TRAF2, JNK (MAPK8-10), NF-kB p50/p65, MEKK1 (MAP3K1), c-IAP1, CCL21, CXCL13, LTB, IKK-alpha, VCAM1, TNF-beta, Caspase-3, Caspase-7, NF-kB2 (p52), NF-kB p52/RelB, IKK-beta, IKK-gamma, Cytochrome c, RelB (NF-kB subunit), NF-kB2 (p100), IL-8, Smac/Diablo, Bax, Caspase-9, NIK (MAP3K14), CCL19, Apaf-1, NF-kB1 (p50), RelA (p65 NF-kB subunit), MKK7 (MAP2K7), LTBR(TNFRSF3), ASK1 (MAP3K5), SDF-1, TRAF5, I-kB, MEK4 (MAP2K4), IKK (cat), TRAF3, IL-2, LIGHT(TNFSF14), c-Jun
Lymphotoxin-beta receptor signaling
Lymphotoxin-beta receptor ( LTBR ), a member of the tumor necrosis factor receptor superfamily, is essential for the development and organization of secondary lymphoid tissue. The LTBR binds specific ligands, such as the membrane form of lymphotoxin heterotrimer, Lymphotoxin-Alpha1Beta2 ( TNF-beta/ LTB heterotrimer); lymphotoxin LT-beta ( LTB ); and homotrimer LIGHT. Expression of TNF-beta/ LTB heterotrimer is restricted to activated hematopoetic cells, whereas LIGHT is expressed both by hematopoetic and non-hematopoetic cells. LTBR activates multiple signaling pathways leading to the expression of adhesion molecules and chemokines, and cell death , , .
LTBR binds to TNF Receptor-Associated Factors ( TRAF2, - 3, and - 5 ) and mediates stimulation of two separate signaling pathways, leading to activation of distinct NF-kB (transcriptional factor) complexes , .
After triggering expression of LTBR by TNF-beta/ LTB heterotrimer, TRAF2 and TRAF5 activate NIK (NF-kB-Inducing Kinase) . NIK, in turn, phosphorylates and activates IKK-alpha (Inhibitor of KappaB Kinase-Alpha). Both proteins are required for degradation of the NF-kB2 (p52) precursor, NF-kB2 (p100), to yield the mature p52, which heterodimerizes with RelB to form NF-kB p52/RelB heterodimers . NF-kB p52/RelB involves in the expression of chemokines SDF-1, CXCL13, CCL19 and CCL21 .
The other NF-kB pathway that leads to the formation of NF-kB p50/p65 heterodimers, involving the Alpha ( IKK-alpha ), Beta ( IKK- beta ) and Gamma ( IKK-gamma ) subunits of the IKK complex, can be turned on after LTBR activation by TNF-beta/ LTB heterotrimer or LTB. IKK -dependent degradation of I-kB (NF-kB inhibitor) and subsequent activation of NF-kB1 (p50) and RelA(p65) is independent of NIK , . NF-kB1 and NF-kB p50/p65 regulate a transcription of genes that encode vascular cell adhesion molecule VCAM1, and interleukins IL-2 and IL-8 , , .
LIGHT binding to LTBR also induces JNK/c-Jun activation. All three TRAFs ( TRAF2, - 3, and - 5 ) induce activation of kinases ASK1, MEK4, MKK7 and JNK1/2. TRAF2 also induces MEKK1 / MKK7/ JNK pathway. JNK1/2 kinases phosphorylate and activate transcriptional factor c-Jun that regulates expression of interleukins IL-2 and IL-8 , , , .
In addition, LIGHT causes cell death by apoptosis of various tumor cells expressing LTBR. Upon the binding of LIGHT to LTBR, TRAF2 is first recruited to the receptor followed by TRAF3 and c-IAP1 (apoptosis inhibitor 1) recruitment, during which the BIR1 domain of c-IAP1 is cleaved. Thereby c-IAP1, which inhibits activity of caspases by direct interaction with Caspase-9, -7, and -3, is inactivated. The LIGHT - LTBR complex also triggers the mitochondria-mediated apoptosis pathway by an unknown mechanism, which induces the release of Cytochrom c and Smac (second mitochondria-derived activator of caspases) from mitochondria. TRAF3 has been suggested to trigger the release of Smac from mitochondria. The cytosolic Smac is then recruited to the receptor via its interaction with c-IAP1 . Smac causes ubiquitination and the rapid degradation of c-IAP1 . Cytochrom c released from mitochondria promotes the activation of caspase-9 through APAF-1 (apoptotic protease activating factor) . Caspases cascade signaling leads to cell death by apoptosis.