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

Abstract

<div>Abstract<p>Tumor necrosis factor (TNF) receptor–associated factor 2 (TRAF2) is an adaptor protein that modulates the activation of the c-Jun NH<sub>2</sub> terminal kinase (JNK)/c-Jun and IκB kinase (IKK)/nuclear factor-κB (NF-κB) signaling cascades in response to TNFα stimulation. Although many serine/threonine kinases have been implicated in TNFα-induced IKK activation and NF-κB–dependent gene expression, most of them do not directly activate IKK. Here, we report that protein kinase Cζ phosphorylates TRAF2 at Ser<sup>55</sup>, within the RING domain of the protein, after TNFα stimulation. Although this phosphorylation event has a minimal effect on induction of the immediate/transient phase of IKK and JNK activation by TNFα, it promotes the secondary/prolonged phase of IKK activation and inhibits that of JNK. Importantly, constitutive TRAF2 phosphorylation increased both basal and inducible NF-κB 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 TNFα-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation is one of the events that are responsible for elevated basal NF-κB activity in certain human cancers. [Cancer Res 2009;69(8):3665–72]</p></div>