title: ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Tattym
authors.initials: T
authors.lastname: Shaikenov
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Peterson
authors.forename: Rakhan
authors.initials: R
authors.lastname: Aimbetov
authors.forename: Amangeldy K
authors.initials: AK
authors.lastname: Bissenbaev
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Dos D
authors.initials: dos D
authors.lastname: Sarbassov
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012694:Serine / Q000378:metabolism; D013312:Stress, Physiological; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C493245:CRTC2 protein, human; D002352:Carrier Proteins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3