Phosphorylation of protein phosphatase inhibitor-1 by protein kinase C

Academic Article

Abstract

  • Inhibitor-1 becomes a potent inhibitor of protein phosphatase 1 when phosphorylated by cAMP-dependent protein kinase at Thr . Moreover, Ser of inhibitor-1 serves as a substrate for cyclin-dependent kinase 5 in the brain. Here, we report that dephosphoinhibitor-1 but not phospho-Ser inhibitor-1 was efficiently phosphorylated by protein kinase C at Ser in vitro. In contrast, Ser phosphorylation by cyclin-dependent kinase 5 was unaffected by phospho-Ser . Protein kinase C activation in striatal tissue resulted in the concomitant phosphorylation of inhibitor-1 at Ser and Ser , but not Ser alone. Selective pharmacological inhibition of protein phosphatase activity suggested that phospho-Ser inhibitor-1 is dephosphorylated by protein phosphatase 1 in the striatum. In vitro studies confirmed these findings and suggested that phospho-Ser protects phospho-Ser inhibitor-1 from dephosphorylation by protein phosphatase 1 in vivo. Activation of group I metabotropic glutamate receptors resulted in the up-regulation of diphospho-Ser /Ser inhibitor-1 in this tissue. In contrast, the activation of N-methyl-D-aspartate-type ionotropic glutamate receptors opposed increases in striatal diphospho-Ser /Ser inhibitor-1 levels. Phosphomimetic mutation of Ser and/or Ser did not convert inhibitor-1 into a protein phosphatase 1 inhibitor. On the other hand, in vitro and in vivo studies suggested that diphospho-Ser /Ser inhibitor-1 is a poor substrate for cAMP-dependent protein kinase. These observations extend earlier studies regarding the function of phospho-Ser and underscore the possibility that phosphorylation in this region of inhibitor-1 by multiple protein kinases may serve as an integrative signaling mechanism that governs the responsiveness of inhibitor-1 to cAMP-dependent protein kinase activation. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc. 35 67 67 65 67 65 65 67 65 65 67 65 65 67 65 67 65 67 65 67 67
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    Digital Object Identifier (doi)

    Author List

  • Sahin B; Shu H; Fernandez J; El-Armouche A; Molkentin JD; Nairn AC; Bibb JA
  • Start Page

  • 24322
  • End Page

  • 24335
  • Volume

  • 281
  • Issue

  • 34