X-linked Inhibitor of Apoptosis Protein Functions as a Cofactor in Transforming Growth Factor-β Signaling

X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of apoptotic cell death, which functions by directly inhibiting caspases, the principal effectors of apoptosis. Here we report that XIAP can also function as a cofactor in the regulation of gene expression by transforming growth factor-β (TGF-β). XIAP, but not the related proteins c-IAP1 or c-IAP2, associated with several members of the type I class of the TGF-β receptor super-family and potentiated TGF-β-induced signaling. Although XIAP-mediated activation of c-Jun N-terminal kinase and nuclear factor κB was found to require the TGF-β signaling intermediate Smad4, the ability of XIAP to suppress apoptosis was found to be Smad4-independent. These data implicate a role for XIAP in TGF-β-mediated signaling that is distinct from its anti-apoptotic functions.