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Oncogene. 2014 Feb 6;33(6):745-55. doi: 10.1038/onc.2013.2. Epub 2013 Feb 11.

Site-specific activation of AKT protects cells from death induced by glucose deprivation.

Author information

  • 11] 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.
  • 2Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.

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.

PMID:
23396361
[PubMed - indexed for MEDLINE]
PMCID:
PMC3874430
[Available on 2015/2/6]
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