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TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha


Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor _ B (NF- _ B) signaling, and sensitize cells to tumor necrosis factor _ (TNF _ ). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1 ? Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1 ? TRAF2 in a cIAP1- dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF- _ B signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNF _ - induced death occurs. TWEAK-induced loss of the cIAP1 ? TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNF _ -induced death, whereas primary cells remain resistant. Conversely, cIAP1 ? TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNF _ sensitization. Lysosomal degradation of cIAP1 ? TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death

Type Journal
ISBN 1540-8140
Authors Vince, J.E.;Chau, D;Callus, B.;Wong, W.W;Hawkins, C.J.; Schneider, P;McKinlay, M;Benetatos, C.A.;Condon, S. M.; Chunduru, S.K.; Yeoh, G.;Brink, R.;Vaux, D.L.;Silke, J.:
Published Date 2008-07-14
Published Volume 182
Published Issue 1
Published Pages 171-84
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version