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J. Biol. Chem., Vol. 280, Issue 33, 29462-29469, August 19, 2005

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Role of Sphingosine Kinase 2 in Cell Migration toward Epidermal Growth Factor^*

Nitai C. Hait, Sukumar Sarkar, Hervé Le Stunff, Aki Mikami, Michael Maceyka, Sheldon Milstien¶, and Sarah Spiegel||

From the Department of Biochemistry and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 and the ^¶Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 20892

Sphingosine 1-phosphate (S1P), produced by two sphingosine kinase isoenzymes, denoted SphK1 and SphK2, is the ligand for a family of five specific G protein-coupled receptors that regulate cytoskeletal rearrangements and cell motility. Whereas many growth factors stimulate SphK1, much less is known of the regulation of SphK2. Here we report that epidermal growth factor (EGF) stimulated SphK2 in HEK 293 cells. This is the first example of an agonist-dependent regulation of SphK2. Chemotaxis of HEK 293 cells toward EGF was inhibited by N,N-dimethylsphingosine, a competitive inhibitor of both SphKs, implicating S1P generation in this process. Down-regulating expression of SphK1 in HEK 293 cells with a specific siRNA abrogated migration toward EGF, whereas decreasing SphK2 expression had no effect. EGF contributes to the invasiveness of human breast cancer cells, and EGF receptor expression is associated with poor prognosis. EGF also stimulated SphK2 in MDA-MB-453 breast cancer cells. Surprisingly, however, down-regulation of SphK2 in these cells completely eliminated migration toward EGF without affecting fibronectin-induced haptotaxis. Our results suggest that SphK2 plays an important role in migration of MDA-MB-453 cells toward EGF.

Received for publication, March 16, 2005 , and in revised form, June 7, 2005.

^* This work was supported by NCI, National Institutes of Health Grant R01CA61774 (to S. S.) and a Ruth L. Kirschstein National Research Service Award (to M. M.). 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.

Present address: Laboratoire de Physiopathologie de la Nutrition, Université Paris 7, CNRS UMR 7059, 75251 Paris Cedex 05, France.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0614. Tel.: 804-828-9330; Fax: 804-828-8999; E-mail: sspiegel{at}vcu.edu.

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