A phosphorylation site in Bruton's tyrosine kinase selectively regulates B cell calcium signaling efficiency by altering phospholipase C-gamma activation

Proceedings of the National Academy of Sciences of the United States of America
Shuling GuoO N Witte

Abstract

Loss of function of Bruton's tyrosine kinase (Btk) causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice (xid). By using MS analysis and phosphopeptide-specific antibodies, we identified a tyrosine phosphorylation site (Y617) near the carboxyl terminus of the Btk domain from Btk expressed in 293T as well as DT-40 cells. Y617 is conserved in all Tec family kinases except murine Tec. Replacement of Y617 with a negatively charged glutamic acid (E) suppressed Btk-mediated phospholipase Cgamma2 activation and calcium response in DT-40 cells, whereas Akt activation was not affected. The Btk Y617E mutant could partially restore conventional B cell development and proliferation in Btk(-)/Tec(-) mice but failed to rescue CD5(+) B-1 cell development and the TI-II immune response to 2,4,6,-trinitrophenyl-Ficoll. These data suggest that Y617 phosphorylation or a negative charge at this site may down-regulate the function of Btk by selectively suppressing the B cell calcium signaling pathway.

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Citations

Jun 18, 2009·The Journal of Biological Chemistry·Katy L EverettMatilda Katan
Feb 14, 2009·The EMBO Journal·Christian SchmidtPhilip W Tucker
Feb 13, 2016·Expert Review of Clinical Immunology·Leslie J CroffordPeggy L Kendall
Mar 11, 2009·Journal of Biomedical Science·Xuejuan Gao, Da Xing
Nov 14, 2013·PLoS Biology·Chaohong LiuWenxia Song
Dec 2, 2011·The Journal of Allergy and Clinical Immunology·Annick A J M van de VenMarianne Boes

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