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J. Biol. Chem., Vol. 281, Issue 52, 39891-39896, December 29, 2006

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Protein Phosphatase 6 Down-regulates TAK1 Kinase Activation in the IL-1 Signaling Pathway^*

Taisuke Kajino, Hong Ren, Shun-ichiro Iemura^¶, Tohru Natsume^¶, Bjarki Stefansson^||, David L. Brautigan^||, Kunihiro Matsumoto^**, and Jun Ninomiya-Tsuji^**1

From the Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan, Cell Signaling Technology, Danvers, Massachusetts 01923, ^¶National Institutes of Advanced Industrial Science and Technology, Biological Information Research Center, Kohtoh-ku, Tokyo 135-0064, Japan, ^||Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, ^**Solution-oriented Research for Science and Technology, Japan Science and Technology Agency, Japan, and Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695-7633

TAK1 (transforming growth factor -activated kinase 1) is a serine/threonine kinase that is a mitogen-activated protein kinase kinase kinase and an essential intracellular signaling component in inflammatory signaling pathways. Upon stimulation of cells with inflammatory cytokines, TAK1 binds proteins that stimulate autophosphorylation within its activation loop and is thereby catalytically activated. This activation is transient; it peaks within a couple of minutes and is subsequently down-regulated rapidly to basal levels. The mechanism of down-regulation of TAK1 has not yet been elucidated. In this study, we found that toxin inhibition of type 2A protein phosphatases greatly enhances interleukin 1 (IL-1)-dependent phosphorylation of Thr-187 in the TAK1 activation loop as well as the catalytic activity of TAK1. From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187. Ectopic and endogenous PP6 co-precipitated with TAK1, and expression of PP6 reduced IL-1 activation of TAK1 but did not affect osmotic activation of MLK3, another MAPKKK. Reduction of PP6 expression by small interfering RNA enhances IL-1-induced phosphorylation of Thr-187 in TAK1. Enhancement occurred without change in levels of PP2A showing specificity for PP6. Our results demonstrate that PP6 specifically down-regulates TAK1 through dephosphorylation of Thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via TAK1 signaling pathways.

Received for publication, August 24, 2006 , and in revised form, October 30, 2006.

^* This work was supported by special grants for Solution-oriented Research for Science and Technology and Advanced Research on Cancer from the Ministry of Education, Culture, and Science of Japan (to K. M.) and by National Institutes of Health Grants GM068812 and AR050972 (to J. N.-T.), and CA077584 (to D. L. 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. Tel.: 919-513-1586; Fax: 919-515-7169; E-mail: Jun_Tsuji{at}ncsu.edu.

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