ref="ordinalpos=1&amp;ncbi_uid=84335&amp;link_uid=84335" style="color: rgb(100, 42, 143); font-family: arial, helvetica, clean, sans-serif; font-size: 13px; line-height: 17.9998016357422px; white-space: nowrap; background-color: rgb(213, 222, 227);">AKT1S1</a></div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">84335</span></div>

 2015-11-15T20:56:32Z

40S ribosomal protein S6<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P62753" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">P62753</a></div><div>Gene Name: RPS6</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">6194</span></div><br><br>null

 2015-11-15T20:56:32Z

Retinoblastoma 1<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P06400" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(255, 255, 255);">P06400</a></div><div>Gene Name: RB1</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5925</span></div>

 2015-11-15T20:56:32Z

<p style="orphans: 3; widows: 3; line-height: 1.5em; margin: 0.4em 0px 0.5em; color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; background-color: rgb(255, 255, 255);"><span id="parentSpecies:viewSpeciesDescription"><span style="line-height: 16px;"><font face="Georgia" size="2">Epidermal growth factor receptor</font></span></span></p><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">UniProt ID:&nbsp;</span>P00533</font></div><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><span style="line-height: 16px;"><font face="Georgia" size="2">Gene Name: EGFR</font></span></div><div style="font-size: 12px; color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2"><span style="line-height: 16px;">Gene ID:&nbsp;</span><span style="line-height: 18.8888893127441px;">1956</span></font></div>

 2015-11-15T20:56:32Z

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

 2015-11-15T20:56:32Z

<div>RAF proto-oncogene serine/threonine-protein kinase aka&nbsp;proto-oncogene c-RAF</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P04049" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P04049</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene Name: RAF1</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5894</span></div>

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

 2015-11-15T20:56:32Z

TP53 = tumor protein p53<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P04637" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P04637</a></div><div>Gene Name: TP53</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">7157</span></div>

 2015-11-15T20:56:32Z 2015-11-15T20:56:32Z

Mitogen-activated protein kinase 3 (ERK1)<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P27361" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P27361</a><br/>Gene Name: MAPK1</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5594</span></div><div><span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);"><br/></span></div><div>Mitogen-activated protein kinase 1 (ERK2)</div><div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P28482" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P28482</a></div><div>Gene Name: MAPK1&nbsp;</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5594</span></div>

 2015-11-15T20:56:32Z

\r\n \r\n \r\n \r\n <div class="page" title="Page 1">\r\n <div class="layoutArea">\r\n <div class="column">\r\n <p><font face="Georgia" size="2">v-jun sarcoma virus 17\r\noncogene homolog</font></p><p><span style="font-family: Georgia; font-size: small;">UniProt ID:&nbsp;</span><span style="font-family: Georgia; font-size: small; background-color: rgb(255, 255, 255);">P05412</span></p><p><font face="Georgia" size="2">Gene Name: JUN</font></p><p><font face="Georgia" size="2">Gene ID:&nbsp;<span style="background-color: rgb(255, 255, 255); line-height: 18.88888931274414px;">3725</span></font></p>\r\n </div>\r\n </div>\r\n </div>

 2015-11-15T20:56:32Z

PTEN = phosphatase and tensin homolog<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/P60484" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">P60484</a></div><div>Gene Name: PTEN</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">5728</span></div>

 2015-11-15T20:56:32Z

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

 2015-11-15T20:56:32Z

FoxO1 mutant 3a<div>UniProt ID:&nbsp;<a href="http://www.uniprot.org/uniprot/Q12778" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: Verdana, Arial, sans-serif; font-size: 13.0571994781494px; line-height: 20.081974029541px; background-color: rgb(222, 239, 245);">Q12778</a><br/><div>Gene Name: FoxO1</div><div>Gene ID:&nbsp;<span style="color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; font-size: 11.6999998092651px; line-height: 16.199821472168px; background-color: rgb(213, 222, 227);">2308</span></div></div>

 2015-11-15T20:56:32Z

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

 2015-11-15T20:56:32Z 2015-11-15T20:56:32Z

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p38 positively regulates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT activates p38 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT activates p38 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p38 positively regulates itself [1]</span>

