Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation

Caryll Waugh, Linda Sinclair, David Finlay, Jose R. Bayascas, Doreen Cantrell

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    The present study explored the consequences of phosphoinositide (3,4,5)-triphosphate [PI(3,4,5) P-3] binding to the pleckstrin homology (PH) domain of the serine/threonine kinase 3-phosphoinositide-dependent kinase 1 (PDK1). The salient finding is that PDK1 directly transduces the PI(3,4,5)P-3 signaling that determines T-cell trafficking programs but not T-cell growth and proliferation. The integrity of the PDK1 PH domain thus is not required for PDK1 catalytic activity or to support cell survival and the proliferation of thymic and peripheral T cells. However, a PDK1 mutant that cannot bind PI(3,4,5)P-3 cannot trigger the signals that terminate the expression of the transcription factor KLF2 in activated T cells and cannot switch the chemokine and adhesion receptor profile of naOve T cells to the profile of effector T cells. The PDK1 PH domain also is required for the maximal activation of Akt/protein kinase B (PKB) and for the maximal phosphorylation and inactivation of Foxo family transcription factors in T cells. PI(3,4,5)P-3 binding to PDK1 and the strength of PKB activity thus can dictate the nature of the T-cell response. Low levels of PKB activity can be sufficient for T-cell proliferation but insufficient to initiate the migratory program of effector T cells.

    Original languageEnglish
    Pages (from-to)5952-5962
    Number of pages11
    JournalMolecular and Cellular Biology
    Issue number21
    Publication statusPublished - 1 Nov 2009


    • NF-Kappa-B
    • Pleckstrin-homology-domain
    • L-selectin
    • Phosphatidylinositol 3-kinase
    • Antigen receptor
    • Immunological synapse
    • Development requires
    • Docking site
    • PKC-theta
    • In vivo

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