T cell large granular lymphocyte (T-LGL) leukemia features a clonal expansion of antigen-primed, competent, cytotoxic T lymphocytes (CTL). To systematically understand signaling components that determine the survival of CTL in T-LGL leukemia, we constructed a T-LGL survival signaling network by integrating the signaling pathways involved in normal CTL activation and the known deregulations of survival signaling in leukemic T-LGL. This network was subsequently translated into a predictive, discrete, dynamic model. Our model suggests that the persistence of IL-15 and PDGF is sufficient to reproduce all known deregulations in leukemic T-LGL. This finding leads to the following predictions: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NF?B are essential for the long-term survival of CTL in T-LGL leukemia. (iii) NF?B functions downstream of PI3K and prevents apoptosis through maintaining the expression of myeloid cell leukemia sequence 1. (iv) T box expressed in T cells (T-bet) should be constitutively activated concurrently with NF?B activation to reproduce the leukemic T-LGL phenotype. We validated these predictions experimentally. Our study provides a model describing the signaling network involved in maintaining the long-term survival of competent CTL in humans. The model will be useful in identifying potential therapeutic targets for T-LGL leukemia and generating long-term competent CTL necessary for tumor and cancer vaccine development. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2013-06-26T11:38:44Z 2017-05-15T16:34:31Z

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);">External activator in the 2008 T-LGL Survival Signaling Network</span>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

External Activator in the 2008 T-LGL Survival Signaling Network

2015-11-15T18:16:28Z

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>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">small mothers against </font><span style="font-family: Arial, Verdana; font-size: small;">decapentaplegic 2</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/Q15796" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">Q15796</a></div><div><br/></div><div><div><font face="Arial, Verdana" size="2">small mothers against </font><span style="font-family: Arial, Verdana; font-size: small;">decapentaplegic 3</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P84022" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">P84022</a></div></div><div><br/></div><div>(MAPK Network [1])</div><div><div>SMAD family member 4</div><div><font face="Arial, Verdana" size="2">small mothers against </font><span style="font-family: Arial, Verdana; font-size: small;">decapentaplegic 4</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/Q13485" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">Q13485<br/></a></div></div><div><div>Gene Name: SMAD4</div><div>Gene ID: 4089</div></div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">sphingosine kinase 1</font><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/Q9NYA1" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">Q9NYA1</a></div><div><br/></div><div>Fore more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/67022648</div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Ceramide, a small molecule</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">for more info:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68002518</font></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">cytotoxic T-lymphocyte-associated </font><span style="font-family: Arial, Verdana; font-size: small;">protein 4</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P16410" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P16410</a></div><div>Gene Name: CTLA4</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);">1493</span></div><div><span style="font-family: Arial, Verdana; font-size: small;"><br/></span></div><div><span style="font-family: Arial, Verdana; font-size: small;">For more info:</span></div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/67556706</font></div>

2015-11-15T18:16:28Z

<font style="font: 10pt/normal Arial, Verdana;" size="2" face="Georgia"><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">Zeta-chain (</span><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);" class="highlight">TCR</span><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">) associated protein kinase 70kDa [</span><em style="line-height: 17.99px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">(human)]</span></font><div style="font: 10pt/normal Arial, Verdana;"><font size="2" face="Georgia"><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a style="text-decoration: none; background-color: rgb(255, 255, 255);" href="http://www.uniprot.org/uniprot/Q6ISU1">Q6ISU1</a></font></div><div style="font: 10pt/normal Arial, Verdana;"><font size="2" face="Georgia"><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">Gene Name: </span><a style="line-height: 17.99px; white-space: nowrap; background-color: rgb(255, 255, 255);" href="http://www.ncbi.nlm.nih.gov/gene/7535" ref="ordinalpos=9&ncbi_uid=7535&link_uid=7535">ZAP70</a></font></div><div style="font: 10pt/normal Arial, Verdana;"><font size="2" face="Georgia"><span style="line-height: 17.99px; background-color: rgb(255, 255, 255);">NCBI Gene ID: </span><span style="line-height: 16.19px; background-color: rgb(255, 255, 255);">7535</span></font></div><div style="font: 10pt/normal Arial, Verdana;"><font size="2" face="Georgia"><span style="line-height: 16.19px; background-color: rgb(255, 255, 255);"><br></span></font></div><div><font style="font: 10pt/normal Arial, Verdana;" size="2" face="Georgia"><span style="line-height: 16.19px; background-color: rgb(255, 255, 255);">T Cell Receptor complex </span></font><font size="2" face="Georgia"><span style="line-height: 16.19px;"> coreceptors in CD8 </span></font><span style="line-height: 16.19px; font-family: Georgia; font-size: small;">cells</span></div><div><font style="font: 10pt/normal Arial, Verdana;" size="2" face="Georgia"><span style="line-height: 16.19px; background-color: rgb(255, 255, 255);">For more info: </span></font><font size="2" face="Georgia"><span style="line-height: 16.19px;"><a href="http://www.ncbi.nlm.nih.gov/mesh/68019672">http://www.ncbi.nlm.nih.gov/mesh/68019672</a></span></font></div><div><font size="2" face="Georgia"><span style="line-height: 16.19px;"></span></font> </div><div><font size="2" face="Georgia"><span style="line-height: 16.19px;">For [1]:</span></font></div><div><font size="2" face="Georgia"><span style="line-height: 16.19px;"><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: 30pt;" height="40">\r\n\r\n <td style="border: 0px black; width: 723pt; height: 30pt; background-color: transparent;" class="xl66" height="40" width="964"><font size="3" face="Calibri">T-cell\r\n receptor complex (TCR?,?, CD3?,?,?,?) The TCR comprises an ab heterodimer\r\n that confers antigen recognition and specificity and the associated,\r\n non-polymorphic polypeptides that constitute the CD3 complex (g, d, e, and\r\n the disulfide linked z-z chains).</font></td>\r\n\r\n </tr>\r\n</tbody></table></span></font></div>

2015-11-15T18:16:28Z

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>

2015-11-15T18:16:28Z

Cell Event [1]