 S_1 1 S_5 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Cyclin B1 self-activates [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p53 inhibits CyclinB1 [1, 2].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p53 inhibits CyclinB1 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Cyclin B1 self-activates [1]</span>

 S_3 1 S_16 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">TSC2 positively regulates itself [1]. RB positively regulates TSC2 [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">GSK3a_b inhibits TSC2 [1, 2].</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT inhibits TSC2 [1, 2, 3].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 inhibits TSC2 [1, 4].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">TSC2 positively regulates itself [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 inhibits TSC2 [1, 4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT inhibits TSC2 [1, 2, 3]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">GSK3a_b inhibits TSC2 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">RB positively regulates TSC2 [1]</span>

 S_10 1 S_18 1 S_19 1 S_5 1 S_4 1 S_18 1 S_19 1 S_5 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT positively regulates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CyclinB1 positively regulates Akt [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB1 activates Akt [1, 2, 3].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB2 activates Akt [1, 4, 5, 6, 7, 8].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB3 activates Akt [1, 7, 8, 9, 10].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PTEN inhibits Akt [1, 11]</span>

ERBB2 activates Akt [1, 4, 5, 6, 7, 8]

AKT positively regulates itself [1]

ERBB3 activates Akt [1, 7, 8, 9, 10]

ERBB1 activates Akt [1, 2, 3]

CyclinB1 activates Akt and contributes to PI3K signaling [1]

PTEN inhibits Akt [1, 11]

 S_12 1 S_21 1 S_5 1 S_21 1 S_3 1 S_21 1 S_6 1 S_21 1 S_11 1 S_21 1

<span style="orphans: 3; widows: 3;">ERBB3 positively regulates itself [1]. Stimulus positively regulates ERBB3 [1].&nbsp;</span><span style="orphans: 3; widows: 3;">RPS6 positively regulates ERBB3 [1]. Erlotinib inhibits ERBB3 [1, 2, 3].&nbsp;</span><span style="orphans: 3; widows: 3;">Pertuzumab inhibits ERBB3 [1, 4].</span>

<span style="font-family: 'Times New Roman'; font-size: medium; orphans: 3; widows: 3;">RPS6 positively regulates ERBB3 [1]</span>

<span style="font-family: 'Times New Roman'; font-size: medium; orphans: 3; widows: 3;">ERBB3 positively regulates itself [1]</span>

<span style="font-family: 'Times New Roman'; font-size: medium; orphans: 3; widows: 3;">Pertuzumab inhibits ERBB3 [1, 4]</span>

<span style="font-family: 'Times New Roman'; font-size: medium; orphans: 3; widows: 3;">Erlotinib inhibits ERBB3 [1, 2, 3]</span>

<span style="font-family: 'Times New Roman'; font-size: medium; orphans: 3; widows: 3;">Stimulus positively regulates ERBB3 [1]</span>

 S_17 1 S_13 1 S_2 1 S_9 1 S_13 1 S_2 1 S_6 1 S_13 1 S_2 1

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

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

cJUN activates PRAS [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PRAS positively regulates itself [1]</span>

 S_8 1 S_5 1 S_20 1 S_5 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">RPS6 activates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">p70s6k activates RPS6 [1, 2].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">RPS6 activates itself [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p70s6k activates RPS6 [1, 2]</span>

 S_22 1 S_9 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">RB activates itself [1]. p53</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;activates Rb [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CyclinD1 inhibits Rb [1, 2].</span>

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

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

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CyclinD1 inhibits Rb [1, 2]</span>

 S_16 1 S_3 1 S_10 1 S_3 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB1 positively regulates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">cJUN positively regulates ERBB1 [1]. ErbB3</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;positively regulates ERBB1 [1].</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">&nbsp;Stimulus activates ERBB1 [1]. Erlotinib inhibits ERBB1 [1, 2]. Pertuzumab inhibits ERBB1 [1, 3, 4].</span>

<span style="font-size: 13.3333330154419px;">ERBB3 positively regulates ERBB1 [1]</span>

cJUN positively regulates ERBB1 [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB1 positively regulates itself [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug pertuzumab inhibits ERBB1 [1, 3, 4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Erlotinib inhibits ERBB1 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Stimulus activates ERBB1 [1]</span>

