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J. Biol. Chem., Vol. 282, Issue 23, 17259-17271, June 8, 2007

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The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition^*

Samudra K. Dissanayake, Michael Wade, Carrie E. Johnson¹, Michael P. O'Connell, Poloko D. Leotlela, Amanda D. French, Kavita V. Shah^¶, Kyle J. Hewitt², Devin T. Rosenthal³, Fred E. Indig^||, Yuan Jiang⁴, Brian J. Nickoloff^**, Dennis D. Taub, Jeffrey M. Trent, Randall T. Moon^¶, Michael Bittner, and Ashani T. Weeraratna⁵

From the Laboratory of Immunology, Gerontology Research Center, and the ^||Research Resources Branch, Gerontology Research Center, NIA, National Institutes of Health (NIH), Baltimore, Maryland 21224, the Cancer Genetics Branch, NHGRI, NIH, Bethesda, Maryland 20892, the ^¶Department of Pharmacology, Howard Hughes Medical Institute, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98195, the ^**Department of Pathology, Loyola University Medical Center, Maywood, Illinois 60153, and The Translational Genomics Research Institute, Phoenix, Arizona 85004

We have shown that Wnt5A increases the motility of melanoma cells. To explore cellular pathways involving Wnt5A, we compared gain-of-function (WNT5A stable transfectants) versus loss-of-function (siRNA knockdown) of WNT5A by microarray analysis. Increasing WNT5A suppressed the expression of several genes, which were re-expressed after small interference RNA-mediated knockdown of WNT5A. Genes affected by WNT5A include KISS-1, a metastasis suppressor, and CD44, involved in tumor cell homing during metastasis. This could be validated at the protein level using both small interference RNA and recombinant Wnt5A (rWnt5A). Among the genes up-regulated by WNT5A was the gene vimentin, associated with an epithelial to mesenchymal transition (EMT), which involves decreases in E-cadherin, due to up-regulation of the transcriptional repressor, Snail. rWnt5A treatment increases Snail and vimentin expression, and decreases E-cadherin, even in the presence of dominant-negativeTCF4, suggesting that this activation is independent of Wnt/-catenin signaling. Because Wnt5A can signal via protein kinase C (PKC), the role of PKC in Wnt5A-mediated motility and EMT was also assessed using PKC inhibition and activation studies. Treating cells expressing low levels of Wnt5A with phorbol ester increased Snail expression inhibiting PKC in cells expressing high levels of Wnt5A decreased Snail. Furthermore, inhibition of PKC before Wnt5A treatment blocked Snail expression, implying that Wnt5A can potentiate melanoma metastasis via the induction of EMT in a PKC-dependent manner.

Received for publication, January 3, 2007 , and in revised form, March 26, 2007.

^* This work was supported by the Intramural Research Program of NIA, National Institutes of Health (NIH). 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 Fig. S1.

¹ Present address: Dept. of Pharmacology and Cancer Biology, Duke University, Durham, NC 90065.

² Present address: Program in Cell and Molecular Physiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111.

³ Present address: Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, MI 48109.

⁴ Present address: Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892.

⁵ To whom correspondence should be addressed: Laboratory of Immunology, NIA, NIH, 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8506; Fax: 410-558-8284; E-mail: weerarat{at}grc.nia.nih.gov.

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