Phosphorylation of TRAF2 within Its RING Domain Inhibits Stress-Induced Cell Death by Promoting IKK and Suppressing JNK Activation

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an adaptor protein that modulates the activation of the c-Jun NH2 terminal kinase (JNK)/c-Jun and I kappa B kinase (IKK)/nuclear factor-kappa B (NF-kappa B) signaling cascades in response to TNF alpha stimulation. Although many serine/threonine kinases have been implicated in TNF alpha-induced IKK activation and NF-kappa B-dependent gene expression, most of them do not directly activate IKK. Here, we report that protein kinase C zeta phosphorylates TRAF2 at Ser(55), within the RING domain of the protein, after TNF alpha stimulation. Although this phosphorylation event has a minimal effect on induction of the immediate/transient phase of IKK and JNK activation by TNF alpha, it promotes the secondary/prolonged phase of IKK activation and inhibits that of JNK. Importantly, constitutive TRAF2 phosphorylation increased both basal and inducible NF-kappa B activation and rendered Ha-Ras-V12-transformed cells resistant to stress-induced apoptosis. Moreover, TRAF2 was found to be constitutively phosphorylated in some malignant cancer cell lines and Hodgkin's lymphoma. These results reveal a new level of complexity in TNFa-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation is one of the events that are responsible for elevated basal NF-kappa B activity in certain human cancers. [Cancer Res 2009;69(8):3665-72]