 S_11 1 S_2 1 S_13 1 S_20 1 S_2 1 S_13 1 S_17 1 S_2 1 S_13 1 S_6 1 S_2 1 S_13 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB2 positively regulates itself [1]. Stimulus positively regulates ERBB2 [1]. Erlotinib inhibits ERBB2 [1, 2, 3]. Pertuzumab inhibits ERBB2 [1, 4]. Trastuzumab inhibits ERBB2 [1, 4].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERBB2 positively regulates itself [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug pertuzumab inhibits ERBB2 [1, 4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug erlotinib inhibits ERBB2 [1, 2, 3]</span>

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

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">The drug trastuzumab inhibits ERBB2 [1, 4]</span>

 S_12 1 S_7 1 S_2 1 S_13 1 S_17 1 S_7 1 S_2 1 S_13 1

<span style="font-size: 13.3333330154419px;">cRAF activates itself [1].&nbsp;</span><span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERBB1 activates cRAF [1, 3, 4].&nbsp;</span><span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERBB2 activates cRAF [1, 3, 4, 5].&nbsp;</span><span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERK1_2 inhibits cRAF [1, 2].</span>

<span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERBB2 activates cRAF [1, 3, 4, 5]</span>

<span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERK1_2 inhibits cRAF [1, 2].</span>

<span style="font-size: 13.3333330154419px; orphans: 3; widows: 3;">ERBB1 activates cRAF [1, 3, 4]</span>

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

 S_12 1 S_19 1 S_11 1 S_19 1 S_14 1 S_19 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Nfkb positively regulates itself [1].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Nfkb positively regulates itself [1]</span>

 S_15 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">CyclinB1 activates p53 [1, 2].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">p38activates p53 [1, 3].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">p53 activates itself [1]</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 18px; orphans: 3; widows: 3; font-size: 13.3333330154419px; background-color: rgb(255, 255, 255);">RB activates p53 [1, 4].&nbsp;</span>

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

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">RB activates p53 [1, 4]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Cyclin B1 positively regulates p53 [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p38 activates p53 [1, 3]</span>

 S_10 1 S_16 1 S_1 1 S_3 1

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

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

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

 S_16 1 S_18 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 positively regulates itself [1]. cRAF positively regulates ERK1_2 [1, 2, 3].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ErbB-1 drives activation of ERK1/2 [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 self-regulates [1]</span>

ErbB-1 drives activation of ERK1/2 [1]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">cRAF positively activates ERK1_2 [1, 2, 3]</span>

 S_19 1 S_14 1 S_11 1

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

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

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

 S_20 1 S_18 1

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

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

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PTEN positively regulates itself [1]</span>

cRAF activates PTEN [1]

 S_14 1 S_18 1 S_21 1 S_18 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p70s6k regulates itself [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 positively regulates p70s6k [1, 2].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PRAS inhibits p70s6k [1, 3, 4].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">TSC2 inhibits p70s6k [1, 5]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">TSC2 inhibits p70s6k [1, 5]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 positively regulates p70s6k [1, 2]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p70s6k regulates itself [1]</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">PRAS inhibits p70s6k [1, 3, 4]</span>

 S_22 1 S_4 1 S_8 1 S_19 1 S_4 1 S_8 1

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

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

<span style="font-size: 13.3333330154419px;">FoxO1_3a self-regulates [1]</span>

 S_23 1 S_5 1

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

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

 S_24 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Cyclin D self-regulates [1].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">AKT activates CyclinD1 [1, 2, 3].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 positively regulates CyclinD1 [1, 4].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">p70S6K activates CyclinD1 [1, 5].&nbsp;</span><span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">cJUN activates CyclinD1 [1, 6].</span>

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">ERK1_2 positively regulates CyclinD1 [1, 4]</span>

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

cJUN activates CyclinD1 [1, 6]

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 13.3333330154419px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Cyclin D self-regulates [1]</span>

p70S6K activates CyclinD1 [1, 5]

 S_25 1 S_19 1 S_20 1 S_5 1 S_22 1