TWEAK shall inherit the earth

Abstract

Sometimes size really does not matter: recent papers on the tumour necrosis factor (TNF)-like ligand, TWEAK (tumour necrosis factor-like weak inducer of apoptosis), and its diminutive 129 amino-acid receptor, FN14 (fibroblast growth factor (FGF) -inducible 14 kDa protein), describe an impressive and potent range of biological effects. The TNF superfamily (TNSF) receptor FN14 has a small cytoplasmic domain, and the limited similarity of its extracellular domain to the cysteine-rich domains of the TNFSF receptors was only appreciated retrospectively when it was discovered that it bound TWEAK.1 Recent work has demonstrated that TWEAK knockout animals have an activated immune system that is skewed by elevated numbers of natural killer (NK) cells and responds lethally to bacterial endotoxins, but also shows a powerful ability to prevent tumour growth.2 Other topical papers show that TWEAK and FN14 work to promote liver regeneration following injury and prevent the differentiation of a diverse range of cell types. The role of TWEAK and FN14 in cancer has yet to be conclusively established, but several groups have observed high expression of FN14 in cancerous tissues, and demonstrated that it can promote cellular functions important for tumorigenesis, including cytokine production, cellular proliferation, survival, migration and angiogenesis.3