Inhibition of JNK by cellular stress- and tumor necrosis factor α-induced AKT2 through activation of the NFκB pathway in human epithelial cells

Previous studies have demonstrated that AKT1 and AKT3 are activated by heat shock and oxidative stress via both phosphatidylinositol 3-kinase-dependent and -independent pathways. However, the activation and role of AKT2 in the stress response have not been fully elucidated. In this study, we show that AKT2 in epithelial cells is activated by UV-C irradiation, heat shock, and hyperosmolarity as well as by tumor necrosis factor alpha (TNFalpha) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UV-and TNFalpha-induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stress- and TNFalpha-induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates IkappaB kinase alpha. The phosphorylation of IkappaB kinase a and activation of NFkappaB mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UV- and TNFalpha-induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNFalpha stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stress- and TNFalpha-induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NFkappaB pathway.