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J. Biol. Chem., Vol. 276, Issue 8, 5753-5759, February 23, 2001
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From the Departments of Protein phosphatase 2C (PP2C) is implicated in
the negative regulation of stress-activated protein kinase
cascades in yeast and mammalian cells. In this study, we determined the
role of PP2C
Regulation of the TAK1 Signaling Pathway by Protein
Phosphatase 2C*
§,
,
,
,
**
Biochemistry and
§ Clinical Oncology, Institute of Development, Aging, and
Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku,
Sendai 980-8575, the ¶ Department of Molecular Biology,
Graduate School of Science, Nagoya University, Chikusa-ku,
Nagoya 464-8602, and the
Department of Geriatric Dentistry,
Tohoku University School of Dentistry, 4-1 Seiryomachi, Aoba-ku,
Sendai 980-8575, Japan
-1, a major isoform of mammalian PP2C, in the TAK1
signaling pathway, a stress-activated protein kinase cascade that is
activated by interleukin-1, transforming growth factor-
, or stress.
Ectopic expression of PP2C
-1 inhibited the TAK1-mediated
mitogen-activated protein kinase kinase 4-c-Jun amino-terminal
kinase and mitogen-activated protein kinase kinase 6-p38 signaling
pathways. In vitro, PP2C
-1 dephosphorylated and
inactivated TAK1. Coimmunoprecipitation experiments indicated that
PP2C
-1 associates with the central region of TAK1. A
phosphatase-negative mutant of PP2C
-1, PP2C
-1 (R/G), acted as a
dominant negative mutant, inhibiting dephosphorylation of TAK1 by
wild-type PP2C
-1 in vitro. In addition, ectopic
expression of PP2C
-1(R/G) enhanced interleukin-1-induced activation
of an AP-1 reporter gene. Collectively, these results indicate that PP2C
negatively regulates the TAK1 signaling pathway by direct dephosphorylation of TAK1.
*
This work was supported in part by a grant-in-aid for
scientific research from the Ministry of Education, Science, Sports, and Culture of Japan and by the Smoking Research Foundation and the
Takeda Science Foundation.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.
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