Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance

Jose R. Bayascas, Stephan Wullschleger, Kei Sakamoto, Juan M. Garcia-Martinez, Carol Clacher, David Komander, Daan M. F. van Aalten, Krishna M. Boini, Florian Lan, Christopher Lipina, Lisa Logie, Calum Sutherland, John A. Chudek, Janna A. van Diepen, Peter J. Voshol, John M. Lucocq, Dario R. Alessi

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    Abstract

    PDK1 activates a group of kinases, including. protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

    Original languageEnglish
    Pages (from-to)3258-3272
    Number of pages15
    JournalMolecular and Cellular Biology
    Volume28
    Issue number10
    DOIs
    Publication statusPublished - May 2008

    Keywords

    • IN-VIVO ROLE
    • MICE LACKING
    • GLUCOSE-HOMEOSTASIS
    • S6 KINASE
    • PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE
    • HYPOMORPHIC MICE
    • KNOCKIN MUTATION
    • CELL-SIZE
    • B-GAMMA
    • GROWTH

    Cite this

    Bayascas, J. R., Wullschleger, S., Sakamoto, K., Garcia-Martinez, J. M., Clacher, C., Komander, D., van Aalten, D. M. F., Boini, K. M., Lan, F., Lipina, C., Logie, L., Sutherland, C., Chudek, J. A., van Diepen, J. A., Voshol, P. J., Lucocq, J. M., & Alessi, D. R. (2008). Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Molecular and Cellular Biology, 28(10), 3258-3272. https://doi.org/10.1128/MCB.02032-07