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J. Biol. Chem., Vol. 282, Issue 22, 16511-16520, June 1, 2007

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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, Jr.^**, Angus C. Nairn, and James A. Bibb¹

From the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan, ^¶Protein/DNA Technology Center and Laboratory of Cellular and Molecular Neuroscience, Rockefeller University, New York, New York 10021, ^||Central Nervous System Research, Boehringer Ingelheim Pharma KG, 88397 Biberach an der Riss, Germany, ^**Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, and Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508

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.

Received for publication, February 5, 2007 , and in revised form, March 13, 2007.

^* This work was supported by Individual Pre-doctoral National Research Service Award MH072062 from the National Institutes of Health Office of Extramural Research (to C. N.); National Institute on Drug Abuse Grants DA16672 (to J. A. B.) and DA10044 (to A.C. N.); National Institute of Mental Health Grant MH67777 (to J. A. B.); NHLBI, National Institutes of Health, Grant HL077101 (to J. A. B.); and the Ella McFadden Charitable Trust Fund at the Southwestern Medical Foundation (to J. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9070. Tel.: 214-648-4168; Fax: 214-648-1293; E-mail: james.bibb{at}utsouthwestern.edu.

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