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J. Biol. Chem. 278 (41): 40330-40336

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Sphingosine Kinase Type 2 Is a Putative BH3-only Protein That Induces Apoptosis*

Hong Liu {ddagger}, Rachelle E. Toman {ddagger} §, Sravan K. Goparaju {ddagger}, Michael Maceyka {ddagger}, Victor E. Nava ¶, Heidi Sankala {ddagger}, Shawn G. Payne ||, Meryem Bektas {ddagger}, Isao Ishii **, Jerold Chun {ddagger}{ddagger}, Sheldon Milstien ||, and Sarah Spiegel {ddagger} §§

{ddagger}Department of Biochemistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0614, §Interdisciplinary Program in Neuroscience and Department of Biochemistry, Georgetown University Medical Center, Washington, D. C. 20007, Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892, **Department of Molecular Genetics, National Institute of Neuroscience, Tokyo 187-8502, Japan, {ddagger}{ddagger}Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, ||Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 20892

Abstract: There are two isoforms of sphingosine kinase (SphK) that catalyze the formation of sphingosine 1-phosphate, a potent sphingolipid mediator. Whereas SphK1 stimulates growth and survival, here we show that SphK2 enhanced apoptosis in diverse cell types and also suppressed cellular proliferation. Apoptosis was preceded by cytochrome c release and activation of caspase-3. SphK2-induced apoptosis was independent of activation of sphingosine 1-phosphate receptors. Sequence analysis revealed that SphK2 contains a 9-amino acid motif similar to that present in BH3-only proteins, a pro-apoptotic subgroup of the Bcl-2 family. As with other BH3-only proteins, co-immunoprecipitation demonstrated that SphK2 interacted with Bcl-xL. Moreover, site-directed mutation of Leu-219, the conserved leucine residue present in all BH3 domains, markedly suppressed SphK2-induced apoptosis. Hence, the apoptotic effect of SphK2 might be because of its putative BH3 domain.

Received for publication April 29, 2003. Revision received June 18, 2003.

* This work was supported by National Institutes of Health Grants CA61774 (to S. S.) and in part by MH01723 (to J. C.). 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.

§§ To whom correspondence should be addressed. Tel.: 804-828-9330; Fax: 804-828-8999; E-mail: sspiegel{at}vcu.edu.

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