TNF-related weak inducer of apoptosis (TWEAK) is a type II transmembrane protein belonging to the TNF superfamily and has been designated TNFSF12. Mouse TWEAK is a 249 amino acid (aa) protein with an N-terminal 21 aa cytoplasmic domain, a 21 aa transmembrane region and a 204 aa C-terminal extracellular domain (1). The primary structures of the extracellular domains of human and mouse TWEAK are 88% identical. A soluble form of TWEAK is generated from the
membrane-associated molecules by proteolytic cleavage suggesting that TWEAK may have long-range effects. TWEAK is expressed widely in many tissues and cells (1). Although TWEAK has been proposed as a ligand that signals through the death domain receptor 3 (DR3) (2), a TNF receptor superfamily member currently designated TNFRSF25, subsequent studies did not demonstrate binding of TWEAK to cell lines that express DR3 (3). In cells that lack DR3, TWEAK has been shown to bind TWEAK receptor (TWEAK R), a novel TNF receptor superfamily member designated TNFRSF12A (4-7). TWEAK R, also known as fibroblast growth
factor-inducible 14 (Fn14), is a growth factor-inducible immediate-early response gene that is expressed in fibroblasts, hepatocellular carcinomas and endothelial cells. TWEAK-TWEAK R interaction has been shown to promote NF-kappa B activation and mediate multiple cell death pathways. On endothelial cells, TWEAK R plays a role in endothelial cell growth and migration. This effect of TWEAK is not due to up-regulation of VEGF (8).