Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5.
Sphingosine 1-phosphate (S1P) regulates cell proliferation, apoptosis, motility, and neurite retraction. Contradictory reports propose that S1P acts as either an intracellular second messenger or an extracellular ligand for cell-surface receptors. Hence, the precise signaling mechanisms mediating the diverse cellular effects of S1P remain to be determined. Here, we investigate whether S1P stimulation of cell proliferation, survival, and related signaling events can be mediated by the recently cloned Edg family members of G protein-coupled receptors. We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. Edg3 and Edg5 transduced S1P-evoked signaling events relevant to cell proliferation and survival, including activation of the ERK/MAP kinases, and immediate-early induction of c-Jun and c-Fos. Trancriptional activation of reporter genes for the c-fos promoter and the serum response element by Edg3 and Edg5 transfected in Jurkat cells was inhibited by pertussis toxin and C3 exoenzyme, implicating G(i/o)- and Rho-dependent pathways. Our data also indicated that Edg3 and Edg5 mediated the serum response element activation through transcriptional factors Elk-1 and serum response factor. Thus, specific G protein-coupled receptors Edg3 and Edg5 account for, at least in part, S1P-induced cell proliferation, survival, and related signaling events.
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Department of Medicine, University of California, San Francisco, California 94143-0711, USA. songzhu@itsa.ucsf.edu
Zheng
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Bleu
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D002455:Cell Division; D002470:Cell Survival; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D008246:Lysophospholipids; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D026362:Serum Response Factor; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D020672:I-kappa B Proteins; D008246:Lysophospholipids; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D026362:Serum Response Factor; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020741:rho GTP-Binding Proteins; D013110:Sphingosine