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Originally published In Press as doi:10.1074/jbc.M107558200 on January 25, 2002

J. Biol. Chem., Vol. 277, Issue 15, 13312-13320, April 12, 2002
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KEPI, a PKC-dependent Protein Phosphatase 1 Inhibitor Regulated by Morphine*

Qing-Rong Liu, Ping-Wu Zhang, Qiaoxi Zhen, Donna Walther, Xiao-Bing Wang, and George R. UhlDagger

From the Molecular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224

cDNAs encoding KEPI, a novel protein kinase C (PKC)-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatase (PP1), were identified. They were found among morphine-regulated brain mRNAs identified using subtracted differential display techniques. Full-length rat, mouse, and human cDNA and genomic sequences were elucidated with library screening and data base searching. Rat, mouse, and human KEPI cDNAs encode 164-165 amino acid proteins with calculated isoelectric points of 5.2. Each species' amino acid sequence contains consensus sequences for phosphorylation by PKC (KVT72VK), protein kinase A (RKLS154), and casein kinase II (S43SRE, S120EEE). Multiple KEPI N-terminal myristoylation consensus sites provide potential regions for membrane anchoring. Subcellular fractionation and Western analyses revealed that most KEPI immunoreactivity was associated with P2 and P3 membrane-enriched fractions and little in cytosolic fractions. 2.6-kb KEPI mRNAs were detected in brain, especially in the cerebral cortex and hippocampus, and in heart and skeletal muscle. Brain KEPI mRNA was up-regulated by both acute and chronic morphine treatments. The human KEPI gene contains four exons extending over more than 100 kb of genomic sequence on 6q24-q25, near the µ opiate receptor gene. These sequences displayed sufficient homology with the porcine PP1 inhibitor CPI-17 that we asked whether KEPI could share the ability of CPI-17 to modulate PP1 activity in a PKC-dependent fashion. Recombinant mouse KEPI is phosphorylated by PKC with a Km of 2.6 µM and a t1/2 of 20 min. Phospho-KEPI inhibits PP1alpha with an IC50 of 2.7 nM, a potency more than 600-fold greater than that displayed by unphosphorylated KEPI. Neither phospho- nor dephospho-KEPI inhibits protein phosphatase 2A. Up-regulation of KEPI expression by morphine, an agonist at PKC-regulating G-protein-coupled µ receptors, provides a novel signaling paradigm in which the half-lives of serine/threonine phosphorylation events can be influenced by activities at Gi/Go-coupled receptors that modulate KEPI expression, KEPI phosphorylation, and KEPI regulation of PP1 activity.

* This work was supported by the National Institutes on Drug Abuse.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Molecular Neurobiology Branch, National Institute on Drug Abuse IRP, P. O. Box 5180, 5500 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-550-1589; Fax: 410-550-1535; E-mail: guhl@intra.nida.nih.gov.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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