RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for tumor necrosis factor-induced ASK1-JNK/p38 activation.

摘要: Previously, we have shown that ASK1-interacting protein 1 (AIP1, also known as DAB2IP), a novel member of the Ras-GAP (Ras-GTPase-activating protein) family, opens its conformation in response to tumor necrosis factor (TNF), allowing it form complex with TRAF2-ASK1 leads activation ASK1-JNK/p38 signaling endothelial cells (EC). In present study, show TNF-inducible 14-3-3-binding site on AIP1 is critical for opening and AIP1-mediated TNF signaling. Ser-604, located C-terminal domain AIP1, was identified site. treatment EC induces phosphorylation at Ser-604 detected by phospho-specific antibody, similar kinetics activation. 14-3-3 associates an open, active state assessed vitro pulldown assay. Mutation (AIP1-S604A) blocks TNF-induced formation 14-3-3. normally association TRAF2-ASK1. The interactions TRAF2 ASK1 do not occur AIP1-S604A, suggesting this only creates but up binding ASK1. Overexpression AIP1-S604A ASK1-JNK We further RIP1 (the Ser/Thr kinase receptor-interacting GAP mediates JNK/p38 demonstrated both overexpression small interfering RNA knockdown EC. Furthermore, synergizes (but AIP1-S604A) inducing apoptosis. Our results demonstrate RIP1-mediated essential TRAF2-RIP1-AIP1-ASK1 apoptotic