TWEAK Protein, Human

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), also known as TNFSF12, is a member of the TNF ligand superfamily initially characterized in 1997. TWEAK is synthesized as a type II transmembrane protein and can be proteolytically cleaved by furin into a soluble cytokine. It exerts its biological functions primarily by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14), which contains a TRAF-binding motif that activates downstream signaling cascades including NF-κB, MAPK, PI3K-Akt, and Notch pathways. While Fn14 is the critical signaling receptor, CD163 can also bind soluble TWEAK as a scavenger receptor. The TWEAK/Fn14 axis regulates diverse cellular processes including proliferation, differentiation, migration, angiogenesis, inflammation, and apoptosis, with Fn14 expression being markedly upregulated during tissue injury, inflammation, and regeneration.