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

作者：Chen Chien Hung; Shaikenov Tattym; Peterson Timothy R; Aimbetov Rakhan; Bissenbaev Amangeldy K; Lee Szu Wei; Wu Juan; Lin Hui Kuan; Sarbassov Dos D^*

来源：Science Signaling, 2011, 4(161): ra10.

DOI：10.1126/scisignal.2001731

In response to environmental cues, cells coordinate a balance between anabolic and catabolic pathways. In eukaryotes, growth factors promote anabolic processes and stimulate cell growth, proliferation, and survival through activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. Akt-mediated phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) inhibits its enzymatic activity, thereby stimulating glycogen synthesis. We show that GSK-3 beta itself inhibits Akt by controlling the mammalian target of rapamycin complex 2 (mTORC2), a key activating kinase for Akt. We found that during cellular stress, GSK-3 beta phosphorylated the mTORC2 component rictor at serine-1235, a modification that interfered with the binding of Akt to mTORC2. The inhibitory effect of GSK-3 beta on mTORC2-Akt signaling and cell proliferation was eliminated by blocking phosphorylation of rictor at serine-1235. Thus, in response to cellular stress, GSK-3 beta restrains mTORC2-Akt signaling by specifically phosphorylating rictor, thereby balancing the activities of GSK-3 beta and Akt, two opposing players in glucose metabolism.

• 出版日期2011-2-22