The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a bird's-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network. Helikar Tomas thelika@unmc.edu University of Nebraska - Lincoln 2014-06-02T15:59:23Z 2018-06-05T17:06:09Z

<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>

2015-11-15T20:10:21Z

<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>

2015-11-15T20:10:21Z

<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>

2017-07-19T16:18:52Z

<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>

2017-07-19T17:02:08Z

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>

2017-07-19T17:42:08Z

<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>

2017-07-19T16:29:14Z

<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>

2017-07-19T17:16:20Z

<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>

2017-07-19T17:45:36Z

<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>

2017-07-19T15:00:16Z

Cell Event [1]

2017-07-19T17:11:06Z

<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>

2017-07-19T17:18:43Z

<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>

2017-07-19T17:30:39Z

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

2017-07-19T17:17:34Z

<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>

2017-07-19T17:08:49Z

<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>

2017-07-19T17:40:56Z

<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>

2017-07-19T16:42:18Z

<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>

2017-07-19T17:21:37Z

<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>

2017-07-19T17:25:04Z

<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>

2017-07-19T16:10:45Z

<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>

2017-07-19T17:33:54Z

<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>

2017-07-19T17:43:17Z

<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>

2017-07-19T16:25:12Z

<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>

2017-07-19T17:23:37Z

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>

2017-07-19T16:25:12Z

<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>

2017-07-19T17:06:37Z

<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>

2017-07-19T17:29:14Z

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>

2017-07-19T17:21:37Z

<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>

2017-07-19T15:23:35Z

<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>

2017-07-19T17:45:36Z

<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>

2017-07-19T15:46:56Z

<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>

2017-07-19T17:36:35Z

<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>

2017-07-19T17:31:27Z

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>

2017-07-19T16:14:05Z

<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>

2017-07-19T15:46:03Z

Cell death

2017-07-19T17:45:36Z

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>

2017-07-19T16:20:51Z

<table style="width: 723pt; border-collapse: collapse;" border="0" cellSpacing="0" cellPadding="0" width="964">\r\n <colgroup><col style="width: 723pt; mso-width-source: userset; mso-width-alt: 30848;" width="964">\r\n <tbody><tr style="height: 15pt;" height="20">\r\n\r\n <td style="border: 0px black; width: 723pt; height: 15pt; background-color: transparent;" class="xl65" height="20" width="964"><font size="3"><font face="Calibri">zeta-chain\r\n (TCR) associated protein kinase 70kDa<span style="mso-spacerun: yes;"> </span></font></font></td>\r\n\r\n </tr>\r\n</tbody></table><p> </p><p>UniProt ID: <a href="http://www.uniprot.org/uniprot/P43403">P43403</a></p><p>Gene Name: ZAP70</p><p>Gene ID: 7535</p>

2017-07-19T16:03:16Z

<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>

2017-07-19T17:05:26Z

<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>

2017-07-19T17:29:14Z

<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>

2017-07-19T16:33:20Z

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>

2017-07-19T17:39:05Z

<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>

2017-07-19T15:34:16Z

<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>

2017-07-19T16:29:14Z

<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>

2017-07-19T17:26:47Z

<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>

2017-07-19T17:33:54Z

<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>

2017-07-19T17:09:52Z

<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>

2017-07-19T16:10:45Z

<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>

2017-07-19T15:35:51Z

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

2017-07-19T17:15:14Z

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

2017-07-19T17:02:08Z

<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>

2017-07-19T17:37:39Z

<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>

2017-07-19T16:42:48Z

<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>

2017-07-19T17:12:12Z

<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>

2017-07-19T17:34:54Z

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>

2017-07-19T16:05:06Z

<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>

2017-07-19T17:13:51Z

Apoptosis negatively regulates MEK.

S_19 1 S_35 1

Apoptosis negatively regulates IL2RA.

S_41 1 S_54 1 S_2 1 S_35 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 positively regulates GPCR [1, 2, 3, 4, 5].</span> Apoptosis negatively regulates GPCR.

Apoptosis negatively regulates GPCR.

S_7 1 S_35 1

Apoptosis negatively regulates NFAT.

S_24 1 S_35 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, 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);">IL2 positively regulates IFNG [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);">IFNGT positively regulates IFNG [1, 2, 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);"> </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);">P2 negatively regulates IFNG [1, 4]. SMAD negatively regulates IFNG [1, 3, 4].</span> Apoptosis negatively regulates IFNG.

