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J. Biol. Chem., Vol. 282, Issue 16, 12058-12065, April 20, 2007

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Sphingosine Kinase Type 2 Activation by ERK-mediated Phosphorylation^*

Nitai C. Hait, Andrea Bellamy, Sheldon Milstien, Tomasz Kordula¹, and Sarah Spiegel¹²

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), a potent lipid mediator, is a ligand for a family of five G protein-coupled receptors (S1P_1–5) that have been shown to regulate a variety of biological responses important for cancer progression. The cellular level of S1P is low and tightly regulated in a spatio-temporal manner through its synthesis catalyzed by two sphingosine kinases, denoted SphK1 and SphK2. Many stimuli activate and translocate SphK1 to the plasma membrane by mechanisms that are dependent on its phosphorylation. Much less is known about activation of SphK2. Here we demonstrate that epidermal growth factor (EGF) as well as the protein kinase C activator, phorbol ester, induce rapid phosphorylation of hSphK2 which was markedly reduced by inhibition of MEK1/ERK pathway. Down-regulation of ERK1 blocked EGF-induced phosphorylation of SphK2. Recombinant ERK1 phosphorylated hSphK2 in vitro and increased its enzymatic activity. ERK1 also was found to be in a complex with hSphK2 in vivo. Site-directed mutagenesis indicated that hSphK2 is phosphorylated on Ser-351 and Thr-578 by ERK1 and that phosphorylation of these residues is important for EGF-stimulated migration of MDA-MB-453 cells. These studies provide the first clues to the mechanism of agonist-mediated SphK2 activation and enhance understanding of the regulation of SphK2 activity by phosphorylation and its role in movement of human breast cancer cells toward EGF.

Received for publication, October 10, 2006 , and in revised form, January 29, 2007.

^* This work was supported by National Institutes of Health Grants R01CA61774 and R37GM043880 (to S. S.) and the National Institute of Mental Health Intramural Research Program (to S. 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.

¹ These two authors contributed equally to this paper.

² To whom correspondence should be addressed: Dept. of Biochemistry, Virginia Commonwealth School of Medicine, 1101 E. Marshall St., 2-011 Sanger Hall, Box 980614, Richmond, VA 23298. Tel.: 804-828-9330; Fax: 804-828-8999; E-mail: sspiegel{at}vcu.edu.

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