Differential Activation Mechanisms of Erk-1/2 and p70S6K by Glucose in Pancreatic β-Cells

  1. Isabelle Briaud,
  2. Melissa K. Lingohr,
  3. Lorna M. Dickson,
  4. Christian E. Wrede and
  5. Christopher J. Rhodes
  1. From the Pacific Northwest Research Institute and Department of Pharmacology, University of Washington, Seattle, Washington


    Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70S6K, in β-cells, contributing to an increase in mitogenesis. However, the signaling mechanism by which glucose induces Erk-1/2 and p70S6K phosphorylation activation is undefined. Increased glucose metabolism increases [Ca2+]i and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70S6K activation in pancreatic β-cells. Blocking Ca2+ influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. Increasing cAMP levels by GLP-1 potentiated glucose-induced Erk-1/2 phosphorylation via PKA activation. Elevation of [Ca2+]i by glyburide potentiated Erk-1/2 phosphorylation, which was also inhibited by H89, suggesting increased [Ca2+]i preceded PKA for glucose-induced Erk-1/2 activation. Adenoviral-mediated expression of dominant negative Ras in INS-1 cells decreased IGF-1-induced Erk-1/2 phosphorylation but had no effect on that by glucose. Collectively, our study indicates that a glucose-induced rise in [Ca2+]i leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. In contrast, glucose-induced p70S6K activation, in the same β-cells, was mediated by a distinct signaling pathway independent of Ca2+/cAMP, most likely via mTOR-kinase acting as an “ATP-sensor.”


    • Address correspondence and reprint requests to Christopher J. Rhodes, PhD, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. E-mail: cjr{at}

      Received for publication 25 July 2002 and accepted in revised form 23 December 2002.

      C.E.W. is currently affiliated with Medizinische Klinik I, Universitat Regensburg, F.S. Staub-Allee II, 93042 Regensburg, Germany.

      EIA, enzyme immunoassay; GH, growth hormone; GLP-1, glucagon-like peptide-1; Grb2, growth factor receptor-bound protein-2; GSK3, glycogen synthase kinase-3; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; PKA, protein kinase A; PKB, protein kinase B; MEK, MAP/Erk kinase; mSOS, mammalian Son of Sevenless; mTOR, mammalian target of rapamycin.

    | Table of Contents