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J. Biol. Chem., Vol. 279, Issue 23, 24889-24898, June 4, 2004

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Regulation of the Multifunctional Ca²⁺/Calmodulin-dependent Protein Kinase II by the PP2C Phosphatase PPM1F in Fibroblasts^*

Bohdan P. Harvey, Satnam S. Banga, and Harvey L. Ozer

From the Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School and UMDNJ-Graduate School of Biomedical Sciences, Newark, New Jersey 07101

The regulation of the multifunctional calcium/calmodulin dependent protein kinase II (CaMKII) by serine/threonine protein phosphatases has been extensively studied in neuronal cells; however, this regulation has not been investigated previously in fibroblasts. We cloned a cDNA from SV40-transformed human fibroblasts that shares 80% homology to a rat calcium/calmodulin-dependent protein kinase phosphatase that encodes a PPM1F protein. By using extracts from transfected cells, PPM1F, but not a mutant (R326A) in the conserved catalytic domain, was found to dephosphorylate in vitro a peptide corresponding to the auto-inhibitory region of CaMKII. Further analyses demonstrated that PPM1F specifically dephosphorylates the phospho-Thr-286 in autophosphorylated CaMKII substrate and thus deactivates the CaMKII in vitro. Coimmunoprecipitation of CaMKII with PPM1F indicates that the two proteins can interact intracellularly. Binding of PPM1F to CaMKII involves multiple regions and is not dependent on intact phosphatase activity. Furthermore, overexpression of PPM1F in fibroblasts caused a reduction in the CaMKII-specific phosphorylation of the known substrate vimentin(Ser-82) following induction of the endogenous CaM kinase. These results identify PPM1F as a CaM kinase phosphatase within fibroblasts, although it may have additional functions intracellularly since it has been presented elsewhere as POPX2 and hFEM-2. We conclude that PPM1F, possibly together with the other previously described protein phosphatases PP1 and PP2A, can regulate the activity of CaMKII. Moreover, because PPM1F dephosphorylates the critical autophosphorylation site of CaMKII, we propose that this phosphatase plays a key role in the regulation of the kinase intracellularly.

Received for publication, January 20, 2004 , and in revised form, March 24, 2004.

^* This work was supported in part by Grant AG04821 from the NIA, National Institutes of Health. 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.

Supported in part by Grant T32 CA09665 from the NCI, National Institutes of Health.

To whom correspondence should be addressed: UMDNJ-New Jersey Medical School, 185 South Orange Ave., MSB, Rm. C-671, Newark, NJ 07101-1709. Tel.: 973-972-3558; Fax: 973-972-7104; E-mail: ozerhl{at}umdnj.edu.

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