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.

Document Type


Publication Date


Notes/Citation Information

Published in PLOS One, v. 9, no. 12, article e115602, p. 1-15.

© 2014 Cai, Andres.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)


Funding Information

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.

journal.pone.0115602.s001.TIF (139 kB)
S1 Fig. Deletion of Rictor reduces Sin1, but not Raptor, in MEFs.