Regulation of protein phosphatase inhibitor-1 by cyclin-dependent kinase 5

Academic Article


  • Inhibitor-1, the first identified endogenous inhibitor of protein phosphatase 1 (PP-1), was previously reported to be a substrate for cyclin-dependent kinase 5 (Cdk5) at Ser . Further investigation has revealed the presence of an additional Cdk5 site identified by mass spectrometry and confirmed by site-directed mutagenesis as Ser . Basal levels of phospho-Ser inhibitor-1, as detected by a phosphorylation state-specific antibody against the site, existed in specific regions of the brain and varied with age. In the striatum, basal in vivo phosphorylation and dephosphorylation of Ser were mediated by Cdk5, PP-2A, and PP-1, respectively. Additionally, calcineurin contributed to dephosphorylation under conditions of high Ca . In biochemical assays the function of Cdk5-dependent phosphorylation of inhibitor-1 at Ser and Ser was demonstrated to be an intramolecular impairment of the ability of inhibitor-1 to be dephosphorylated at Thr ; this effect was recapitulated in two systems in vivo. Dephosphorylation of inhibitor-1 at Thr is equivalent to inactivation of the protein, as inhibitor-1 only serves as an inhibitor of PP-1 when phosphorylated by cAMP-dependent kinase (PKA) at Thr . Thus, inhibitor-1 serves as a critical junction between kinase- and phosphatase-signaling pathways, linking PP-1 to not only PKA and calcineurin but also Cdk5. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. 67 6 6 6 2+ 6 67 35 35 35
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    Author List

  • Nguyen C; Nishi A; Kansy JW; Fernandez J; Hayashi K; Gillardon F; Hemmings HC; Nairn AC; Bibb JA
  • Start Page

  • 16511
  • End Page

  • 16520
  • Volume

  • 282
  • Issue

  • 22