Research ArticleCell Biology

ER Stress Inhibits mTORC2 and Akt Signaling Through GSK-3β–Mediated Phosphorylation of Rictor

Sci. Signal.  22 Feb 2011:
Vol. 4, Issue 161, pp. ra10
DOI: 10.1126/scisignal.2001731

You are currently viewing the editor's summary.

View Full Text
As a service to the community, AAAS/Science has made this article free with registration.

No Access During Stressful Times

Under conditions of cellular stress, cells tend to halt anabolic processes, such as cell growth and proliferation, to conserve resources. mTORC2 (mammalian target of rapamycin complex 2), which mediates its effects through activation of the kinase Akt, is a key signaling complex that promotes anabolic processes. Chen et al. investigated the mechanisms by which mTORC2 activity is inhibited by endoplasmic reticulum (ER) stress. They found that glycogen synthase kinase–3β (GSK-3β), which is activated by ER stress, phosphorylated rictor, a component of mTORC2 that helps to determine substrate specificity for the complex. This phosphorylation event decreased binding of Akt to mTORC2, resulting in reduced activation of Akt and cell proliferation. Furthermore, transformed cells expressing a mutant form of rictor lacking the GSK-3β phosphorylation site formed larger tumors in mice than did those expressing wild-type rictor or a rictor mutant that mimicked a constitutively phosphorylated form. These results define a pathway by which mTORC2 and Akt signaling can be attenuated by cellular stress and provide a potential therapeutic target for limiting cell proliferation (such as in cancer).