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

TitleRegulation of protein phosphatase inhibitor-1 by cyclin-dependent kinase 5.
Publication TypeJournal Article
Year of Publication2007
AuthorsNguyen C, Nishi A, Kansy JW, Fernandez J, Hayashi K, Gillardon F, Hemmings HC, Nairn AC, Bibb JA
JournalJ Biol Chem
Date Published2007 Jun 1
KeywordsAmino Acid Substitution, Animals, Brain, Calcineurin, Cyclic AMP-Dependent Protein Kinases, Cyclin-Dependent Kinase 5, Male, Mutagenesis, Site-Directed, Mutation, Missense, PC12 Cells, Phosphoprotein Phosphatases, Phosphorylation, Protein Phosphatase 1, Protein Processing, Post-Translational, Proteins, Rats, Signal Transduction

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 Ser67 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.

Alternate JournalJ. Biol. Chem.
PubMed ID17400554
Grant ListDA10044 / DA / NIDA NIH HHS / United States
DA16672 / DA / NIDA NIH HHS / United States
HL077101 / HL / NHLBI NIH HHS / United States
MH072062 / MH / NIMH NIH HHS / United States
MH67777 / MH / NIMH NIH HHS / United States
P01 DA010044 / DA / NIDA NIH HHS / United States