2015-11-15T18:16:28Z

<div>Formation of the interleukin 2 low <span style="font-size: 10pt;">affinity receptor complex with </span><span style="font-size: 10pt;">interleukin 2 receptor, beta, gamma, </span><span style="font-size: 10pt;">also response to interleukin 15</span></div><div><span style="font-size: 10pt;">UniProt Accession ID: </span><a href="http://www.uniprot.org/uniprot/P14784" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P14784</a></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">Fas (TNF receptor superfamily, member </font><span style="font-family: Arial, Verdana; font-size: small;">6)</span></div>

2015-11-15T18:16:28Z

<font face="Georgia" size="2" style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Cytokine inducible SH2-containing 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);"> (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: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/O15524" style="text-decoration: none; background-color: rgb(255, 255, 255);">O15524</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">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/1154" ref="ordinalpos=1&ncbi_uid=1154&link_uid=1154" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);">CISH</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">NCBI Gene ID: 1154</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"><br/></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">For Survival Signaling 2008 and 2011:</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"><br/></font></div><div><font face="Georgia" size="2"></font><div>SOCS1 suppressor of cytokine signaling 1</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/O15524" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">O15524</a></div><div><br/></div><font face="Georgia" size="2"></font><div>SOCS2 suppressor of cytokine signaling 2</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/O14508" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">O14508</a></div><font face="Georgia" size="2"></font><div><br/></div><div>SOCS3 suppressor of cytokine signaling 3</div><div>UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/O14543" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">O14543</a></div><div><br/></div><div>For more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/68050826</div></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">T cell activation </font><span style="font-family: Arial, Verdana; font-size: small;">signal stimulation</span></div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

<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>

2017-05-15T16:29:58Z

<div><font face="Georgia" size="2">Sphingosine-1-phosphate</font></div><div><font face="Georgia" size="2">PubChem ID: <a name="cid2entrez" href="http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pccompound&term=5283560[uid]" style="border: 0px; outline: 0px; line-height: 19px; vertical-align: baseline; margin: 0px; padding: 0px; text-decoration: none; background-color: rgb(255, 255, 255);">5283560</a></font></div><div><font face="Georgia" size="2"><span style="border: 0px; outline: 0px; line-height: 17px; vertical-align: baseline; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">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);">18</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);">38</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">NO</span><sub style="border: 0px; outline: 0px; line-height: 0; margin: 0px; padding: 0px; background-color: rgb(255, 255, 255);">5</sub><span style="line-height: 17px; background-color: rgb(255, 255, 255);">P   </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);"> 379.471782</span></font></div>

2015-11-15T18:16:28Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Mitogen-activated protein kinase kinase kinase 8 [</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);"> (human)]</span><br/></font><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P41279" style="text-decoration: none; background-color: rgb(255, 255, 255);">P41279</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/1326" ref="ordinalpos=1&ncbi_uid=1326&link_uid=1326" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">MAP3K8</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 1326</font></div>

2015-11-15T18:16:28Z

<div><font face="Georgia" size="2"><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">BH3 interacting domain death agonist [</span><em style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span></font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P55957" style="text-decoration: none; background-color: rgb(255, 255, 255);">P55957<br/></a><font>Gene Name: </font><a href="http://www.ncbi.nlm.nih.gov/gene/637" ref="ordinalpos=1&ncbi_uid=637&link_uid=637" style="color: rgb(100, 42, 143); line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">BID</span></a></font></div><div><font face="Georgia" size="2">Gene ID: 637</font></div>

2015-11-15T18:16:28Z

G protein coupled receptors<div>(mouse) UniProt AccessionID: <a href="http://www.uniprot.org/uniprot/P35413" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P35413</a></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">transcript of Fas (TNF receptor </font><span style="font-family: Arial, Verdana; font-size: small;">superfamily, member 6)</span></div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Caspase3, Apoptosis cysteine related peptidase</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P42574" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P42574</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Caspase8, Apoptosis cysteine related peptidase</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/Q14790" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">Q14790</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">For more info on Caspase3:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68053148</font></div><div><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;">For more info on Caspase8:</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">http://www.ncbi.nlm.nih.gov/mesh/68053181</div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">transcript of interferon, gamma</font>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Janus kinase 1 (a protein tyrosine kinase)</font><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/P23458" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P23458</a></div><div><br/></div><div><font face="Arial, Verdana">Janus kinase 2 (a protein tyrosine kinase)</font><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/O60674" style="font-size: 10pt; text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">O60674</a></div></div><div><br/></div><div><font face="Arial, Verdana" size="2">Janus kinase 3 (a protein tyrosine kinase)</font></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P52333" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">P52333</a></div>

2015-11-15T18:16:28Z

<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">Tumor necrosis factor, alpha-induced protein 3</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">UniProt Accession ID: P21580</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">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/7128" ref="ordinalpos=3&ncbi_uid=7128&link_uid=7128" style="line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);">TNFAIP3</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">Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">7128</span></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="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;"><br/></span></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="background-color: rgb(255, 255, 255); line-height: 17.999801635742188px;">For more info:</span></font></div><div><span style="background-color: rgb(255, 255, 255); line-height: 17.9998016357422px;"><font face="Georgia" size="2">http://www.ncbi.nlm.nih.gov/mesh/67076529</font></span></div>

2015-11-15T18:16:28Z

<div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Fas (TNF receptor superfamily, member <span style="font-size: 10pt;">6)</span></div><div><span style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">Uniprot ID: </span><font face="Arial, Verdana" size="2">P25445</font></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">transcript of interleukin 2 receptor, beta; </font><span style="font-family: Arial, Verdana; font-size: small;">presence of the interleukin 2 low affinity </span><span style="font-family: Arial, Verdana; font-size: small;">receptor complex; also response to </span><span style="font-family: Arial, Verdana; font-size: small;">interleukin 15</span></div>

