c-Src-p38 MAPK Signaling is Required for Akt Activation in response to Ionizing Radiation

초록

The Akt and MAP kinase pathways have been implicated in tumor cell survival and contribute to radiation resistance. However, the molecular basis for link between MAPK and Akt in cell survival response to radiation is unclear. Here, we demonstrate that c-Src-Rac1-p38 MAPK pathway signals Akt activation and cell survival in response to radiation. Ionizing radiation triggered activity-related Thr308 and Ser473 phosphorylation of Akt. Exposure of cells to radiation also induced p38 MAPK and JNK activations. Inhibition of JNK suppressed radiation-induced cell death, while inhibition of p38 MAPK effectively increased sensitivity to radiation. Interestingly, inhibition of p38 MAPK completely attenuated radiation-induced Ser473 phosphorylation of Akt, but did not affect Thr308 phosphorylation. Conversely, overexpression of p38 MAPK enhanced Ser473 phosphorylation of Akt in response to radiation. In addition, inhibition of p38 MAPK failed to alter PI3K and PDK activities. Ectopic expression of RacN17, dominant-negative forms of Rac1 inhibited p38 MAPK activation and Ser473 phosphorylation of Akt. Following exposure to radiation, c-Src was selectively activated among Src family tyrosine kinases. Inhibition of c-Src attenuated Rac1 and p38 MAPK activations, and Ser473 phosphorylation of Akt. Our results support the notion that the c-Src-Rac1-p38 MAPK pathway is required for the activity-related Ser473 phosphorylation of Akt in response to radiation, and plays a cytoprotective role against radiation in human cancer cells.