<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);">Stimuli positively regulates IFNG [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);">SMAD directly inhibits IFNG [1, 3, 4]</span>

Apoptosis negatively regulates IFNG.

<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);">translation of IFNG is negatively regulates by IFNGT transcripts [1, 2, 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);">P2 negatively regulates IFNG [1, 4]</span>

S_15 1 S_52 1 S_35 1 S_12 1 S_21 1 S_37 1 S_52 1 S_35 1 S_12 1 S_21 1 S_41 1 S_52 1 S_35 1 S_12 1 S_21 1

SPHK1 positively regulates S1P [1, 2, 3, 5]. Ceramide negatively regulates S1P [1, 4, 5]. Apoptosis negatively regulates S1P.

<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);">There exists a mutual inhibition between S1P and Ceramide. They are functionally opposing species [1, 4, 5]</span>

Apoptosis negatively regulates S1P.

<font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">"SPHK1 catalyzes the synthesis of S1P, which </font><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">binds to the S1P receptors (belonging to the family of G protein </span><span style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; font-size: small; background-color: rgb(255, 255, 255);">coupled receptors and represented by ??GPCR??) and initiates </span><font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">S1P signaling." [1, 2, 3, 5]</font>

S_29 1 S_11 1 S_35 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);">TCR positively regulates CTLA4. Apoptosis negatively regulates CTLA4 and is dominant to TCR. [1, 2, 3].</span>

TCR AND NOT Apoptosis,

<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);">After prolonged activation of TCR, TCR will indirectly activate CTLA4 [1, 2, 3]</span>

S_28 1 S_35 1

STAT3 positively regulates Proliferation [1, 3].P27 negatively regulates Proliferation [1, 2, 3]. Apoptosis negatively regulates Proliferation.

Apoptosis negatively regulates Proliferation.

S_13 1 S_48 1 S_35 1

CREB in conjunction with IFNG positively regulate GZMB [1, 3]. TBET positively regulates GZMB [1, 2, 3]. Apoptosis negatively regulates GZMB.

<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 regulate GZMB [1, 3]</span>

Apoptosis negatively regulates GZMB.

<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 the transcription of GZMB [1, 2, 3]</span>

S_57 1 S_35 1 S_60 1 S_6 1 S_35 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);">Fas positively regulates Ceramide [1, 3]. S1P negatively regulates Ceramide [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);">Apoptosis negatively regulates Ceramide [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 Ceramide [1].</span>

S_26 1 S_35 1 S_7 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, 2]. 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, 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);"> Stimuli2 negatively regulates P2 [1, 2].</span> Apoptosis negatively regulates P2.

Apoptosis negatively regulates P2.

Stimuli2 negatively regulates P2 [1, 2]

S_12 1 S_35 1 S_53 1 S_6 1 S_35 1 S_53 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);">JAK positively regulates STAT3 [1, 2, 3, 4].</span>Apoptosis negatively regulates STAT3.

Apoptosis negatively regulates STAT3.

S_39 1 S_35 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);">IL2RB, NFKB, PI3K, and STAT3 all in conjunction positively regulates MCL1 [1, 2, 3, 4, 5, 6, 7, 8, 9]. DISC negatively regulates MCL1 [9].</span> Apoptosis negatively regulates MCL1.

DISC negatively regulates MCL1 [9]

Apoptosis negatively regulates MCL1.

S_56 1 S_13 1 S_24 1 S_22 1 S_35 1 S_32 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);">ERK and TBET in conjunction activates IL2RBT [1, 2, 3, 4, 5].</span>Apoptosis negatively regulates IL2RBT.

<font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);">An ??AND?? is used between TBET and ERK to indicate their </font><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">synergistic positive effect on IL2RBT in the Boolean rules </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">because otherwise the simulation result would conflict the </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">known experimental result that inhibiting ERK alone can induce </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">apoptosis in leukemic T-LGL [1, 4, 5]</span>

Apoptosis negatively regulates IL2RBT.

<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);">TBET faciliates the expresion of IL2RBT through Eomes [1, 2, 3, 5]</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="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, 5]"</span></div>

S_36 1 S_57 1 S_35 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);">TAX positively regulates Tpl2 [1, 4, 5]. PI3K in conjunction with TNF positively regulates Tpl2 [1, 2, 3, 5].</span> Apoptosis negatively regulates Tpl2.

Apoptosis negatively regulates Tpl2.