2015-11-15T18:16:28Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Granzyme B (granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1) [</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);"> (human)]</span><br/></font><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Uniprot AccessionID: <a href="http://www.uniprot.org/uniprot/P10144" style="text-decoration: none; background-color: rgb(255, 255, 255);">P10144</a></font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/3002" ref="ordinalpos=1&ncbi_uid=3002&link_uid=3002" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">GZMB</span></a></font></div><div style="font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><font face="Georgia" size="2">NCBI Gene ID: 3002</font></div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Phospholipase C, gamma 1</font><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/Q4LE43" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">Q4LE43</a></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;"><br/></div><div style="font-family: Arial, Verdana; font-size: 10pt; font-style: normal; font-variant: normal; font-weight: normal; line-height: normal;">For more info:</div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/67522157</font></div>

2017-05-15T16:29:58Z

Cell death

2015-11-15T18:16:28Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Interleukin 2 [</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);"> (human)]</span></font><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P60568" style="text-decoration: none; background-color: rgb(255, 255, 255);">P60568</a></font></div><div><font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Gene Name: </span><a href="http://www.ncbi.nlm.nih.gov/gene/3558" ref="ordinalpos=1&ncbi_uid=3558&link_uid=3558" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">IL2</span></a></font></div><div><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);"><font face="Georgia" size="2">NCBI Gene ID: 3558</font></span></div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">transcript of interleukin 2 recoptor, alpha</font>

2017-05-15T16:34:31Z

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>

2015-11-15T18:16:28Z

<font face="Georgia" size="2"><span style="line-height: 17.999801635742188px; background-color: rgb(255, 255, 255);">Interferon, gamma [</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);">(human)]</span><br/></font><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P01579" style="text-decoration: none; background-color: rgb(255, 255, 255);">P01579</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/3458" ref="ordinalpos=2&ncbi_uid=3458&link_uid=3458" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">IFNG</span></a></font></div><div><font size="2" face="Georgia">NCBI Gene ID: 3458</font></div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">FLICE </font><span style="font-family: Arial, Verdana; font-size: small;">inhibitory protein/</span><font face="Arial, Verdana" size="2"> CASP8 and FADD-like apoptosis </font><span style="font-family: Arial, Verdana; font-size: small;">regulator</span></div><div><span style="font-family: Arial, Verdana; font-size: small;"><br/></span></div><div><span style="font-family: Arial, Verdana; font-size: small;"><br/></span></div><div><span style="font-family: Arial, Verdana; font-size: small;">For more info: </span></div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68053446</font></div>

2015-11-15T18:16:28Z

<font face="Georgia"><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">TNFRSF1A-associated via death domain [</span><em style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);">Homo sapiens</em><span style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; background-color: rgb(255, 255, 255);"> (human)]</span><br/></font><div><font face="Georgia"><font size="2">UniProt Accession ID: </font><a href="http://www.uniprot.org/uniprot/Q15628" style="font-size: small; text-decoration: none; background-color: rgb(255, 255, 255);">Q15628</a></font></div><div><font face="Georgia">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/8717" ref="ordinalpos=1&ncbi_uid=8717&link_uid=8717" style="font-size: 13.333333969116211px; line-height: 19.999780654907227px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">TRADD</span></a></font></div><div><font face="Georgia">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); font-size: 12.222222328186035px; line-height: 17.999801635742188px;">8717</span></font></div>

2015-11-15T18:16:28Z

<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);">Indication of the cellular activities</span>

2015-11-15T18:16:28Z

<font size="2" style="font-style: normal;" face="Georgia">baculoviral IAP repeat-containing 2 (BIRC2)</font><div style="font-style: normal;"><font face="Georgia"><font size="2">UniProt Accession ID: Q13490</font><font size="2"><br/></font></font><div><font size="2" face="Georgia"><br/></font></div><div><font face="Georgia" size="2">baculoviral IAP repeat-containing 3 (BIRC3)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: Q13489</font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">baculoviral IAP repeat-containing 4 (BIRC4)</font></div></div><div style="font-style: normal;"><font face="Georgia" size="2">UniProt Accession ID: P98170</font></div><div style="font-style: normal;"><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">In the <em>Apoptosis Network</em>, IAP represents inhibitors of apoptosis [1].</font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">In Survival Signaling 2008 and 2011, IAP represents inhibitors of apoptosis.</font></div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

tumor necrosis factor (TNF superfamily, member 2)<div>UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P01375" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P01375</a></div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">myeloid cell leukemia sequence 1 </font><span style="font-family: Arial, Verdana; font-size: small;">(BCL2-related)</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/Q07820" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">Q07820</a></div><div><br/></div><div>For more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/67579095</div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">CCL5 chemokine (C-C motif) ligand 5 RANTES Overexpression; elevation in patient sera 9</font></div><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/P13501" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P13501</a></div><div><br/></div><div><font face="Arial, Verdana" size="2">CCL3 chemokine (C-C motif) ligand 3 MIP-1-alpha</font></div><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/P10147" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P10147</a></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana" size="2">CCL4 chemokine (C-C motif) ligand 4 MIP-1-beta</font></div><div><font face="Arial, Verdana" size="2">UniProt AccessionID: </font><a href="http://www.uniprot.org/uniprot/P13236" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">P13236</a></div><div><br/></div><div>For more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/68018946</div>

2015-11-15T18:16:28Z

<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>

2015-11-15T18:16:28Z

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>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Death inducing signaling complex</font><div><font face="Arial, Verdana" size="2">UniProt AcessionID: </font><a href="http://www.uniprot.org/uniprot/O14763" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(255, 255, 255);">O14763</a></div><div><br/></div><div>For more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/?term=death+inducing+signaling+complex</div>

2015-11-15T18:16:28Z

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

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">cyclin-dependent kinase inhibitor 2B (CDKN2B)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P42772</font></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1A (CDKN1A)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: Q6FI05</font></div></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1B (CDKN1B)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P46527</font></div></div><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana">cyclin-dependent kinase inhibitor 1C (CDKN1C)</font><div><font face="Arial, Verdana" size="2">UniProt Accession ID: P49918</font></div></div>

