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

Pathology Graduate Program and Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa

^* To whom correspondence should be addressed. E-mail: hasem-habelhah{at}uiowa.edu.

	Abstract

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 IB kinase (IKK)/nuclear factor-B (NF-B) signaling cascades in response to TNF stimulation. Although many serine/threonine kinases have been implicated in TNF-induced IKK activation and NF-B–dependent gene expression, most of them do not directly activate IKK. Here, we report that protein kinase C phosphorylates TRAF2 at Ser⁵⁵, within the RING domain of the protein, after TNF stimulation. Although this phosphorylation event has a minimal effect on induction of the immediate/transient phase of IKK and JNK activation by TNF, it promotes the secondary/prolonged phase of IKK activation and inhibits that of JNK. Importantly, constitutive TRAF2 phosphorylation increased both basal and inducible NF-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 TNF-induced IKK activation modulated by TRAF2 phosphorylation and suggest that TRAF2 phosphorylation is one of the events that are responsible for elevated basal NF-B activity in certain human cancers. [Cancer Res 2009;69(8):OF1–8]

Key Words: apoptosis, JNK, NF-B, phosphorylation, TRAF2