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Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN

PNAS, 8 August 2006
Vol. 103, Issue 32, p. 12093-12097
DOI: 10.1073/pnas.0604628103

Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN

  1. Cullen M. Taniguchi *,
  2. Thien T. Tran *,
  3. Tatsuya Kondo ,
  4. Ji Luo , § ,
  5. Kohjiro Ueki ,
  6. Lewis C. Cantley , § , , and
  7. C. Ronald Kahn * , **
  1. *Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215;
  2. Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan;
  3. Department of Systems Biology, Harvard Medical School, Boston, MA 02215;
  4. §Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and
  5. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
  1. Contributed by Lewis C. Cantley, June 3, 2006

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin on liver. Here, we show that mice with a liver-specific deletion of the p85α regulatory subunit of PI3K (L-Pik3r1KO) exhibit a paradoxical improvement of hepatic and peripheral insulin sensitivity. Although PI3K enzymatic activity is diminished in L-Pik3r1KO livers because of a reduced level of regulatory and catalytic subunits of PI3K, insulin-stimulated Akt activity is actually increased. This increased Akt activity correlates with increased phosphatidylinositol (3,4,5)-trisphosphate levels which are due, at least in part, to diminished activity of the (3,4,5)-trisphosphate phosphatase PTEN. Thus, the regulatory subunit p85α is a critical modulator of insulin sensitivity in vivo not only because of its effects on PI3K activation, but also as a regulator of PTEN activity.

  • conditional gene knockout
  • diabetes
  • insulin resistance

Footnotes

  • To whom correspondence may be addressed. E-mail: lcantley{at}hms.harvard.edu
  • **To whom correspondence may be addressed at:
    Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.
    E-mail: c.ronald.kahn{at}joslin.harvard.edu
  • Author contributions: C.M.T., K.U., and L.C.C. designed research; C.M.T., T.T.T., T.K., and J.L. performed research; L.C.C. contributed new reagents/analytic tools; C.M.T., T.K., J.L., and C.R.K. analyzed data; and C.M.T., J.L., L.C.C., and C.R.K. wrote the paper.

  • Conflict of interest statement: No conflicts declared.

  • Abbreviations:
    HGP,
    hepatic glucose production;
    PI3K,
    phosphoinositide 3-kinase;
    PIP3,
    phosphatidylinositol (3,4,5)-trisphosphate;
    pTyr,
    phosphotyrosine.
  • Freely available online through the PNAS open access option.

Citation:

C. M. Taniguchi, T. T. Tran, T. Kondo, J. Luo, K. Ueki, L. C. Cantley, and C. R. Kahn, Phosphoinositide 3-kinase regulatory subunit p85α suppresses insulin action via positive regulation of PTEN. PNAS 103, 12093-12097 (2006).

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