SHIP modulates immune receptor responses by regulating membrane association of Btk.
Membrane recruitment of SHIP is responsible for the inhibitory signal generated by FcgammaRIIB coligation to the BCR. By reducing the level of PIP3, SHIP regulates the association of the tyrosine kinase Btk with the membrane through PH domain-phosphoinositol lipid interactions. Inhibition of BCR signaling by either FcgammaRIIB coligation, membrane expression of SHIP, or inhibition of P13K, conditions which result in decreased levels of PIP3, is suppressed by the expression of Btk as a membrane-associated chimera. Conversely, increasing PIP3 levels by deletion of SHIP results in increased Btk association with the membrane and hyperresponsive BCR signaling. These results suggest a central role for PIP3 in regulating the B cell stimulatory state by modulating Btk localization and thereby calcium fluxes.
Bolland
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Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York 10021, USA.
Pearse
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Kurosaki
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Ravetch
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D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002645:Chickens; D006801:Humans; D008954:Models, Biological; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction
D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium