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

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. Apopt...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-10, Vol.278 (41), p.40330-40336
Main Authors: Liu, Hong, Toman, Rachelle E., Goparaju, Sravan K., Maceyka, Michael, Nava, Victor E., Sankala, Heidi, Payne, Shawn G., Bektas, Meryem, Ishii, Isao, Chun, Jerold, Milstien, Sheldon, Spiegel, Sarah
Format: Article
Language:English
Subjects:
3T3 Cells
Amino Acid Sequence
Animals
Apoptosis - physiology
Base Sequence
Cell Line
Conserved Sequence
DNA, Complementary - genetics
Humans
Isoenzymes - chemistry
Isoenzymes - genetics
Isoenzymes - physiology
Mice
Molecular Sequence Data
Mutagenesis, Site-Directed
PC12 Cells
Peptide Fragments - chemistry
Phosphotransferases (Alcohol Group Acceptor) - chemistry
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - physiology
Proto-Oncogene Proteins - chemistry
Rats
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Transfection
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M304455200