2015-11-15T18:16:28Z

<font face="Arial, Verdana" size="2">Fas ligand (TNF superfamily, member 6)</font><div><font face="Arial, Verdana" size="2"><br/></font></div><div><font face="Arial, Verdana" size="2">UniProt Accession ID: </font><a href="http://www.uniprot.org/uniprot/P48023" style="font-size: small; text-decoration: none; font-family: sans-serif; background-color: rgb(255, 255, 255);">P48023</a></div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">Formation of the interleukin 2 high affinity </font><span style="font-family: Arial, Verdana; font-size: small;">receptor complex with the interleukin 2 </span><span style="font-family: Arial, Verdana; font-size: small;">receptor: alpha, beta, gamma</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P01589" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">P01589</a></div><div><br/></div><div>For more info:</div><div>http://www.ncbi.nlm.nih.gov/mesh/68053645</div>

2015-11-15T18:16:28Z

<div><font face="Arial, Verdana" size="2">platelet-derived growth factor receptor, </font><span style="font-family: Arial, Verdana; font-size: small;">alpha polypeptide</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">UniProt AccessionID: </span><a href="http://www.uniprot.org/uniprot/P09619" style="text-decoration: none; color: rgb(64, 148, 180); border-bottom-width: 0px; cursor: pointer; font-family: verdana, arial; font-size: 13px; line-height: 20.0819721221924px; background-color: rgb(222, 239, 245);">P09619</a></div><div><span style="font-family: Arial, Verdana; font-size: small;"><br/></span></div><div><span style="font-family: Arial, Verdana; font-size: small;">for more info:</span></div><div><font face="Arial, Verdana" size="2">http://www.ncbi.nlm.nih.gov/mesh/68017479</font></div>

2015-11-15T18:16:28Z

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>

2015-11-15T18:16:28Z

<div><span style="font-size: 10pt;">lymphocyte specific Src-family protein tyrosine kinase p56lck</span></div><div><span style="font-size: 10pt;">UniProt ID: </span><a href="http://www.uniprot.org/uniprot/P06239" 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);">P06239</a></div><div><span style="font-size: 10pt;">Gene Name: LCK</span></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);">3932</span></div>

2015-11-15T18:16:28Z

<font face="Georgia" size="2">T-box expressed in T cells</font><div><font face="Georgia" size="2">T-box 21 (TBX21)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/Q9UL17" style="text-decoration: none; background-color: rgb(255, 255, 255);">Q9UL17</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/30009" ref="ordinalpos=2&ncbi_uid=30009&link_uid=30009" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">TBX21</span></a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">30009</span></font></div><div><font face="Georgia" size="2"><br/></font></div><div><font face="Georgia" size="2">Eomesodermin homolog (Xenopus laevis) (EOMES)</font></div><div><font face="Georgia" size="2">UniProt Accession ID: <a href="http://www.uniprot.org/uniprot/P79944" style="text-decoration: none; background-color: rgb(255, 255, 255);">P79944</a></font></div><div><font face="Georgia" size="2">Gene Name: <a href="http://www.ncbi.nlm.nih.gov/gene/495078" ref="ordinalpos=12&ncbi_uid=495078&link_uid=495078" style="line-height: 17.999801635742188px; white-space: nowrap; background-color: rgb(255, 255, 255);"><span class="highlight">tbx21</span></a></font></div><div><font face="Georgia" size="2">NCBI Gene ID: <span style="background-color: rgb(255, 255, 255); line-height: 16.19982147216797px;">495078</span></font></div><div style="font-size: 10pt; font-family: Arial, Verdana;"><br/></div>

2015-11-15T18:16:28Z

<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);">STAT3 positively regulates Bclxl [1]. NFKB</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);"> positively regulates Bclxl [1, 4, 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);">Apoptosis negatively regulates Bclxl [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);">BID negatively regulates Bclxl [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);">DISC negatively regulates Bclxl [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);">GZMB negatively regulates Bclxl [1].</span>

Apoptosis negatively regulates Bclxl [1].

GZMB negatively regulates Bclxl [1].

STAT3 positively regulates Bclxl [1].

NFKB directly activates transcription of Bclxl [1, 4, 5]

BID indirectly interacts with the node to inhibit Bclxl [1, 2, 3]

DISC negatively regulates Bclxl [1].

S_54 1 S_30 1 S_20 1 S_53 1 S_33 1 S_39 1 S_30 1 S_20 1 S_53 1 S_33 1

GPCR positively regulates SMAD [1, 2]. Apoptosis negatively regulates SMAD [1]

Apoptosis negatively regulates SMAD [1]

GPCR indirectly activates SMAD [1, 2]

S_21 1 S_33 1

PDGFR positively regulates SPHK1 [1, 2, 3]. Apoptosis negatively regulates SPHK1 [1].

Apoptosis negatively regulates SPHK1 [1]

<div><font face="Arial, Verdana" size="2">Sphingosine kinases 1 (SPHK1) can be activated by PDGF </font><span style="font-family: Arial, Verdana; font-size: small;">pathways [1, 2]</span></div><div><span style="font-family: Arial, Verdana; font-size: small;">PDGFR indirectly activates SPHK1 [1, 3]</span></div>

S_58 1 S_33 1

Fas positively regulates Ceramide [1]. Apoptosis negatively regulates Ceramide [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);">S1P negatively regulates Ceramide [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);">Apoptosis negatively regulates Ceramide [1].</span>

S1P indirectly inhibits Ceramide [1, 2]

<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);">Fas positively regulates Ceramide [1].</span>

S_28 1 S_33 1 S_18 1

TCR positively regulates CTLA4 [1, 2]. Apoptosis negatively regulates CTLA4 [1].

After prolonged activation of TCR, TCR will indirectly activate CTLA4 [1, 2]

S_7 1 S_33 1

Stimuli positively regulates TCR [1, 2]. Apoptosis negatively regulates TCR [1]. CTLA4 negatively regulates TCR [1, 3].

Apoptosis negatively regulates TCR [1]

CTLA directly inhibits TCR [1, 3]

Stimuli directly activates TCR [1, 2]

S_51 1 S_6 1 S_33 1

RAS or PDGFR independently positively regulate PI3K [1, 2, 3]. Apoptosis negatively regulates PI3K [1].

