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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/ TweakR. Evidence for a second TWEAK receptor.

Tumor necrosis factor-like weak inducer of apoptosis ( TWEAK) is a member of the tumor necrosis factor family that is implicated in apoptosis, proliferation, migration, and inflammation. We describe our findings showing that TWEAK mediated the differentiation of RAW264.7 (RAW) monocyte/macrophage cells into multinuclear, functional osteoclasts. The effect of TWEAK was direct and not mediated by the receptor activator of nuclear factor-kappa B ( NF-kappa B) ligand ( RANKL) as shown by the use of TWEAK- or RANKL-neutralizing antibodies and by osteoprotegerin, a decoy receptor for RANKL. Recently, fibroblast growth factor-inducible 14 (Fn14) was suggested to be a receptor for TWEAK. We show that the Fn14/ TWEAK receptor ( TweakR) was not responsible for the osteoclastic effect of TWEAK on RAW cells. Flow cytometry analysis did not reveal the expression of Fn14/ TweakR on RAW cells. Moreover, Fn14/ TweakR-neutralizing antibodies did not block TWEAK-induced RAW cell differentiation into osteoclasts. This indicated that a second TweakR, TweakR2, exists on RAW cells and is responsible for mediating TWEAK-induced differentiation. We next compared the signaling pathways that are activated by the two receptors. TWEAK binding to TweakR2 activated the NF-kappa B, mitogen-activated protein kinase and c-Jun N-terminal kinase signaling cascades in RAW cells. In contrast, TWEAK binding to Fn14/ TweakR activated the NF-kappa B and c-Jun N-terminal kinase pathways but induced only a weak activation of MAPK in HT-29 human colon adenocarcinoma cells expressing endogenous Fn14/ TweakR. We propose that the biological effects of TWEAK are mediated by binding to one of at least two distinct receptors that induce differential activation of downstream signaling pathways.[1]


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