Abstract
Mitogen stimulation of cytoskeletal changes and c-jun amino-terminal kinases is mediated by Rac small guanine nucleotide-binding proteins. Vav, a guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange factor for Rac that stimulates the exchange of bound GDP for GTP, bound to and was directly controlled by substrates and products of phosphoinositide (PI) 3-kinase. The PI 3-kinase substrate phosphatidylinositol-4,5-bisphosphate inhibited activation of Vav by the tyrosine kinase Lck, whereas the product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav by Lck. Control of Vav in response to mitogens by the products of PI 3-kinase suggests a mechanism for Ras-dependent activation of Rac.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line
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Enzyme Activation
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GTP Phosphohydrolases / metabolism*
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GTP-Binding Proteins / metabolism*
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Guanine Nucleotide Exchange Factors
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Guanosine Diphosphate / metabolism*
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Guanosine Triphosphate / metabolism
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Inositol 1,4,5-Trisphosphate / metabolism
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Inositol 1,4,5-Trisphosphate / pharmacology
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
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Mutagenesis, Site-Directed
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Oncogene Proteins / chemistry
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Oncogene Proteins / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphatidylinositol 4,5-Diphosphate / metabolism
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Phosphatidylinositol 4,5-Diphosphate / pharmacology
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Phosphatidylinositol Phosphates / metabolism
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Phosphatidylinositol Phosphates / pharmacology
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Phosphatidylinositols / metabolism*
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Phosphatidylinositols / pharmacology
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Phosphorylation
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Proteins / metabolism
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Proto-Oncogene Proteins c-vav
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Rats
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rac GTP-Binding Proteins
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ras Guanine Nucleotide Exchange Factors
Substances
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Guanine Nucleotide Exchange Factors
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Oncogene Proteins
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Phosphatidylinositol 4,5-Diphosphate
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Phosphatidylinositol Phosphates
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Phosphatidylinositols
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Proteins
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Proto-Oncogene Proteins c-vav
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Vav1 protein, rat
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phosphatidylinositol 3,4-diphosphate
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ras Guanine Nucleotide Exchange Factors
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Guanosine Diphosphate
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Inositol 1,4,5-Trisphosphate
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Guanosine Triphosphate
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Phosphatidylinositol 3-Kinases
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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GTP Phosphohydrolases
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GTP-Binding Proteins
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rac GTP-Binding Proteins