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Apoptosis and survival Lymphotoxin-beta receptor signaling


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Apoptosis and survival Lymphotoxin-beta receptor signaling

Lymphotoxin-beta receptor signaling

Lymphotoxin-beta receptor ( LTBR ), a member of the tumor necrosis factorreceptor superfamily, is essential for the development and organization of secondarylymphoid tissue. The LTBR binds specific ligands, such as the membrane form oflymphotoxin heterotrimer, Lymphotoxin-Alpha1Beta2 ( TNF-beta/ LTBheterotrimer); lymphotoxin LT-beta ( LTB ); and homotrimer LIGHT.Expression of TNF-beta/ LTB heterotrimer is restricted to activatedhematopoetic cells, whereas LIGHT is expressed both by hematopoetic andnon-hematopoetic cells. LTBR activates multiple signaling pathways leading to theexpression of adhesion molecules and chemokines, and cell death [1], [2], [3].

LTBR binds to TNF Receptor-Associated Factors ( TRAF2, - 3, and- 5 ) and mediates stimulation of two separate signaling pathways, leading toactivation of distinct NF-kB (transcriptional factor) complexes [4],[5].

After triggering expression of LTBR by TNF-beta/ LTBheterotrimer, TRAF2 and TRAF5 activate NIK (NF-kB-Inducing Kinase)[6]. NIK, in turn, phosphorylates and activates IKK-alpha(Inhibitor of KappaB Kinase-Alpha). Both proteins are required for degradation of theNF-kB2 (p52) precursor, NF-kB2 (p100), to yield the mature p52, whichheterodimerizes with RelB to form NF-kB p52/RelB heterodimers [7]. NF-kB p52/RelB involves in the expression of chemokines SDF-1,CXCL13, CCL19 and CCL21 [8].

The other NF-kB pathway that leads to the formation of NF-kB p50/p65heterodimers, involving the Alpha ( IKK-alpha ), Beta ( IKK- beta ) andGamma ( IKK-gamma ) subunits of the IKK complex, can be turned on afterLTBR activation by TNF-beta/ LTB heterotrimer or LTB.IKK -dependent degradation of I-kB (NF-kB inhibitor) and subsequent activation ofNF-kB1 (p50) and RelA(p65) is independent of NIK [9],[8]. NF-kB1 and NF-kB p50/p65 regulate a transcription ofgenes that encode vascular cell adhesion molecule VCAM1, and interleukinsIL-2 and IL-8 [10], [11], [12].

LIGHT binding to LTBR also induces JNK/c-Junactivation. 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 transcriptionalfactor c-Jun that regulates expression of interleukinsIL-2 and IL-8 [13], [4], [14], [15].

In addition, LIGHT causes cell death by apoptosis of various tumor cellsexpressing LTBR. Upon the binding of LIGHT to LTBR, TRAF2is first recruited to the receptor followed by TRAF3 and c-IAP1 (apoptosisinhibitor 1) recruitment, during which the BIR1 domain of c-IAP1 is cleaved.Thereby c-IAP1, which inhibits activity of caspases by direct interaction withCaspase-9, -7, and -3, is inactivated. The LIGHT -LTBR complex also triggers the mitochondria-mediated apoptosis pathway by anunknown mechanism, which induces the release of Cytochrom c and Smac(second mitochondria-derived activator of caspases) from mitochondria. TRAF3 hasbeen suggested to trigger the release of Smac from mitochondria. The cytosolicSmac is then recruited to the receptor via its interaction with c-IAP1[5]. Smac causes ubiquitination and the rapid degradation ofc-IAP1 [16]. Cytochrom c released from mitochondria promotesthe activation of caspase-9 through APAF-1 (apoptotic protease activatingfactor) [17]. Caspases cascade signaling leads to cell death byapoptosis.