Apoptosis negatively regulates PI3K [1]

RAS directly activates PI3K [1, 3]

PDGFR directly activates PI3K [1, 2]

S_58 1 S_33 1 S_17 1 S_33 1

STAT3 positively regulates Proliferation [1]. Apoptosis negatively regulates Proliferation [1]. P27 negatively regulates Proliferation [1, 2].

Apoptosis negatively regulates Proliferation [1]

STAT3 positively regulates Proliferation [1]

P27 indirectly inhibits Proliferation [1, 2]

S_54 1 S_33 1 S_55 1

Il2RBT in conjunction with either IL15 or IL2 positively regulates IL2RB [1, 2, 3, 4]. Apoptosis negatively regulates IL2RB [1].

 Apoptosis negatively regulates IL2RB [1]

IL2RBT translates IL2RB [1]<div><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);">Il2RBT in conjunction with either IL15 or IL2 positively regulates IL2RB [1, 2, 3, 4]</span></div>

IL2 directly activates IL2RB [1, 2]<div><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);">Il2RBT in conjunction with either IL15 or IL2 positively regulates IL2RB [1, 2, 3, 4]</span></div>

S_29 1 S_4 1 S_34 1 S_33 1

FasT positively regulates sFas [1]. Apoptosis negatively regulates sFas [1].

FasT translates sFas [1]

Apoptosis negatively regulates sFas [1]

S_22 1 S_33 1

JAK positively regulates SOCS [1, 2]. Apoptosis negatively regulates SOCS [1]. IL15 negatively regulates SOCS [1]. IL2 negatively regulates SOCS [1]

IL15 negatively regulates SOCS [1]

Apoptosis negatively regulates SOCS [1]

JAK directly activates SOCS [1, 2]

IL2 negatively regulates SOCS [1]

S_26 1 S_4 1 S_34 1 S_33 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);">IFNG positively regulates P2 [1]. P2 </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);">positively regulates P2 [1]. </span>Apoptosis negatively regulates P2 [1]. Stimuli2 negatively regulates P2 [1].

Apoptosis negatively regulates P2 [1]

P2 positively regulates itself [1]

IFNG positively regulates P2 [1]

Stimuli2 negatively regulates P2 [1]

S_38 1 S_33 1 S_47 1 S_15 1 S_33 1 S_47 1

TCR positively regulates FYN [1, 2]. IL2RB positively regulates FYN [1, 3]. Apoptosis negatively regulates FYN [1].

Apoptosis negatively regulates FYN [1]

TCR directly activates FYN [1, 2]

IL2RB indirectly activates FYN [1, 3]

S_7 1 S_33 1 S_10 1 S_33 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);">GRB2 positively regulates Ras [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);">PDGFR positively regulates Ras [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);">Apoptosis negatively regulates Ras [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);">GAP negatively regulates Ras [1, 2]</span>

Apoptosis negatively regulates Ras [1]

GRB2 positively regulates Ras [1]

GAP negatively regulates Ras [1, 2]

S_32 1 S_59 1 S_33 1 S_52 1 S_59 1 S_33 1

SPHK1 positively regulates S1P [1, 2, 3]. Apoptosis negatively regulates S1P [1]. Ceramide negatively regulates S1P [1, 4]

Apoptosis negatively regulates S1P [1]

There exists a mutual inhibition between S1P and Ceramide. They are functionally opposing species [1, 4]

<font face="Arial, Verdana" size="2">"SPHK1 catalyzes the synthesis of S1P, which </font><span style="font-family: Arial, Verdana; font-size: small;">binds to the S1P receptors (belonging to the family of G protein </span><span style="font-family: Arial, Verdana; font-size: small;">coupled receptors and represented by ??GPCR??) and initiates </span><font face="Arial, Verdana" size="2">S1P signaling." [1, 2, 3]</font>

S_3 1 S_33 1 S_5 1

TAX positively regulates Tpl2 [1, 4]. PI3K in conjunction with TNF positively regulates Tpl2 [1, 2, 3]. Apoptosis negatively regulates Tpl2 [1].

Apoptosis negatively regulates Tpl2 [1]

TNF indirectly activates transcription of Tpl2 [1, 2, 3]<div>PI3K in conjunction with TNF positively regulates Tpl2 [1, 2, 3].</div>

PI3K in conjunction with TNF positively regulates Tpl2 [1, 2, 3].

TAX indirectly activates Tpl2 [1, 4]

S_14 1 S_33 1 S_8 1 S_45 1 S_33 1

Caspase positively regulates BID [1, 3, 4]. GZMB positively regulates BID [1, 2, 5, 6]. Apoptosis negatively regulates BID [1]. Bclxl negatively regulates BID [1]. MCL1 negatively regulates BID [1, 7].

<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);">Bclxl negatively regulates BID [1]</span>

MCL1 directly inhibits BID [1, 7]

GZMB activates BID [1, 2, 5, 6]

Caspase directly activates BID [1, 3, 4]

S_23 1 S_1 1 S_33 1 S_48 1 S_30 1 S_1 1 S_33 1 S_48 1

S1P positively regulates GPCR [1, 2, 3, 4]. Apoptosis negatively regulates GPCR [1].

Apoptosis negatively regulates GPCR [1]

S1P directly activates GPCR [1, 2, 3, 4]

S_18 1 S_33 1

NFKB positively regulates FasT [1, 2]. Apoptosis negatively regulates FasT [1].

Apoptosis negatively regulates FasT [1]

NFKB directly activates transcription of FasT [1, 2]

S_39 1 S_33 1

BID in conjunction with either TRADD or GZMB positively regulates Caspase [1, 2, 6, 7, 8, 9]. DISC positively regulates Caspsase [1, 2]. Apoptosis negatively regulates Caspase [1]. IAP negatively regulates Caspase [1, 3, 4, 5].

