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J. Biol. Chem., Vol. 279, Issue 19, 20461-20470, May 7, 2004

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Mint-3 Regulates the Retrieval of the Internalized Membrane-type Matrix Metalloproteinase, MT5-MMP, to the Plasma Membrane by Binding to Its Carboxyl End Motif EWV^*

Ping Wang, Xing Wang, and Duanqing Pei

From the Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota 55455

Membrane type matrix metalloproteinases (MT-MMPs) play a critical role in promoting cell growth and migration within the extracellular matrix by trafficking to specialized areas. Here we show that the carboxyl EWV motif of MT5-MMP serves as a retrieval signal for internalized MT5-MMP by interacting with Mint-3, a protein with two type III PDZ domains. Deletion of the EWV signal impairs the recycling of MT5-MMP without affecting its internalization, leading to decreased activity on the cell surface. A yeast two-hybrid screening identified Mint-3 as the EWV-binding protein. Mint-3 stimulates MT5-MMP activity when expressed at low levels in an EWV-dependent fashion, but inhibits its activity at higher levels independent of the EWV motif. siRNA-mediated knockdown of endogenous Mint-3 decreased MT5-MMP activity. Furthermore, Mint-3 significantly increased the level of MT5-MMP on the cell surface without affecting its synthesis and internalization. Therefore, Mints may be the adaptor proteins that regulate the trafficking of MT-MMPs.

Received for publication, January 12, 2004 , and in revised form, February 22, 2004.

^* This work was supported in part by National Institutes of Health Grant CA76308, Department of Defense Prostate Cancer Research Program DAMD17-03-1-0089, American Cancer Society Grant RPG-00-056-01-CSM, and American Lung Association Grant CI-0220N. 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.

A career investigator of the American Lung Association. To whom correspondence should be addressed: 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-626-1468; Fax: 612-624-3952; E-mail: peixx003{at}umn.edu.

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