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J. Biol. Chem., Vol. 281, Issue 43, 32574-32586, October 27, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/43/32574    most recent M604338200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, N.-Y. Articles by Ethell, I. M. Search for Related Content PubMed PubMed Citation Articles by Yang, N.-Y. Articles by Ethell, I. M. Social Bookmarking                      What's this?

The EphB4 Receptor-tyrosine Kinase Promotes the Migration of Melanoma Cells through Rho-mediated Actin Cytoskeleton Reorganization^*

Nai-Ying Yang, Elena B. Pasquale, Laurie B. Owen^¶, and Iryna M. Ethell¹

From the Division of Biomedical Sciences, University of California Riverside, Riverside, California 92521, The Burnham Institute for Medical Research, La Jolla, California 92037, and ^¶BioLegend, San Diego, California 92121

Several studies have reported the up-regulation of EphB receptor-tyrosine kinases and ephrin-B ligands in a variety of tumors, suggesting a functional relation between EphB/ephrin-B signaling and tumor progression. The ability of the EphB receptors to regulate cell migration and promote angiogenesis likely contributes to tumor progression and metastasis. Here we show that EphB receptors, and especially EphB4, regulate the migration of murine melanoma cells. Highly malignant melanoma cells express the highest levels of EphB4 receptor and migrate faster than less malignant melanoma cells. Furthermore, inhibition of EphB receptor forward signaling by overexpression of a form of EphB4 lacking the cytoplasmic portion or by treatment with competitively acting soluble EphB2-Fc results in slower melanoma cell migration. In contrast, overexpression of active EphB4 significantly enhances cell migration. The effects of EphB4 receptor on cell migration and cell morphology require its kinase activity because the inhibition of EphB4 kinase activity by overexpression of kinase dead EphB4 inhibits cell migration and affects the organization of actin cytoskeleton. Activation of EphB4 receptor with its ligand ephrin-B2-Fc enhances the migratory ability of melanoma cells and increases RhoA activity, whereas inhibiting EphB receptor forward signaling decreases RhoA activity. Moreover, expression of dominant negative RhoA blocks the effects of active EphB4 on cell migration and actin organization. These data suggest that EphB4 forward signaling contributes to the high migratory ability of invasive melanoma cells by influencing RhoA-mediated actin cytoskeleton reorganization.

Received for publication, May 5, 2006 , and in revised form, July 26, 2006.

^* This work is supported by a University of California Cancer Research Coordinating Committee grant (to I. M. E.). 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 Figs. S1-S3 and Table S1.

¹ To whom correspondence should be addressed. Tel.: 951-827-2186; Fax: 951-827-7121; E-mail: iryna.ethell{at}ucr.edu.

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