Abstract
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.
Highlights
Reactive oxygen species (ROS) stimulate signaling pathways that influence diverse cellular processes, from survival to aging [1]
Since Akt is a well-characterized mammalian target of rapamycin (mTOR) complex 2 (mTORC2) substrate [6, 7], we examined whether mTORC2 was required for Rit-mediated Akt activation by transfecting wild-type (WT) and Rictor null (Rictor-/-) mouse embryonic fibroblasts (MEFs) with either empty vector or a Flag-RitQ79L expression vector (Fig. 1C)
We report here that mTORC2 signaling plays an essential role in Rit-mediated Akt activation in response to oxidative stress
Summary
Reactive oxygen species (ROS) stimulate signaling pathways that influence diverse cellular processes, from survival to aging [1]. The generation of excessive ROS results in oxidative stress and leads to molecular and cellular damage, contributing to the pathogenesis of numerous human diseases. ROS-activated signaling pathways have evolved to promote cell survival and homeostasis, by coupling stress stimuli to appropriate cellular responses. A balance must be maintained between pathways that promote survival or death. Exposure of cells to oxidative damage induces activation of numerous intracellular signaling pathways, including cascades controlled by the p38 MAPK, known as stressactivated protein kinase [2]. We recently identified a fundamental role for the Rit
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