Notch-induced T cell development requires phosphoinositide-dependent kinase 1

April P. Kelly, David K. Finlay, Heather J. Hinton, Rosie G. Clarke, Emma Fiorini, Freddy Radtke, Doreen A. Cantrell

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    96 Citations (Scopus)

    Abstract

    Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development.
    Original languageEnglish
    Pages (from-to)3441-3450
    Number of pages10
    JournalEMBO Journal
    Volume26
    Issue number14
    DOIs
    Publication statusPublished - 25 Jul 2007

    Keywords

    • 3-Phosphoinositide-Dependent Protein Kinases
    • Animals
    • Cell Differentiation
    • Cell Proliferation
    • Food
    • Mice
    • Mutant Proteins
    • Protein Kinase Inhibitors
    • Protein Kinases
    • Protein-Serine-Threonine Kinases
    • Receptors, Notch
    • Ribosomal Protein S6 Kinases
    • Stem Cells
    • T-Lymphocytes
    • TOR Serine-Threonine Kinases

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  • Cite this

    Kelly, A. P., Finlay, D. K., Hinton, H. J., Clarke, R. G., Fiorini, E., Radtke, F., & Cantrell, D. A. (2007). Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO Journal, 26(14), 3441-3450. https://doi.org/10.1038/sj.emboj.7601761