Apoptosis negatively regulates Caspase [1]

GZMB activates Caspase [1, 2, 6, 7, 8]<div>BID in conjunction with either TRADD or GZMB positively regulates Caspase [1]</div>

BID in conjunction with either TRADD or GZMB positively regulates Caspase [1]

DISC formation causes the activation of Caspase [1, 2]

TRADD directly activates Caspase [1, 9]<div>BID in conjunction with either TRADD or GZMB positively regulates Caspase [1]</div>

IAPs inhibit Caspases activity [1, 3, 4, 5]

S_30 1 S_20 1 S_33 1 S_43 1 S_41 1 S_20 1 S_33 1 S_43 1 S_53 1 S_33 1

RAS positively regulates Mek [1]. Apoptosis negatively regulates Mek [1].

Apoptosis negatively regulates Mek [1].

RAS positively regulates Mek [1].

S_17 1 S_33 1

STAT3 positively regulates IFNGT [1]. NFAT positively regulates IFNGT [1, 2]. TBET positively regulates IFNGT [1, 3]. Apoptosis negatively regulates IFNGT [1].

Apoptosis negatively regulates IFNGT [1]

NFAT activates transcription of IFNGT [1, 2]

STAT3 positively regulates IFNGT [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);">TBET activates transcription of IFNGT [1, 3]</span>

S_44 1 S_33 1 S_54 1 S_33 1 S_61 1 S_33 1

IFNG positively regulates JAK [1, 2]. IL2RA positively regulates JAK [1, 3, 4]. IL2RB positively regulates JAK [1, 6]. RANTES positively regulates JAK [1, 7]. Apoptosis negatively regulates JAK [1]. CD45 negatively regulates JAK [1, 5]. SOCS negatively regulates JAK [1].

<div><font color="#575757" face="arial, helvetica, clean, sans-serif"><span style="font-size: 11px; line-height: 15.4063005447388px; white-space: nowrap; background-color: rgb(255, 255, 255);">JAKs (represented by </span></font><span style="font-size: 11px; line-height: 15.4063005447388px; white-space: nowrap; color: rgb(87, 87, 87); font-family: arial, helvetica, clean, sans-serif; background-color: rgb(255, 255, 255);">??JAK??) activate and in turn are negatively regulated by sup</span><font color="#575757" face="arial, helvetica, clean, sans-serif"><span style="font-size: 11px; line-height: 15.4063005447388px; white-space: nowrap;">pressors of cytokine signaling (SOCSs, represented by ??SOCS??). [1]</span></font></div>

IL2RA directly activates JAK [1, 3, 4]

Apoptosis negatively regulates JAK [1]

<div><font face="Arial, Verdana" size="2"> IFNG in turn </font><span style="font-family: Arial, Verdana; font-size: small;">promotes the activation of T-bet and CREB through the JAK-</span><font face="Arial, Verdana" size="2">STAT pathway [1, 2]</font></div>

RANTES indirectly activates JAK [1, 7]

CD45 directly inhibits JAK [1, 5]

S_10 1 S_13 1 S_12 1 S_33 1 S_57 1 S_13 1 S_12 1 S_33 1 S_49 1 S_13 1 S_12 1 S_33 1 S_38 1 S_13 1 S_12 1 S_33 1

NFKB positively regulates A20 [1]. Apoptosis negatively regulates A20 [1].

S_39 1 S_33 1

FasT in conjunction with FasL positively regulates FAS [1, 2]. Apoptosis negatively regulates Fas [1]. sFAS negatively regulates Fas [1, 3]

FasT translates FAS [1]<div><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);">FasT in conjunction with FasL positively regulates FAS [1, 2].</span></div>

Apoptosis negatively regulates Fas [1]

FasL directly activates FAS [1, 2]<div><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);">FasT in conjunction with FasL positively regulates FAS [1, 2].</span></div>

sFAS directly inhibits FAS [1, 3]

S_22 1 S_56 1 S_33 1 S_11 1

ERK and TBET in conjunction activates IL2RBT [1, 2, 3, 4]. Apoptosis negatively regulates IL2RBT [1].

Apoptosis negatively regulates IL2RBT [1]

<div><font face="Arial, Verdana" size="2">An ??AND?? is used between TBET and ERK to indicate their </font><span style="font-family: Arial, Verdana; font-size: small;">synergistic positive effect on IL2RBT in the Boolean rules </span><span style="font-family: Arial, Verdana; font-size: small;">because otherwise the simulation result would conflict the </span><span style="font-family: Arial, Verdana; font-size: small;">known experimental result that inhibiting ERK alone can induce </span><span style="font-family: Arial, Verdana; font-size: small;">apoptosis in leukemic T-LGL [1, 4]</span></div>

TBET faciliates the expresion of IL2RBT through Eomes [1, 2, 3]<div>"<font face="Arial, Verdana" style="font-size: 10pt;">An ??AND?? is used between TBET and ERK to indicate their </font><span style="font-size: small;">synergistic positive effect on IL2RBT in the Boolean rules </span><span style="font-size: small;">because otherwise the simulation result would conflict the </span><span style="font-size: small;">known experimental result that inhibiting ERK alone can induce </span><span style="font-size: small;">apoptosis in leukemic T-LGL [1, 4]</span><span style="font-size: 10pt;">"</span></div>

S_36 1 S_61 1 S_33 1

CREB in conjunction with IFNG positively regulate GZMB [1]. TBET positively regulates GZMB [1, 2]. Apoptosis negatively regulates GZMB [1].

Apoptosis negatively regulates GZMB [1]

CREB in conjunction with IFNG positively regulate GZMB [1]

TBET activates the transcription of GZMB [1, 2]

S_61 1 S_33 1 S_46 1 S_38 1 S_33 1

GRB2 positively regulates PLCG1 [1]. PDGFR positively regulates PLCG1 [1, 2]. Apoptosis negatively regulates PLCG1 [1].

Apoptosis negatively regulates PLCG1 [1].

PDGFR directly activates PLCG1 [1, 2]

S_52 1 S_33 1 S_58 1 S_33 1

Apoptosis positively regulates Apoptosis [1]. Caspase positively regulates Apoptosis [1].

