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, G. B. Mills, Z. Ding

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    37 Scopus citations

    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

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    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., Jonasch, E., Yang, X., Mills, G. B., & 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