BCR activation of PI3K is Vav-independent in murine B cells.
BCR (B-cell antigen receptor)-induced Ca(2+) signalling is initiated by activation of tyrosine kinases, which in concert with adaptor proteins and lipid kinases regulate PLC (phospholipase C) gamma2 activation. Vav and PI3K (phosphoinositide 3-kinase) are required for optimal Ca(2+) responses, although it has not been established, in primary B-cells, if both proteins are components of the same pathway. In vitro evidence suggests that binding of the PI3K lipid product PIP3 to Vav pleckstrin homology domain contributes to Vav activation. However, pharmacological inhibition of PI3K by wortmannin or deletion of the p110delta catalytic subunit has no effect on Vav activation in response to BCR engagement, suggesting that this mechanism does not operate in vivo. We also show that PI3K recruitment to phosphorylated-tyrosine-containing complexes is Vav-independent. Taken together with our previous observation that protein kinase B phosphorylation is normal in Vav-deficient B-cells, we suggest that PI3K activation is Vav-independent in response to strong signals delivered by multivalent cross-linking.
Vigorito
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Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
Clayton
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Turner
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D047468:Immunoprecipitation; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; C496619:Vav1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D002118:Calcium; D000077191:Wortmannin