The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation

Abstract

Fn14 is a growth-factor-inducible immediate-early-response gene encoding a 102-amino-acid type I transmembrane protein. The human Fn14 protein was recently identified as a cell-surface receptor for the tumour necrosis factor (TNF) superfamily member named TWEAK (TNF-like weak inducer of apoptosis). In the present paper, we report that the human TWEAK extracellular domain can also bind the murine Fn14 protein. Furthermore, site-specific mutagenesis and directed yeast two-hybrid interaction assays revealed that the TNFR-associated factor (TRAF) 1, 2, 3 and 5 adaptor molecules bind the murine Fn14 cytoplasmic tail at an overlapping, but non-identical, amino acid sequence motif. We also found that TWEAK treatment of quiescent NIH 3T3 cells stimulates inhibitory kappaBalpha phosphorylation and transcriptional activation of a nuclear factor-kappaB (NF-kappaB) enhancer/luciferase reporter construct. Fn14 overexpression in transiently transfected NIH 3T3 cells also promotes NF-kappaB activation, and this cellular response requires an intact TRAF binding site. These results indicate that Fn14 is a functional TWEAK receptor that can associate with four distinct TRAF family members and stimulate the NF-kappaB transcription factor signalling pathway.

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

“…Treatment of BMOL and BMOL-TAT cells with rhTWEAK led to activation of the transcription factor NFjB, which was an expected outcome after stimulation of Fn14. 11,12 NFjB activation was dosedependent, however, only at lower concentrations (Fig. 5B).…”

“…Instead, it associates with tumor necrosis factor receptor-associated factor (TRAF) adaptor molecules and activates nuclear factor kappa light chain enhancer of activated B cells (NFjB) and the extracellular signalregulated kinase and c-Jun N-terminal kinase mitogenactivated protein kinase pathways. 11,12 TWEAK regulates a diverse range of cellular processes, including proliferation, differentiation, migration, cell survival, and cell death, and has also been shown to act as a proangiogenic and proinflammatory factor. 13 Although TWEAK is almost ubiquitously expressed in adult tissues, including the liver, its cognate receptor is barely detectable in hepatic tissue except during injury and repair.…”

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

“…This small membrane protein is able to mediate a variety of intracellular signals in a cellspecific fashion including apoptosis, necrosis, proliferation, and survival (17,22,31,43). Proliferative signals elicited by Fn14 are likely to be mediated by association of TNFR-associated factor proteins with the Fn14 cytoplasmic domain and subsequent stimulation of NF-B activity (29,30), whereas survival signals involve NF-B-mediated up-regulation of Bcl-XL and Bcl-W expression (44). Death signals initiated by Fn14 have been thoroughly studied in tumor cell lines and have been shown to involve caspase activation as well as cathepsin B-dependent necrosis (31).…”

“…DR3-independent signaling has been ascribed to a recently identified receptor for TWEAK, originally cloned as a mitogen-inducible gene in murine fibroblasts and named fibroblast growth factor-inducible 14 (Fn14) (27,28). Fn14 is distantly related to other members of the TNFR family and contains one cysteine-rich domain in the extracellular region and a TNFR-associated factor-binding domain in the cytoplasmic region (29,30). Despite its small size and the absence of a cytoplasmic death domain, Fn14 has been recently shown to mediate multiple pathways of TWEAK-induced cell death in transformed cells, including both caspase-dependent apoptosis and cathepsin Bdependent necrosis (31).…”

Roles of Fibroblast Growth Factor-inducible 14 in Hepatocellular Carcinoma

“…It lacks a death domain and contains the PIEET canonical TRAF (tumor necrosis factor receptor associated factors)-binding sequence that can recruit TRAF adapter proteins via binding of TRAF-1, 2, 3, 5, and then activates downstream signaling pathways of NF-κB as well as the MAPK and AKT pathways (Brown et al, 2003;Saitoh et al, 2003;Ando et al, 2006). Fn14 and TNF-like weak inducer of apoptosis (TWEAK) are a receptor-ligand pair with pleiotropic effects, mediating pro-inflammatory and pro-angiogenic activities as well as stimulating invasion, migration, and survival (Michaelson and Burkly, 2009).…”