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. 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.
Liu
Hong
H
Department of Biochemistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0614, USA.
Toman
Rachelle E
RE
Goparaju
Sravan K
SK
Maceyka
Michael
M
Nava
Victor E
VE
Sankala
Heidi
H
Payne
Shawn G
SG
Bektas
Meryem
M
Ishii
Isao
I
Chun
Jerold
J
Milstien
Sheldon
S
Spiegel
Sarah
S
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099157:Sphingosine Kinase
D018076:DNA, Complementary; D007527:Isoenzymes; D010446:Peptide Fragments; D017853:Phosphotransferases (Alcohol Group Acceptor); D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D000099157:Sphingosine Kinase; C474007:Bax protein (53-86)