Title | Regulation of protein phosphatase inhibitor-1 by cyclin-dependent kinase 5. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Nguyen C, Nishi A, Kansy JW, Fernandez J, Hayashi K, Gillardon F, Hemmings HC, Nairn AC, Bibb JA |
Journal | J Biol Chem |
Volume | 282 |
Issue | 22 |
Pagination | 16511-20 |
Date Published | 2007 Jun 01 |
ISSN | 0021-9258 |
Keywords | Amino 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 |
Abstract | 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. |
DOI | 10.1074/jbc.M701046200 |
Alternate Journal | J Biol Chem |
PubMed ID | 17400554 |
PubMed Central ID | PMC4296900 |
Grant List | HL077101 / HL / NHLBI NIH HHS / United States F30 MH072062 / MH / NIMH NIH HHS / United States R01 MH067777 / MH / NIMH NIH HHS / United States MH67777 / MH / NIMH NIH HHS / United States DA16672 / DA / NIDA NIH HHS / United States P01 DA010044 / DA / NIDA NIH HHS / United States R01 DA016672 / DA / NIDA NIH HHS / United States DA10044 / DA / NIDA NIH HHS / United States MH072062 / MH / NIMH NIH HHS / United States P50 HL077101 / HL / NHLBI NIH HHS / United States |