ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor.

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-3β (GSK-3β) inhibits its enzymatic activity, thereby stimulating glycogen ...
synthesis. We show that GSK-3β 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-3β phosphorylated the mTORC2 component rictor at serine-1235, a modification that interfered with the binding of Akt to mTORC2. The inhibitory effect of GSK-3β on mTORC2-Akt signaling and cell proliferation was eliminated by blocking phosphorylation of rictor at serine-1235. Thus, in response to cellular stress, GSK-3β restrains mTORC2-Akt signaling by specifically phosphorylating rictor, thereby balancing the activities of GSK-3β and Akt, two opposing players in glucose metabolism.
Mesh Terms:
Carrier Proteins, Endoplasmic Reticulum, Enzyme Activation, Glycogen Synthase Kinase 3, Humans, Phosphorylation, Proto-Oncogene Proteins c-akt, Serine, Stress, Physiological, Substrate Specificity, Transcription Factors
Sci Signal
Date: Feb. 24, 2011
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