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

M. Gao, J. Liang, Y. Lu, H. Guo, P. German, S. Bai, E. Jonasch, X. Yang, Gordon Mills, Z. Ding

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)745-755
Number of pages11
JournalOncogene
Volume33
Issue number6
DOIs
StatePublished - Feb 6 2014
Externally publishedYes

Fingerprint

Cell Death
Phosphorylation
Glucose
Physiological Stress
Cell Survival
Protein-Serine-Threonine Kinases
Drug Delivery Systems
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Food
Neoplasms
Proteins

Keywords

  • cell survival
  • glucose deprivation
  • site-specific AKT phosphorylation
  • substrate-specific AKT activation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Gao, M., Liang, J., Lu, Y., Guo, H., German, P., Bai, S., ... Ding, Z. (2014). Site-specific activation of AKT protects cells from death induced by glucose deprivation. Oncogene, 33(6), 745-755. https://doi.org/10.1038/onc.2013.2

Site-specific activation of AKT protects cells from death induced by glucose deprivation. / Gao, M.; Liang, J.; Lu, Y.; Guo, H.; German, P.; Bai, S.; Jonasch, E.; Yang, X.; Mills, Gordon; Ding, Z.

In: Oncogene, Vol. 33, No. 6, 06.02.2014, p. 745-755.

Research output: Contribution to journalArticle

Gao, M, Liang, J, Lu, Y, Guo, H, German, P, Bai, S, Jonasch, E, Yang, X, Mills, G & Ding, Z 2014, 'Site-specific activation of AKT protects cells from death induced by glucose deprivation', Oncogene, vol. 33, no. 6, pp. 745-755. https://doi.org/10.1038/onc.2013.2
Gao, M. ; Liang, J. ; Lu, Y. ; Guo, H. ; German, P. ; Bai, S. ; Jonasch, E. ; Yang, X. ; Mills, Gordon ; Ding, Z. / Site-specific activation of AKT protects cells from death induced by glucose deprivation. In: Oncogene. 2014 ; Vol. 33, No. 6. pp. 745-755.
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