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

@article{Polek:2003p839, abstract = {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.}, author = {Polek, Tara C. and Talpaz, Moshe and Darnay, Bryant G. and Kroizman, Taly S.}, citeulike-article-id = {3046171}, citeulike-linkout-0 = {http://www.jbc.org/cgi/content/full/278/34/32317}, citeulike-linkout-1 = {http://dx.doi.org/10.1074/jbc.M302518200}, doi = {10.1074/jbc.M302518200}, journal = {J Biol Chem}, keywords = {activator, animals, apoptosis, b, blotting, carrier, cell, differentiation, factor, factor-kappa, factors, file-import-08-07-27, glycoproteins, ligand, line, macrophages, membrane, mice, necrosis, nuclear, of, proteins, rank, receptor, receptors, regulatory, signal, transduction, tumor, western}, local-url = {file://localhost/Users/ken/Documents/Papers/2003/Polek/J\%20Biol\%20Chem\%202003\%20Polek.pdf}, month = {Aug}, number = {34}, pages = {32317--23}, posted-at = {2008-07-27 14:45:54}, priority = {2}, title = {TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor}, url = {http://dx.doi.org/10.1074/jbc.M302518200}, volume = {278}, year = {2003} }

TY - JOUR ID - Polek:2003p839 L3 - citeulike-article-id:3046171 N2 - 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. IS - 34 JF - J Biol Chem EP - 23 TI - TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor VL - 278 SP - 32317 KW - activator KW - animals KW - apoptosis KW - b KW - blotting KW - carrier KW - cell KW - differentiation KW - factor KW - factor-kappa KW - factors KW - file-import-08-07-27 KW - glycoproteins KW - ligand KW - line KW - macrophages KW - membrane KW - mice KW - necrosis KW - nuclear KW - of KW - proteins KW - rank KW - receptor KW - receptors KW - regulatory KW - signal KW - transduction KW - tumor KW - western AU - Polek, Tara AU - Talpaz, Moshe AU - Darnay, Bryant AU - Kroizman, Taly PY - 2003/Aug// UR - http://dx.doi.org/10.1074/jbc.M302518200 ER -