Apoptosis positively regulates Apoptosis [1].

Caspase positively regulates Apoptosis [1].

S_33 1 S_23 1

STAT3 positively regulates IL2 [1]. NFAT positively regulates IL2 [1, 3]. NFKB positively regulates IL2 [1, 3, 4, 5]. Apoptosis negatively regulates IL2 [1]. TBET negatively regulates IL2 [1, 2].

Apoptosis negatively regulates IL2 [1]

NFAT activates transcription of IL2 [1, 3]

<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 transcription of IL2 [1, 3, 4, 5]</span>

STAT3 positively regulates IL2 [1].

TBET inhibits IL2 production [1, 2] by inhibiting transcription.

S_44 1 S_33 1 S_61 1 S_54 1 S_33 1 S_61 1 S_39 1 S_33 1 S_61 1

IL2 in conjunction with either STAT3 or NFKB positively regulates IL2RAT [1, 2, 3, 4]. Apoptosis negatively regulates IL2RAT [1].

Apoptosis negatively regulates IL2RAT [1]

IL2 in conjunction with either STAT3 or NFKB positively regulates IL2RAT [1]

NFKB activates transcription of IL2RAT [1, 2, 3]<div>IL2 in conjunction with either STAT3 or NFKB positively regulates IL2RAT [1]</div>

<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);">STAT3 activates transcription of IL2RAT [1, 4]</span><div>IL2 in conjunction with either STAT3 or NFKB positively regulates IL2RAT [1]</div>

S_34 1 S_39 1 S_54 1 S_33 1

MEK in conjunction with PI3K positively regulates Erk [1, 2, 3]. Apoptosis negatively regulates Erk [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);">MEK in conjunction with PI3K positively regulates Erk [1, 2, 3]</span>

MEK directly activates Erk [1, 2, 3]<div><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);">MEK in conjunction with PI3K positively regulates Erk [1]</span></div>

S_24 1 S_8 1 S_33 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);">IL15 positively regulates IFNG [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);">IL2 positively regulates IFNG [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);">IFNGT positively regulates IFNG [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);"> </span>Apoptosis negatively regulates IFNG [1]. P2 negatively regulates IFNG [1]. SMAD negatively regulates IFNG [1, 3].

translation of IFNG is negatively regulates by IFNGT transcripts [1, 2]

IL15 positively regulates IFNG [1]

Apoptosis negatively regulates IFNG [1]

P2 negatively regulates IFNG [1]

Stimuli positively regulates IFNG [1]

IL2 positively regulates IFNG [1]

SMAD directly inhibits IFNG [1, 3]

S_4 1 S_25 1 S_2 1 S_33 1 S_15 1 S_34 1 S_25 1 S_2 1 S_33 1 S_15 1 S_51 1 S_25 1 S_2 1 S_33 1 S_15 1

PI3K positively regulates NFKB [1]. TPL2 positively regulates NFKB [1]. FLIP in conjunction with TRADD and IAP positively regulates NFKB [1, 2]. Apoptosis negatively regulates NFKB [1].

Apoptosis negatively regulates NFKB [1].

FLIP directly activates NFKB [1, 2]<div>FLIP in conjunction with TRADD and IAP positively regulates NFKB [1]</div>

PI3K positively regulates NFKB [1]

TPL2 positively regulates NFKB [1]

FLIP in conjunction with TRADD and IAP positively regulates NFKB [1]

S_40 1 S_43 1 S_41 1 S_33 1 S_8 1 S_33 1 S_19 1 S_33 1

NFKB positively regulates FLIP [1, 2]. CREB in conjunction with IFNG positively regulates FLIP [1, 3, 4]. Apoptosis negatively regulates FLIP [1]. DISC negatively regulates FLIP [1].

NFKB directly activates transcription of FLIP [1, 2]

<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);">DISC negatively regulates FLIP [1]</span>

CREB directly activates FLIP [1, 3, 4]<div><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);">CREB in conjunction with IFNG positively regulates FLIP [1, 3, 4]</span></div>

<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);">CREB in conjunction with IFNG positively regulates FLIP [1, 3, 4]</span>

S_39 1 S_53 1 S_33 1 S_46 1 S_38 1 S_53 1 S_33 1

TNF positively regulates TRADD [1]. Apoptosis negatively regulates TRADD [1]. A20 directly inhibits TRADD [1, 3]. <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);">IAP directly inhibits TRADD [1, 2]</span>

Apoptosis negatively regulates TRADD [1].

TNF positively regulates TRADD [1]

A20 directly inhibits TRADD [1, 3]

IAP directly inhibits TRADD [1, 2]

S_45 1 S_27 1 S_33 1 S_43 1

FYN positively regulates Cytoskeleton_signaling [1]. Apoptosis negatively regulates Cytoskeleton_signaling [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);">FYN positively regulates Cytoskeleton_signaling [1]</span>

S_16 1 S_33 1

Apoptosis negatively regulates IAP [1]

NFKB activates the transcription of IAP [1, 2, 3]

BID negatively regulates IAP [1]

S_39 1 S_33 1 S_20 1

PI3K positively regulates NFAT [1]. Apoptosis negatively regulates NFAT [1].

Apoptosis negatively regulates NFAT [1].

PI3K positively regulates NFAT [1].

S_8 1 S_33 1

NFKB positively regulates TNF [1, 2]. Apoptosis negatively regulates TNF [1]

Apoptosis negatively regulates TNF [1]

NFKB activates transcription of TNF [1, 2]

S_39 1 S_33 1

ERK positively regulates CREB [1, 3, 4]. IFN positively regulates CREB [1, 2]. Apoptosis negatively regulates CREB [1].

Apoptosis negatively regulates CREB [1]

ERK indirectly activates CREB [1, 3, 4]

IFNG promotes the activation of CREB through the Jak-Stat pathway [1, 2]

S_36 1 S_31 1 S_33 1

IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1, 2, 3, 4, 5, 6, 7, 8]. Apoptosis negatively regulates MCL1 [1].

