Reduced formation of phosphatidic acid upon B-cell receptor triggering of mouse B-lymphocytes lacking Bruton's tyrosine kinase.
Btk deficient (BtkM) mouse B-lymphocytes do not proliferate when stimulated with anti-immunoglobulin (anti-Ig) antibodies. In order to characterize the molecular basis of this unresponsiveness we have compared early signal transduction pathways triggered by ligating the B cell antigen receptor (BCR) of purified resting B cells from normal C57BL/6 (wild-type) and BtkM mice on C57BL/6 background. BCR-induced signalling events that occur during the first few minutes of activation, such as bulk tyrosine phosphorylations, mitogen-activated protein kinase (MAPK) activation, PI3-kinase dependent PKB/Akt kinase phosphorylation/activation and PLCgamma2 tyrosine phosphorylation are comparable in wild type and BtkM B cells. However, the initial extracellular calcium influx is reduced and the BCR-induced accumulation of phosphatidic acid (PA) display a more transient profile in the BtkM cells. BCR ligation did not induce detectable phosphatidyl-choline PLD activity, suggesting that the reduced PA is owing to a reduction in the phospho-inositide hydrolysis. These findings further support the notion that the proliferative defect of Btk deficient mouse B cells in response to anti-immunoglobulin stimulation stems from a failure to sustain phospholipase-dependent signalling.
Forssell
J
J
Department of Cell and Molecular Biology, Division of Tumour Biology, Umeå University, SE-901 87 Umeå, Sweden.
Nilsson
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A
Sideras
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D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010712:Phosphatidic Acids / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D013045:Species Specificity; D014443:Tyrosine / Q000378:metabolism
D010712:Phosphatidic Acids; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium