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

Chan Nguyen, Akinori Nishi, Janice W. Kansy, Joseph Fernandez, Kanehiro Hayashi, Frank Gillardon, Hugh C. Hemmings, Angus C. Nairn, James A. Bibb

研究成果: Article査読

22 被引用数 (Scopus)

抄録

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 Ser67. Further investigation has revealed the presence of an additional Cdk5 site identified by mass spectrometry and confirmed by site-directed mutagenesis as Ser6. Basal levels of phospho-Ser6 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 Ser6 were mediated by Cdk5, PP-2A, and PP-1, respectively. Additionally, calcineurin contributed to dephosphorylation under conditions of high Ca2+. In biochemical assays the function of Cdk5-dependent phosphorylation of inhibitor-1 at Ser6 and Ser 67 was demonstrated to be an intramolecular impairment of the ability of inhibitor-1 to be dephosphorylated at Thr35; this effect was recapitulated in two systems in vivo. Dephosphorylation of inhibitor-1 at Thr35 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 Thr35. 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.

本文言語English
ページ(範囲)16511-16520
ページ数10
ジャーナルJournal of Biological Chemistry
282
22
DOI
出版ステータスPublished - 2007 6 1
外部発表はい

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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