Rit, a member of the Ras family of GTPases, has been shown to promote cell survival in response to oxidative stress, in part by directing an evolutionarily conserved p38 MAPK-Akt survival cascade. Aberrant Rit signaling has recently been implicated as a driver mutation in human cancer, adding importance to the characterization of critical Rit effector pathways. However, the mechanism by which Rit-p38 signaling regulated Akt activity was unknown. Here, we identify mTORC2 as a critical downstream mediator of Rit-dependent survival signaling in response to reactive oxygen species (ROS) stress. Rit interacts with Sin1 (MAPKAP1), and Rit loss compromises ROS-dependent mTORC2 complex activation, blunting mTORC2-mediated phosphorylation of Akt kinase. Taken together, our findings demonstrate that the p38/mTORC2/Akt signaling cascade mediates Rit-dependent oxidative stress survival. Inhibition of this previously unrecognized cascade should be explored as a potential therapy of Rit-dependent malignancies.
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This work was supported by National Institutes of Health (NIH) NS045103 (DAA) and P20 GM103486 (DAA), Kentucky Spinal Cord and Head Injury Research Trust Grant 12-1A (DAA), and University of Kentucky Research Professorship (DAA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Cai, Weikang and Andres, Douglas A., "mTORC2 is Required for Rit-Mediated Oxidative Stress Resistance" (2014). Molecular and Cellular Biochemistry Faculty Publications. 78.