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J. Biol. Chem., Vol. 279, Issue 53, 55419-55424, December 31, 2004

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Constitutive Protease-activated Receptor-2-mediated Migration of MDA MB-231 Breast Cancer Cells Requires Both -Arrestin-1 and -2^*

Lan Ge, Sudha K. Shenoy¶, Robert J. Lefkowitz¶||, and Kathryn DeFea**

From the Division of Biomedical Sciences, ^**Biochemical and Molecular Biology Program and Cellular, Molecular and Developmental Biology Program, University of California, Riverside, California 92521 and the ^¶Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710

Protease-activated receptor-2 (PAR-2) is activated by trypsin-like serine proteases and can promote cell migration through an ERK1/2-dependent pathway, involving formation of a scaffolding complex at the leading edge of the cell. Previous studies also showed that expression of a dominant negative fragment of -arrestin-1 reduces PAR-2-stimulated internalization, ERK1/2 activation, and cell migration; however, this reagent may block association of many proteins, including -arrestin-2 with clathrin-coated pits. Here we investigate the role of PAR-2 in the constitutive migration of a metastatic breast cancer cell line, MDA MB-231, and use small interfering RNA to determine the contribution of each -arrestin to this process. We demonstrate that a trypsin-like protease secreted from MDA MB-231 cells can promote cell migration through autocrine activation of PAR-2 and this correlates with constitutive localization of PAR-2, -arrestin-2, and activated ERK1/2 to pseudopodia. Addition of MEK-1 inhibitors, trypsin inhibitors, a scrambled PAR-2 peptide, and silencing of -arrestins with small interfering RNA also reduce base-line migration of MDA MB-231 cells. In contrast, a less metastatic PAR-2 expressing breast cancer cell line does not exhibit constitutive migration, pseudopodia formation, or trypsin secretion; in these cells PAR-2 is more uniformly distributed around the cell periphery. These data demonstrate a requirement for both -arrestins in PAR-2-mediated motility and suggest that autocrine activation of PAR-2 by secreted proteases may contribute to the migration of metastatic tumor cells through -arrestin-dependent ERK1/2 activation.

Received for publication, September 8, 2004 , and in revised form, October 12, 2004.

^* This work was supported by National Institutes of Health Grants R01HL016037 (to R. J. L.) and R01GM066151 (to K. D.) and in part by University of California Breast Cancer Research Program Award 7KB-0093. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental video 1.

These authors contributed equally to this work.

^|| A Howard Hughes Medical Institute Investigator.

To whom all correspondence should be addressed: B605 Statistics Rd., University of California, Riverside, CA 92521. Tel.: 951-827-2871; E-mail: katie.defea{at}ucr.edu.

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