Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Ke Ning, Lisa C. Miller, Hilary A. Laidlaw, Kenneth R. Watterson, Jennifer Gallagher, Calum Sutherland, Michael L. J. Ashford (Lead / Corresponding author)

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    Abstract

    Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic beta-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptin-mediated F-actin depolymerization and consequent ATP-sensitive K+ channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones.

    Original languageEnglish
    Pages (from-to)9331-9340
    Number of pages10
    JournalJournal of Biological Chemistry
    Volume284
    Issue number14
    DOIs
    Publication statusPublished - 3 Apr 2009

    Keywords

    • GLYCOGEN-SYNTHASE KINASE-3
    • TUMOR-SUPPRESSOR PHOSPHATASE
    • TYROSINE PHOSPHORYLATION
    • SIGNALING PATHWAYS
    • CELL-LINE
    • INSULIN
    • NEURONS
    • INHIBITION
    • OBESITY
    • CRI-G1

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