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 (TNF ) through a phosphatidylinositol 3-kinase-dependent pathway. The activation of AKT2 inhibits UVand TNF -induced c-Jun N-terminal kinase (JNK) and p38 activities that have been shown to be required for stressand TNF -induced programmed cell death. Moreover, AKT2 interacts with and phosphorylates I B kinase . The phosphorylation of I B kinase and activation of NF B mediates AKT2 inhibition of JNK but not p38. Furthermore, phosphatidylinositol 3-kinase inhibitor or dominant negative AKT2 significantly enhances UVand TNF -induced apoptosis, whereas expression of constitutively active AKT2 inhibits programmed cell death in response to UV and TNF stimulation with an accompanying decreased JNK and p38 activity. These results indicate that activated AKT2 protects epithelial cells from stressand TNF -induced apoptosis by inhibition of stress kinases and provide the first evidence that AKT inhibits stress kinase JNK through activation of the NF B pathway.