S_24 1 S_27 1 S_35 1 S_3 1 S_35 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);">ERK positively regulates FASL [1, 4]. STAT3 positively regulates FASL [1, 4]. NFKB positively regulates FASL [1, 2, 4]. NFAT positively regulates FASL [1, 3, 4].</span> Apoptosis negatively regulates FASL.

Apoptosis negatively regulates FASL.

S_5 1 S_35 1 S_13 1 S_35 1 S_22 1 S_35 1 S_36 1 S_35 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, 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);">PLCG1 positively regulates Ras [1, 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);">GAP negatively regulates Ras [1, 2, 3].</span>Apoptosis negatively regulates RAS.

Apoptosis negatively regulates RAS.

<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, 3]</span>

S_49 1 S_35 1 S_33 1 S_59 1 S_35 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);">BID in conjunction with either TRADD or GZMB positively regulates Caspase [1, 2, 6, 7, 8, 9, 10]. DISC positively regulates Caspase [1, 2, 10]. IAP negatively regulates Caspase [1, 3, 4, 5, 10].</span> Apoptosis negatively regulates Caspase.

<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 formation causes the activation of Caspase [1, 2, 10]</span>

Apoptosis negatively regulates Caspase.

<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);">IAPs inhibit Caspases activity [1, 3, 4, 5, 10]</span>

S_23 1 S_31 1 S_35 1 S_55 1 S_10 1 S_31 1 S_35 1 S_55 1 S_32 1 S_35 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);">GPCR positively regulates SMAD [1, 2, 3].</span>

Apoptosis negatively regulates SMAD.

S_4 1 S_35 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);">PI3K positively regulates NFKB [1, 3]. TPL2 positively regulates NFKB [1, 3]. FLIP in conjunction with TRADD and IAP positively regulates NFKB [1, 2, 3].</span>Apoptosis negatively regulates NFKB.

<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);">TPL2 positively regulates NFKB [1, 3]</span>

Apoptosis negatively regulates NFKB.

<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);">FLIP in conjunction with TRADD and IAP positively regulates NFKB [1, 3]</span>

S_24 1 S_35 1 S_17 1 S_35 1 S_47 1 S_23 1 S_55 1 S_35 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);">TNF positively regulates TRADD [1, 4]]. A20 directly inhibits TRADD [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);">IAP directly inhibits TRADD [1, 2, 4].</span> Apoptosis negatively regulates TRADD.

<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);">A20 directly inhibits TRADD [1, 3, 4]</span>

Apoptosis negatively regulates TRADD.

S_27 1 S_58 1 S_35 1 S_55 1

Apoptosis negatively regulates PI3K.

<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 directly activates PI3K [1, 2, 4]</span>

S_44 1 S_35 1 S_19 1 S_35 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);">JAK positively regulates SOCS [1, 2, 3]. IL15 negatively regulates SOCS [1, 3]. IL2 negatively regulates SOCS [1, 3]</span>Apoptosis negatively regulates SOCS.

Apoptosis negatively regulates SOCS.

S_39 1 S_41 1 S_15 1 S_35 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);">FasT in conjunction with FasL positively regulates FAS [1, 2, 4]. sFAS negatively regulates Fas [1, 3, 4].</span> Apoptosis negatively regulates Fas.

<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);">sFAS directly inhibits FAS [1, 3, 4]</span>

<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);">FasT translates FAS [1, 4]</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);"><span style="line-height: 18px; orphans: 3; widows: 3;">FasT in conjunction with FasL positively regulates FAS [1, 2, 4]</span></div>

Apoptosis negatively regulates Fas.

S_46 1 S_18 1 S_40 1 S_35 1

Apoptosis negatively regulates TNF.

S_22 1 S_35 1

Apoptosis negatively regulates TCR

<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);">CTLA directly inhibits TCR [1, 3, 4]</span>

S_37 1 S_35 1 S_8 1

Apoptosis negatively regulates SPHK1.

<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="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, 4]</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);"><span style="font-family: Arial, Verdana; font-size: small;">>PDGFR indirectly activates SPHK1 [1, 3, 4]</span></div>

S_44 1 S_35 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);">CD45 activates LCK [1, 2, 5, 8]. IL2RB activates LCK [1, 7, 8]. TCR activates LCK [1, 2, 4, 5, 6, 8]. ZAP70 negatively regulates LCK [1, 8]</span>Apoptosis negatively regulates LCK.

Apoptosis negatively regulates LCK.

