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J. Biol. Chem., Vol. 282, Issue 10, 7624-7631, March 9, 2007

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Tyrosine Phosphorylation of Missing in Metastasis Protein Is Implicated in Platelet-derived Growth Factor-mediated Cell Shape Changes^*

Ying Wang, Kang Zhou, Xianchun Zeng, Jinxiu Lin, and Xi Zhan¹

From the Department of Pathology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201 and Department of Cardiology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China

Missing in metastasis gene, or MTSS1, encodes an intracellular protein that is implicated in actin cytoskeleton reorganization and often down-regulated in certain types of tumor cells. In response to platelet-derived growth factor (PDGF), green fluorescent protein (GFP)-tagged murine Mtss1 (Mtss1-GFP) underwent redistribution from the cytoplasm to dorsal membrane ruffles along with phosphorylation at tyrosine residues in a time-dependent manner. Tyrosine phosphorylation of Mtss1-GFP was also elevated in cells where an oncogenic Src was activated but severely impaired in Src knock-out cells or cells treated with Src kinase inhibitor PP2. Mutagenesis analysis has revealed that phosphorylation occurs at multiple sites, including tyrosine residues Tyr-397 and Tyr-398. Mutation at both Tyr-397 and Tyr-398 abolished the PDGF-mediated tyrosine phosphorylation. Furthermore, recombinant Mtss1 protein was phosphorylated by recombinant Src in a manner dependent on Tyr-397 and Tyr-398. Efficient tyrosine phosphorylation of Mtss1 in response to PDGF also involves a coiled-coil domain, which is essential for a proper distribution to the cell leading edge and dorsal ruffles. Interestingly, overexpression of wild type Mtss1-GFP promoted the PDGF-induced dorsal ruffling, whereas overexpression of a mutant deficient in phosphorylation at Tyr-397 and Tyr-398 or a mutant with deletion of the coiled-coil domain impaired the formation of dorsal ruffles. These data indicate that Mtss1 represents a novel signaling pathway from PDGF receptor to the actin cytoskeleton via Src-related kinases.

Received for publication, September 1, 2006 , and in revised form, January 12, 2007.

^* This work was supported by National Institutes of Health Grants R01CA113809 and R01CA091984 (to X. Z.). 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: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 W. Baltimore St., Baltimore, MD 21201. Tel.: 410-706-8228; Fax: 410-706-8234; E-mail: Hxzhan{at}som.umaryland.edu.

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