Abstract The tumor microenvironment is known to trigger chronic endoplasmic reticulum (ER) and oxidative stresses, and cancer-cell adaptation to such chronic stresses has profound consequences for malignant progression and the response to therapy. TRAF2 regulates cellular response to TNFα, ER and oxidative stresses by activating the JNK/c-Jun and IKK/NF-κB signaling cascades. We mapped two phosphorylation sites (Ser-11 and Ser-55) on the N-terminal RING domain of TRAF2, and reported that phosphorylation at these sites increases basal and TNFα-induced NF-κB activation. Recently, we identified TBK1 and PKCζ as the kinases that directly phosphorylate TRAF2 at Ser-11 and Ser-55 sites, respectively. We found that in addition to TNFα, ER and oxidative stresses also strongly induce TRAF2 phosphorylation at both sites. This dual phosphorylation of TRAF2 promoted IKK activation and inhibited the prolonged phase of JNK activation in response to ER and oxidative stresses. Importantly, TRAF2 phosphorylation was found to be essential for cancer-cell survival under conditions of chronic cellular stress. Specifically, the endogenous TRAF2-dockdown cancer cells that were stable expressed with phospho-null-mutant TRAF2 (TRAF2-S11/55A) did not survive under conditions of chronic ER and oxidative stresses, while their TRAF2-WT counterparts survived under the same conditions. In addition, the TRAF2-S11/55A-expressing cancer cells formed significantly smaller tumors in vivo and exhibited greater sensitivity to anti-cancer drug-induced apoptosis than did TRAF2-WT-expressing counterparts. Functional assays revealed that TRAF2 phosphorylation not only promotes NF-κB-dependent gene expression, but also suppresses JNK-mediated degradation of Bcl-2 and cIAP1 at post-transcriptional level in the context of ER and oxidative stresses. Collectively, these findings suggest that TRAF2 phosphorylation plays a critical role in tumor progression by promoting the expression of anti-apoptotic proteins in cancer cells, and could be a new target for anti-cancer drug development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 198. doi:10.1158/1538-7445.AM2011-198