tnf/stress related signaling
| PAG Title | tnf/stress related signaling |
| PAG ID | WAG000224 |
| Type | P |
| Source Link |  BioCarta |
| Publication Reference | NA |
| PAG Description | TNF acts on several different sigling pathways through two cell surface receptors, TNFR1 and TNFR2 (See TNFR1 and TNFR2 Sigling Pathways) to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kises (SAPKs). Interaction of TNFR1 with TRADD leads to activation of NF-kB and apoptosis pathways, while interaction with TRAF2 has generally been thought to be involved in stress kise and NF-kB activation but is not required for TNF to induce apoptosis. Activation of NF-kB is mediated by TRAF2 through the NIK kise and also by RIP but the observation that TNF activates NF-kB in mice lacking TRAF2 indicates that TRAF-2 does not play an essential role in this process. Stress-activated protein kises, also called JNKs, are a family of map kises activated by cellular stress and inflammatory sigls. Binding of TNF to the TNFR1 receptor activates the germil center kise (GCK) through the TNF adaptor Traf2, activating the map kise MEKK1. Both GCK and MEKK1 interact with Traf2, and GCK is required for MEKK1 activation by TNF, but GCK kise activity does not appear to be required for MEKK1 activation. Instead, GCK activates MEKK1 by causing MEKK1 oligomerization and autophosphorylation. Tank increases the affinity of Traf2 for GCK to increase Map kise activation by TNF. Once activated, MEKK1 stands at the top of a map kise pathways leading to transcriptiol regulation, including JNK phosphorylation of c-Jun to stimulate transcriptiol activation by AP-1, a heterodimer of c-jun and fos or ATF proteins. The activation of the p38 Map kise also contributes to AP-1 activation leading to the transcriptiol activation of many stress and growth related genes. RIP has been suggested as a component of the p38 pathway in addition to playing a role in NF-kB activation. MEKK1 knockout mice support the role of MEKK1 in JNK activation in some cells but did not support MEKK1 dependent activation of NF-kB. Altertive redundant mechanisms may obscure the role of MEKK1 in NF-kB mechanisms. TNF activation of stress kise pathways and downstream transcription factors may help to modulate the apoptotic pathways also activated by TNF. |
| Species | Homo sapiens |
| nCoCo Score | 3,338 |
| Base PAG ID | WAG000224 |
| Human Phenotyte Annotation | |
| Curator | PAGER curation team |
| Curator Contact | PAGER-contact@googlegroups.com |
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