Abstract
Many receptor and nonreceptor tyrosine kinases activate phosphoinositide 3-kinases (PI3Ks). To assess the role of the delta isoform of the p110 catalytic subunit of PI3Ks, we derived enzyme-deficient mice. The mice are viable but have decreased numbers of mature B cells, a block in pro-B-cell differentiation, and a B1 B-cell deficiency. Both immunoglobulin M receptor-induced Ca(2+) flux and proliferation in response to B-cell mitogens are attenuated. Immunoglobulin levels are decreased substantially. The ability to respond to T-cell-independent antigens is markedly reduced, and the ability to respond to T-cell-dependent antigens is completely eliminated. Germinal center formation in the spleen in response to antigen stimulation is disrupted. These results define a nonredundant signaling pathway(s) utilizing the delta isoform of p110 PI3K for the development and function of B cells.
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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Animals
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Antigens, T-Independent / metabolism
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B-Lymphocytes / physiology*
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Calcium / metabolism
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Cells, Cultured
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Class I Phosphatidylinositol 3-Kinases
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Flow Cytometry
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Gene Targeting
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Germinal Center / cytology
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Germinal Center / metabolism
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism
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Humans
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Immunoglobulins / blood
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Macromolecular Substances
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Receptors, Antigen, B-Cell / metabolism*
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Signal Transduction / physiology*
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Stem Cells / cytology
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Stem Cells / physiology
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T-Lymphocytes / physiology
Substances
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Antigens, T-Independent
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Immunoglobulins
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Macromolecular Substances
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Receptors, Antigen, B-Cell
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Phosphatidylinositol 3-Kinases
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Class I Phosphatidylinositol 3-Kinases
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PIK3CD protein, human
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Pik3cd protein, mouse
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Calcium