C-Src-p38 Mitogen-Activated Protein Kinase Signaling Is Required for Akt Activation in Response to Ionizing Radiation

Min-Jung Kim,Su-Jae Lee,Kee-Ho Lee,Chang-Hwan Yun,Joo-Yun Byun,In-Chul Park

doi:10.1158/1541-7786.mcr-08-0084

Abstract

The Akt and mitogen-activated protein kinase (MAPK) 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 show that c-Src-Rac1-p38 MAPK pathway signals Akt activation and cell survival in response to radiation. Ionizing radiation triggered Thr(308) and Ser(473) phosphorylation of Akt. Exposure of cells to radiation also induced p38 MAPK and c-Jun NH(2)-terminal kinase activations. Inhibition of c-Jun NH(2)-terminal kinase suppressed radiation-induced cell death, whereas inhibition of p38 MAPK effectively increased sensitivity to radiation. Interestingly, inhibition of p38 MAPK completely attenuated radiation-induced Ser(473) phosphorylation of Akt but did not affect Thr(308) phosphorylation. Conversely, overexpression of p38 MAPK enhanced Ser(473) phosphorylation of Akt in response to radiation. In addition, inhibition of p38 MAPK failed to alter phosphoinositide 3-kinase and phosphoinositide-dependent protein kinase activities. Ectopic expression of RacN17, dominant-negative form of Rac1, inhibited p38 MAPK activation and Ser(473) 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 Ser(473) phosphorylation of Akt. Our results support the notion that the c-Src-Rac1-p38 MAPK pathway is required for activation of Akt in response to radiation and plays a cytoprotective role against radiation in human cancer cells.

Highlights

Sensitivity of tumor cells to radiation is a critical determinant of the probability of local control and of cure of cancers by radiation therapy
Membrane-bound PDK1 phosphorylates Thr308 in the pleckstrin homology domain of Akt, resulting in activation
We show that the c-Src-Rac1-p38 mitogen-activated protein kinase (MAPK) pathway is required for the Akt activation in response to radiation and that the pathway plays a cytoprotective role against radiation-induced cell death

Summary

Introduction

Sensitivity of tumor cells to radiation is a critical determinant of the probability of local control and of cure of cancers by radiation therapy. Intracellular signaling molecules seem to play an important role in determining the intrinsic radiosensitivity of tumor cells. Exposure of cells to ionizing radiation results in the simultaneous activation or down-regulation of multiple signaling pathways, which play critical roles in cell type-specific control of survival or death in response to ionizing radiation [1,2,3,4]. Akt is cell survival kinase and plays a central role in promoting tumorigenesis [7, 8]. Membrane-bound PDK1 phosphorylates Thr308 in the pleckstrin homology domain of Akt, resulting in activation. Ser473 is phosphorylated at the COOH-terminal domain for full activation of Akt by either autophosphorylation or an uncharacterized kinase, PDK2 [10, 11]

Methods

Results

Conclusion