Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.
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.
Han
J
J
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033-0800, USA.
Luby-Phelps
K
K
Das
B
B
Shu
X
X
Xia
Y
Y
Mosteller
R D
RD
Krishna
U M
UM
Falck
J R
JR
White
M A
MA
Broek
D
D
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism / Q000494:pharmacology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D051381:Rats; D020744:rac GTP-Binding Proteins; D020663:ras Guanine Nucleotide Exchange Factors
D020662:Guanine Nucleotide Exchange Factors; D015513:Oncogene Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; D011506:Proteins; D051567:Proto-Oncogene Proteins c-vav; C496620:Vav1 protein, rat; C060980:phosphatidylinositol 3,4-diphosphate; D020663:ras Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate; D015544:Inositol 1,4,5-Trisphosphate; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins