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J. Biol. Chem., Vol. 283, Issue 16, 10753-10763, April 18, 2008

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Protein Phosphatase 2A Is a Negative Regulator of Transforming Growth Factor-β1-induced TAK1 Activation in Mesangial Cells^*

Sung Il Kim¹, Joon Hyeok Kwak¹, Lin Wang, and Mary E. Choi²

From the Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 and the Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

TAK1 (transforming growth factor (TGF)-β-activated kinase 1) is a serine/threonine kinase that is rapidly activated by TGF-β1 and plays a vital function in its signal transduction. Once TAK1 is activated, efficient down-regulation of TAK1 activity is important to prevent excessive TGF-β1 responses. The regulatory mechanism of TAK1 inactivation following TGF-β1 stimulation has not been elucidated. Here we demonstrate that protein phosphatase 2A (PP2A) plays a pivotal role as a negative regulator of TAK1 activation in response to TGF-β1 in mesangial cells. Treatment with okadaic acid (OA) induces autophosphorylation of Thr-187 in the activation loop of TAK1. In vitro dephosphorylation assay suggests that Thr-187 in TAK1 is a major dephosphorylation target of PP2A. TGF-β1 stimulation rapidly activates TAK1 in a biphasic manner, indicating that TGF-β1-induced TAK1 activation is tightly regulated. The association of PP2A_C with TAK1 is enhanced in response to TGF-β1 stimulation and closely parallels TGF-β1-induced TAK1 activity. Attenuation of PP2A activity by OA treatment or targeted knockdown of PP2A_C with small interfering RNA enhances TGF-β1-induced phosphorylation of TAK1 at Thr-187 and MKK3 (MAPK kinase 3). Endogenous TAK1 co-precipitates with PP2A_C but not PP6_C, another OA-sensitive protein phosphatase, and knockdown of PP6_C by small interfering RNA does not affect TGF-β1-induced phosphorylation of TAK1 at Thr-187 and MKK3. Moreover, ectopic expression of phosphatase-deficient PP2A_C enhances TAK1-mediated MKK3 phosphorylation by TGF-β1 stimulation, whereas the expression of wild-type PP2A_C suppresses the MKK3 phosphorylation. Taken together, our data indicate that PP2A functions as a negative regulator in TGF-β1-induced TAK1 activation.

Received for publication, February 15, 2008

^* This work was supported in part by NIDDK, National Institutes of Health, Grant R01 DK57661 and the M. James Scherbenske Grant from the American Society of Nephrology (to M. E. C.) and Beginning Grant-in-Aid 0665379U from the American Heart Association (to S. I. K.). 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 Both of these authors contributed equally to this work.

² To whom correspondence should be addressed: Renal Division, Brigham and Women's Hospital, Dept. of Medicine, Harvard Medical School, 4 Blackfan Circle, HIM-5, Boston, MA 02115. Fax: 617-525-5923; E-mail: mchoi{at}rics.bwh.harvard.edu.

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