<font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);">"LCK can be inhibited by </font><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">C-SRC kinase (CSK), which is activated by ZAP70 downstream </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">linkers for activation of T cells (LAT) (32). This regulation is </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">represented by an inhibitory effect of ZAP70 on LCK in the </span><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">Boolean rules." [1, 3, 8]</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);">LCK is activates after TCR engagement [1, 2, 4, 5, 6, 8]</span>

S_42 1 S_35 1 S_56 1 S_35 1 S_38 1 S_28 1 S_35 1 S_38 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);">Caspase positively regulates BID [1, 3, 4, 8]. GZMB positively regulates BID [1, 2, 5, 6, 8]. Bclxl negatively regulates BID [1, 8]. MCL1 negatively regulates BID [1, 7, 8].</span> Apoptosis negatively regulates BID.

<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 activates BID [1, 2, 5, 6, 8]</span>

Apoptosis negatively regulates BID.

<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, 8]</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);">MCL1 directly inhibits BID [1, 7, 8]</span>

S_10 1 S_43 1 S_35 1 S_14 1 S_20 1 S_43 1 S_35 1 S_14 1

<span style="color: rgb(79, 79, 79); font-family: Arial, sans-serif; font-size: 12px; line-height: 18px; orphans: 3; widows: 3; background-color: rgb(255, 255, 255);">Ceramide positively regulates DISC [1, 6]. FasT in conjunction with either Fas or IL2 activates DISC [1, 2, 3, 4, 6]. FLIP negative regulates DISC [1, 5, 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);">Apoptosis negatively regulates DISC [1].</span>

<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);">"...IL2 sensitizes activated CTL toward activation induced cell death (AICD) through potentiating the formation of the death inducing signaling complex (DISC)" [1, 2, 3, 6]</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);"><span style="line-height: 18px; orphans: 3; widows: 3;">FasT in conjunction with either Fas or IL2 activates DISC [1, 2, 3, 4, 6]</span></div>

S_46 1 S_26 1 S_47 1 S_11 1 S_41 1 S_26 1 S_35 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);">RAS positively regulates GAP [1, 2, 4]. GAP in conjunction with PDGFR positively regulate GAP [1, 3, 4]. Apoptosis negatively regulates GAP [1, 4]. IL15 negatively regulates GAP [1, 4]. IL2 negatively regulates GAP [1, 4].</span>

Apoptosis negatively regulates GAP.

S_44 1 S_33 1 S_41 1 S_35 1 S_15 1 S_19 1 S_41 1 S_35 1 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);">FYN positively regulates Cytoskeleton_signaling [1, 2].</span>Apoptosis negatively regulates Cytoskeleton_signaling.

Apoptosis negatively regulates Cytoskeleton_signaling.

S_51 1 S_35 1

S_35 1 S_20 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, 4].</span>Apoptosis negatively regulates Erk.

Apoptosis negatively regulates Erk.

S_1 1 S_24 1 S_35 1

LCK positively regulates ZAP70 [1, 2, 3, 4]. FYN negatively regulates ZAP70 [1, 4]. Apoptosis negatively regulates ZAP70.

Apoptosis negatively regulates ZAP70.

S_30 1 S_51 1 S_35 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 JAK [1, 2, 8]. IL2RA positively regulates JAK [1, 3, 4, 8]. IL2RB positively regulates JAK [1, 6, 8]. RANTES positively regulates JAK [1, 7, 8]. CD45 negatively regulates JAK [1, 5, 8]. SOCS negatively regulates JAK [1, 8].</span>Apoptosis negatively regulates JAK.

<font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);">IFNG in turn </font><span style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; font-size: small; background-color: rgb(255, 255, 255);">promotes the activation of T-bet and CREB through the JAK-</span><font face="Arial, Verdana" size="2" style="color: rgb(79, 79, 79); line-height: 14.4000005722046px; background-color: rgb(255, 255, 255);">STAT pathway [1, 2, 8]</font>

Apoptosis negatively regulates JAK.

JAKs (represented by ??JAK??) activate and in turn are negatively regulated by suppressors of cytokine signaling (SOCSs, represented by ??SOCS??). [1, 8]

S_45 1 S_42 1 S_35 1 S_25 1 S_2 1 S_42 1 S_35 1 S_25 1 S_6 1 S_42 1 S_35 1 S_25 1 S_56 1 S_42 1 S_35 1 S_25 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 translates sFas [1, 2]</span></div>FasT and S1P in conjunction with sFAS [2]

<div><span style="font-size: 10pt;">FasT and S1P in conjunction with sFAS [2]</span></div>

Apoptosis negatively regulates sFas.

