title: Site-specific activation of AKT protects cells from death induced by glucose deprivation.
abstract: The serine/threonine kinase AKT is a key mediator of cancer cell survival. We demonstrate that transient glucose deprivation modestly induces AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation induces selective AKTThr308 phosphorylation and phosphorylation of a distinct subset of AKT downstream targets leading to cell survival under metabolic stress. Glucose-deprivation-induced AKTThr308 phosphorylation is dependent on PDK1 and PI3K but not EGF receptor or IGF1R. Prolonged glucose deprivation induces the formation of a complex of AKT, PDK1 and the GRP78 chaperone protein, directing phosphorylation of AKTThr308 but not AKTSer473. Our results reveal a novel mechanism of AKT activation under prolonged glucose deprivation that protects cells from metabolic stress. The selective activation of AKTThr308 phosphorylation that occurs during prolonged nutrient deprivation may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant AKT signaling.
authors: 1] Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, People's Republic of China [2] Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: M
authors: M
authors: Gao
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: J
authors: J
authors: Liang
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Y
authors: Y
authors: Lu
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: H
authors: H
authors: Guo
authors: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: P
authors: P
authors: German
authors: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: S
authors: S
authors: Bai
authors: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: E
authors: E
authors: Jonasch
authors: Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
authors: X
authors: X
authors: Yang
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: G B
authors: GB
authors: Mills
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Z
authors: Z
authors: Ding
mesh_terms: D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
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