Apoptosis negatively regulates MCL1 [1]

IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1]

NFKB directly activates transcription of MCL1 [1, 4, 5, 6, 7, 8]<div>IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1]</div>

STAT3 directly activats MCL1 [1, 2, 3]<div>IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1]</div>

IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1]

S_10 1 S_8 1 S_39 1 S_54 1 S_33 1

NFKB positively regulates RANTES [1, 2, 3]. Apoptosis negatively regulates RANTES [1].

Apoptosis negatively regulates RANTES [1]

NFKB activates the transcription of RANTES [1, 2, 3]

S_39 1 S_33 1

LCK positively regulates ZAP70 [1, 2, 3]. FYN negatively regulates ZAP70 [1]. Apoptosis negatively regulates ZAP70 [1].

LCK directly activates ZAP70 [1, 2, 3]

Apoptosis negatively regulates ZAP70 [1].

FYN has an inhibitory effect on ZAP70 [1]

S_60 1 S_16 1 S_33 1

ZAP70 positively regulates Grb2 [1]. IL2RB positively regulates Grb2 [1, 2]. Apoptosis negatively regulates Grb2 [1].

Apoptosis negatively regulates Grb2 [1]

ZAP70 positively regulates Grb2 [1]

IL2RB directly activates Grb2 [1, 2]

S_50 1 S_33 1 S_10 1 S_33 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);">Ceramide positively regulates DISC [1]. FasT in conjunction with either Fas or IL2 activates DISC [1, 2, 3, 4]. FLIP negative regulates DISC [1, 5]. Apoptosis negatively regulates DISC [1].</span>

FLIP interrupts DISC formation [1, 5]

Ceramide positively regulates DISC [1]

"...IL2 sensitizes activated CTL toward activation induced cell death (AICD) through potentiating the formation of the death inducing signaling complex (DISC)" [1, 2, 3]<div><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);">FasT in conjunction with either Fas or IL2 activates DISC [1, 2, 3, 4].</span></div>

The ligation of Fas induces DISC formation [1, 4]<div><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);">FasT in conjunction with either Fas or IL2 activates DISC [1, 2, 3, 4].</span></div>

S_22 1 S_34 1 S_28 1 S_28 1 S_40 1 S_5 1 S_33 1

JAK positively regulates STAT3 [1, 2, 3]. Apoptosis negatively regulates STAT3 [1]

Apoptosis negatively regulates STAT3 [1]

JAK activates STAT3 [1, 2, 3]

S_26 1 S_33 1

Apoptosis negatively regulates p27 [1]

STAT3 directly activates p27 [1, 2]

S_54 1 S_33 1

ERK positively regulates FASL [1]. STAT3 positively regulates FASL [1]. NFKB positively regulates FASL [1, 2]. NFAT positively regulates FASL [1, 3]. Apoptosis negatively regulates FASL [1].

Apoptosis negatively regulates FASL [1]

ERK positively regulates FASL [1]

STAT3 positively regulates FASL [1]

NFKB activates transcription of FASL [1, 2]

S_44 1 S_33 1 S_39 1 S_33 1 S_54 1 S_33 1 S_36 1 S_33 1

IL2 positively regulates IL2RA [1, 3]. IL2RA positively regulates IL2RA [1, 2]. IL2RAT positively regulates IL2RA [1]. Apoptosis negatively regulates IL2RA [1]

IL2RA inhibits itself [1, 2]

Apoptosis negatively regulates IL2RA [1]

IL2 directly activates IL2RA [1, 3]

IL2RAT directly translates IL2RA [1]

S_34 1 S_35 1 S_57 1 S_33 1

S1P positively regulates PDGFR [1, 2]. PDGF positively regulates PDGFR [1, 2]. Apoptosis negatively regulates PDGFR [1].

Apoptosis negatively regulates PDGFR [1]

PDGF directly activates PDGFR [1, 2]

S1P directly activates PDGFR [1, 2]

S_37 1 S_33 1 S_18 1 S_33 1

RAS positively regulates GAP [1, 2]. GAP in conjunction with PDGFR positively regulate GAP [1, 3]. Apoptosis negatively regulates GAP [1]. IL15 negatively regulates GAP [1]. IL2 negatively regulates GAP [1].

RAS activates RAS GTPase activating protein (GAP) [1, 2]

<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);">GAP in conjunction with PDGFR positively regulate GAP [1, 3].</span>

PDGFR directly activates GAP [1, 3]<div><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);">GAP in conjunction with PDGFR positively regulate GAP [1, 3].</span></div>

S_58 1 S_59 1 S_4 1 S_33 1 S_34 1 S_17 1 S_4 1 S_33 1 S_34 1

CD45 activates LCK [1, 2, 5]. IL2RB activates LCK [1, 7]. TCR activates LCK [1, 2, 4, 5, 6]. Apoptosis negatively regulates LCK [1]. ZAP70 negatively regulates LCK [1]

Apoptosis negatively regulates LCK [1]

<div><font face="Arial, Verdana" size="2">"LCK can be inhibited by </font><span style="font-family: Arial, Verdana; font-size: small;">C-SRC kinase (CSK), which is activated by ZAP70 downstream </span><span style="font-family: Arial, Verdana; font-size: small;">linkers for activation of T cells (LAT) (32). This regulation is </span><span style="font-family: Arial, Verdana; font-size: small;">represented by an inhibitory effect of ZAP70 on LCK in the </span><span style="font-family: Arial, Verdana; font-size: small;">Boolean rules." [1, 3]</span></div>

CD45 directly activates LCK [1, 2, 5]

LCK is activates after TCR engagement [1, 2, 4, 5, 6]

IL2RB directly activates LCK [1, 7]

S_7 1 S_33 1 S_50 1 S_13 1 S_33 1 S_10 1 S_33 1 S_50 1

TBET positively regulates itself [1]. JAK positively regulates TBET [1, 2]. Apoptosis negatively regulates TBET [1]

TBET is activates by the JAK-STAT pathway [1, 2]

TBET positively regulates itself [1]

S_26 1 S_33 1 S_61 1 S_33 1