CD137 signaling in immune cell
CD137(TNFRSF9) is an inducible T cell surface receptor belonging to the tumor necrosis factor receptor superfamily. It presents on the surfaces of activated CD4+ and CD8+ T cells, monocytes and B lymphocytes. CD137(TNFRSF9) signaling is activated by binding to its high-affinity ligand CD137 ligand(TNFSF9) expressed on the antigen-presenting cell surface. CD137(TNFRSF9) signaling promotes cell growth, T cell differentiation and survival (see anti-apoptosis of immune cells , .
CD137(TNFRSF9) mediates its action via association with TRAF1 and TRAF2. CD137(TNFRSF9) binding to TRAF2 leads to activation of the NIK(MAP3K14). NIK(MAP3K14) activates NF-kB via the IKK-alpha/ NFKBIA pathway , , . NF-kB induces transcription of Bcl-XL, Bcl-2 and BFL1, and thus promotes survival (see anti-apoptosis of immune cells , , .
In addition, activation of NF-kB stimulates expression of IL-2, IL-4 and IFN-gamma , .
CD137(TNFRSF9) binding to TRAF2 also promotes activation of the ASK1 (MAP3K5). ASK1 (MAP3K5) induces JNK1(MAPK8) and p38 MAPK activation via MEK3(MAP2K3), MEK4(MAP2K4) and MEK6(MAP2K6). JNK1(MAPK8) and p38 MAPK phosphorylate ATF-2 and c-Jun. Activation of ATF-2 and c-Jun also induces production of IL-2, IL-4 and IFN-gamma and leads to Th1 and Th2 cell development (see T-helper cell differentiation , .
Also, CD137(TNFRSF9) association with TRAF1 and TRAF2 leads to ERK1/2 activation via TRAF1 stimulation of ERK1/2 activity and possible TRAF2/ NIK(MAP3K14)/ MEKK1(MAP3K1)/ MEK1(MAP2K1) pathway , , , . ERK1/2 activation leads to Cyclin D2 transcription possibly via c-Jun. In addition, CD137(TNFRSF9)-induced IL-2 signaling triggers translation of Cyclin D2 protein , . Cyclin D2 stimulates expression of Cyclin E and this leads to cell cycle progression (see positive regulation of cell cycle) and promotes cell proliferation of CD4-positive and CD8-positive cells under CD137(TNFRSF9) control , , , , , , .
CD137(TNFRSF9)-induced ERK1/2 activation also leads to Bim phosphorylation by ERK1/2. It promotes proteosomal degradation of Bim and leads to immune cell survival , .
| ASK1 (MAP3K5) || Mitogen-activated protein kinase kinase kinase 5 |
| ATF-2 || Cyclic AMP-dependent transcription factor ATF-2 |
| BFL1 || Bcl-2-related protein A1 |
| Bcl-2 || Apoptosis regulator Bcl-2 |
| Bcl-XL || Bcl-2-like protein 1 |
| Bim || Bcl-2-like protein 11 |
| CD137 ligand(TNFSF9) || Tumor necrosis factor ligand superfamily member 9 |
| CD137(TNFRSF9) || Tumor necrosis factor receptor superfamily member 9 |
| Cyclin D2 || G1/S-specific cyclin-D2 |
| Cyclin E || G1/S-specific cyclin-E1 |
| ERK1/2 || Erk 1/2 Protein group |
| IFN-gamma || Interferon gamma |
| IKK-alpha || Inhibitor of nuclear factor kappa-B kinase subunit alpha |
| IL-2 || Interleukin-2 |
| IL-4 || Interleukin-4 |
| JNK1(MAPK8) || Mitogen-activated protein kinase 8 |
| MEK1(MAP2K1) || Dual specificity mitogen-activated protein kinase kinase 1 |
| MEK3(MAP2K3) || Dual specificity mitogen-activated protein kinase kinase 3 |
| MEK4(MAP2K4) || Dual specificity mitogen-activated protein kinase kinase 4 |
| MEK6(MAP2K6) || Dual specificity mitogen-activated protein kinase kinase 6 |
| MEKK1(MAP3K1) || Mitogen-activated protein kinase kinase kinase 1 |
| NF-kB || NF-kB Group of complexes |
| NFKBIA || NF-kappa-B inhibitor alpha |
| NIK(MAP3K14) || Mitogen-activated protein kinase kinase kinase 14 |
| TRAF1 || TNF receptor-associated factor 1 |
| TRAF2 || TNF receptor-associated factor 2 |
| c-Jun || Transcription factor AP-1 |
| p38 MAPK || p38 mitogen-activated protein kinase Protein group |
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