TWEAK Signaling


Pathway Description

TWEAK is a cell surface associated type II transmembrane protein belonging to the TNF superfamily. The protein was named TWEAK for its relatedness to TNF and its weak apoptotic ability. TWEAK has multiple biological activities including stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and under some experimental conditions, stimulation of apoptosis. It is produced by IFNγ-stimulated monocytes and induces multiple pathways of cell death in a cell type specific manner, namely caspase-dependent apoptosis, cathepsin-B-dependent necrosis and endogenous TNFα-mediated cell death.DR3, the TWEAK receptor, is a type-I membrane protein belonging to the TNFR family. It is also known as Apo3, LARD, WSL1 or TRAMP and is expressed predominantly in tissues with high lymphocyte content. DR3 contains a set of cysteine rich domains in the extracellular region and a death domain in its cytoplasmic segment. DR3 transduces death signals by interaction with FADD. FADD then recruits other cytoplasmic effectors such as caspase8, TRADD and RIP that activate the apoptotic machinery. DR3 also recruits TRAF2 via TRADD to activate the transcription factor NF-κB that induces the transcription of a number survival genes including Inhibitor of Apoptosis (IAP). In this respect, DR3 (like TNFR1) is capable of inducing both apoptosis and expression of survival/activation genes and is likely to have multiple functions depending on the context of its expression. However, identification of DR3 as the major receptor for TWEAK is controversial. This has been challenged by reports which show that TWEAK could induce cell death in cells lacking DR3.

Recently, Fibroblast Growth Factor Inducible-14 (Fn14) was reported to be a receptor for TWEAK. TweakR/Fn14 is the smallest member of the TNFR superfamily described to date, and it appears to signal via recruitment of several different TNFR associated factors. The cytoplasmic domain of Fn14, like other members of the TNFR superfamily, does not contain consensus amino acid sequences characteristic to domains with enzymatic activity. Therefore, it is likely that proteins interacting with Fn14 mediate NF-κB activation. Reports have shown that the cytoplasmic domain of Fn14 binds to TRAF1, TRAF2, TRAF3 and TRAF5. However, the functional significance of these TRAF proteins in Fn14 mediated NF-κB activation is not well established. TWEAK is a potent inducer of endothelial cell survival and cooperates with bFGF to induce the proliferation and migration of human endothelial cells and morphogenesis of capillary lumen. In contrast, TWEAK antagonizes the morphogenic response of endothelial cells to VEGF without inhibiting VEGF-induced survival or proliferation. Thus, TWEAK may differentially regulate microvascular growth, remodeling and/or maintenance in vivo, depending upon the angiogenic context.


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