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J. Biol. Chem., Vol. 281, Issue 50, 38405-38417, December 15, 2006

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Inhibition of Cell Migration by Autophosphorylated Mammalian Sterile 20-Like Kinase 3 (MST3) Involves Paxillin and Protein-tyrosine Phosphatase-PEST^*

From the ^aDepartment of Biochemistry and Molecular Biology, ^bInstitute of Basic Medical Sciences, the ^fDepartment of Pharmacology, ^gCenter for Gene Regulation and Signal Transduction Research, and the ^hDepartment of Physiology, College of Medicine, ⁱInstitute of Biotechnology, College of Bioscience and Biotechnology, National Cheng Kung University, 701 Tainan, the ^cDepartment of Medical Technology, Chung-Hwa College of Medical Technology, 717 Tainan, ^dDivision of Molecular and Genomic Medicine, National Health Research Institute, 115 Taipei, the ^eDepartment of Cell and Molecular Biology, Institute of Basic Medical Sciences, Medical College of Chang Gung University, 333 Tao-Yuan, and the ^jDepartment of Life Science, National Tsing Hua University, 300 Hsinchu, Taiwan

MST3 is a member of the sterile-20 protein kinase family with a unique preference for manganese ion as a cofactor in vitro; however, its biological function is largely unknown. Suppression of endogenous MST3 by small interference RNA enhanced cellular migration in MCF-7 cells with reduced expression of E-cadherin at the edge of migrating cells. The alteration of cellular migration and protruding can be rescued by RNA interference-resistant MST3. The expression of surface integrin and Golgi apparatus was not altered, but phosphorylation on tyrosine 118 and tyrosine 31 of paxillin was attenuated by MST3 small interfering RNA (siRNA). Threonine 178 was determined to be one of the two main autophosphorylation sites of MST3 in vitro. Mutant T178A MST3, containing alanine instead of threonine at codon 178, lost autophosphorylation and kinase activities. Overexpression of wild type MST3, but not the T178A mutant MST3, inhibited migration and spreading in Madin-Darby canine kidney cells. MST3 could phosphorylate the protein-tyrosine phosphatase (PTP)-PEST and inhibit the tyrosine phosphatase activity of PTP-PEST. We conclude that MST3 inhibits cell migration in a fashion dependent on autophosphorylation and may regulate paxillin phosphorylation through tyrosine phosphatase PTP-PEST.

Received for publication, May 25, 2006 , and in revised form, September 14, 2006.

^* This work was supported in part by Grant of NSC 94-2311-B-006-002 (to M.-D. L.) and in part by the Program for Promoting University Academic Excellence Projects 91-B-FA09-1-4 (to W.-C. C.). 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: Dept. of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Fax: 886-6-2741694; E-mail: a1211207{at}mail.ncku.edu.tw.

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