Abstract
Addition of sphingosine 1-phosphate induces proliferation of quiescent Swiss 3T3 fibroblasts by unknown mechanisms. To identify the pathways involved, the ability of sphingosine 1-phosphate to activate mitogen-activated protein (MAP) kinase was studied. Sphingosine 1-phosphate rapidly activated the Raf/MAP kinase kinase (MKK)/MAP kinase pathway, and the concentration dependence for MAP kinase activation correlated with that for induction of DNA synthesis. Both MKK1 and MKK2 were activated by sphingosine 1-phosphate, assessed by specific immune complex kinase assays. Prior treatment of the Swiss 3T3 cells with pertussis toxin inhibited 70-80% of the sphingosine 1-phosphate-stimulated MAP kinase activity. Thus, one of the direct or indirect targets of exogenous sphingosine 1-phosphate appears to be a G(i)/G(o) protein.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Becaplermin
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Division / drug effects
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DNA / biosynthesis
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DNA Replication / drug effects
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Dose-Response Relationship, Drug
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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GTP-Binding Proteins / metabolism*
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Kinetics
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Lysophospholipids / pharmacology
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Mice
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Mitogen-Activated Protein Kinase Kinases
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Pertussis Toxin
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Platelet-Derived Growth Factor / pharmacology
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-raf
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins / pharmacology
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Virulence Factors, Bordetella / pharmacology
Substances
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Lysophospholipids
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-sis
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Recombinant Proteins
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Virulence Factors, Bordetella
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Becaplermin
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sphingosine 1-phosphate
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DNA
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Pertussis Toxin
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Protein Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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GTP-Binding Proteins
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Sphingosine