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J. Biol. Chem., Vol. 280, Issue 13, 12602-12610, April 1, 2005

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Role of Protein Phosphatase 2A in mGluR5-regulated MEK/ERK Phosphorylation in Neurons^*

Limin Mao, Lu Yang, Anish Arora, Eun Sang Choe, Guochi Zhang, Zhenguo Liu, Eugene E. Fibuch¶, and John Q. Wang¶||

From the Departments of Basic Medical Science and ^¶Anesthesiology, University of Missouri-Kansas City, School of Medicine, Kansas City, Missouri 64108 and Division of Biological Sciences, Pusan National University, Pusan 609-735, Korea

The regulation of protein phosphorylation requires coordinated interaction between protein kinases and protein phosphatases (PPs). Recent evidence has shown that the Gq-protein-coupled metabotropic glutamate receptor (mGluR) 5 up-regulates phosphorylation of MAPK/ERK1/2. However, signaling mechanisms linking mGluR5 to ERK are poorly understood. In this study, roles of a major serine/threonine PP, PP2A, in this event were evaluated in cultured neurons. We found that the PP1/2A inhibitors okadaic acid and calyculin A mimicked the effect of the mGluR5 agonists (RS)-3,5-dihydroxyphenylglycine and (RS)-2-chloro-5-hydroxyphenylglycine in facilitating phosphorylation of ERK1/2 and its upstream kinase, MEK1/2, in a PP2A-dependent but not PP1-dependent manner. Co-administration of either inhibitor with an mGluR5 agonist produced additive phosphorylation of ERK1/2. Enzymatic assays showed a basal level of phosphatase activity of PP2A under normal conditions, and activation of mGluR5 selectively inhibited PP2A, but not PP1, activity. In addition, a physical association of the cytoplasmic C terminus of mGluR5 with PP2A was observed, and ligand activation of mGluR5 reduced mGluR5-PP2A binding. Additional mechanistic studies revealed that mGluR5 activation increased tyrosine (Tyr³⁰⁷) phosphorylation of PP2A, which was dependent on activation of a p60c-Src family tyrosine kinase, but not the epidermal growth factor receptor tyrosine kinase and resulted in dissociation of PP2A from mGluR5 and reduced PP2A activity. Together, we have identified a novel, mGluR5-triggered signaling mechanism involving use- and Src-dependent inactivation of PP2A, which contributes to mGluR5 activation of MEK1/2 and ERK1/2.

Received for publication, October 14, 2004 , and in revised form, January 12, 2005.

^* This work was supported by National Institutes of Health Grants R01DA010355 (to J. Q. W.) and R01MH061469 (to J. Q. W.). 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.

^|| To whom correspondence should be addressed: Dept. of Basic Medical Science, University of Missouri-Kansas City, School of Medicine, 2411 Holmes St., Kansas City, MO 64108. Tel.: 816-235-1786; Fax: 816-235-6517; E-mail: wangjq{at}umkc.edu.

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