S_46 1 S_7 1 S_35 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);">STAT3 positively regulates IL2 [1, 6]. NFAT positively regulates IL2 [1, 3, 6]. NFKB positively regulates IL2 [1, 3, 4, 5, 6]. TBET and Apoptosis negatively regulates IL2 [1, 2, 6].</span>

Apoptosis negatively regulates.

<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 inhibits IL2 production [1, 2, 6] by inhibiting transcription.</span>

S_22 1 S_35 1 S_57 1 S_13 1 S_35 1 S_57 1 S_5 1 S_35 1 S_57 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);">STAT3 positively regulates Bclxl [1, 6]. 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, 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);">BID negatively regulates Bclxl [1, 2, 3, 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);">DISC negatively regulates Bclxl [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);">GZMB negatively regulates Bclxl [1, 6].</span> Apoptosis negatively regulates Bclx.

Apoptosis negatively regulates Bclx.

S_13 1 S_35 1 S_32 1 S_31 1 S_10 1 S_22 1 S_35 1 S_32 1 S_31 1 S_10 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 positively regulates PDGFR [1, 2, 3]. PDGF positively regulates PDGFR [1, 2, 3].</span> Apoptosis negatively regulates PDGFR.

Apoptosis negatively regulates PDGFR.

S_7 1 S_35 1 S_50 1 S_35 1

Apoptosis negatively regulates RANTES.

S_22 1 S_35 1

Apoptosis negatively regulates FasT.

S_22 1 S_35 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);">NFKB positively regulates FLIP [1, 2, 5]. CREB in conjunction with IFNG positively regulates FLIP [1, 3, 4, 5]. DISC negatively regulates FLIP [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);">Apoptosis negatively regulates FLIP [1]</span>

S_22 1 S_35 1 S_32 1 S_60 1 S_6 1 S_35 1 S_32 1

Apoptosis negatively regulates p27.

S_13 1 S_35 1

Apoptosis negatively regulates PLCG1.

S_59 1 S_35 1 S_44 1 S_35 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);">TCR positively regulates FYN [1, 2, 4]. IL2RB positively regulates FYN [1, 3, 4].</span>Apoptosis negatively regulates FYN.

Apoptosis negatively regulates FYN

S_28 1 S_35 1 S_56 1 S_35 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);">STAT3 positively regulates IFNGT [1, 4]. NFAT positively regulates IFNGT [1, 2, 4]. TBET positively regulates IFNGT [1, 3, 4].</span> Apoptosis negatively regulates IFNGT .

Apoptosis negatively regulates IFNGT.

S_57 1 S_35 1 S_5 1 S_35 1 S_13 1 S_35 1

Apoptosis negatively regulates IL2RAT.

S_41 1 S_13 1 S_22 1 S_35 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);">NFKB activates the transcription of IAP [1, 2, 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);">BID negatively regulates IAP [1, 4].</span> Apoptosis negatively regulates IAP.

Apoptosis negatively regulates IAP.

S_22 1 S_35 1 S_31 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);">Il2RBT in conjunction with either IL15 or IL2 positively regulates IL2RB [1, 2, 3, 4, 5].</span>Apoptosis negatively regulates IL2RB.

Apoptosis negatively regulates IL2RB.

S_16 1 S_41 1 S_15 1 S_35 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 positively regulates itself [1, 3]. JAK positively regulates TBET [1, 2, 3].</span> Apoptosis negatively regulates TBET.

Apoptosis negatively regulates TBET.

<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 is activates by the JAK-STAT pathway [1, 2, 3]</span>

S_57 1 S_35 1 S_39 1 S_35 1

Apoptosis negatively regulates A20.

S_22 1 S_35 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);">ZAP70 positively regulates Grb2 [1, 3]. IL2RB positively regulates Grb2 [1, 2, 3].</span>Apoptosis negatively regulates Grb2.

Apoptosis negatively regulates Grb2.

S_56 1 S_35 1 S_38 1 S_35 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);">ERK positively regulates CREB [1, 3, 4, 5]. IFN positively regulates CREB [1, 2, 5].</span>Apoptosis negatively regulates CREB.

Apoptosis negatively regulates CREB.

S_36 1 S_6 1 S_35 1