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- Title
PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization.
- Authors
Kang, S W; Wahl, M I; Chu, J; Kitaura, J; Kawakami, Y; Kato, R M; Tabuchi, R; Tarakhovsky, A; Kawakami, T; Turck, C W; Witte, O N; Rawlings, D J
- Abstract
Mutations in Bruton's tyrosine kinase (Btk) result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. While targeted disruption of the protein kinase C-beta (PKCbeta) gene in mice results in an immunodeficiency similar to xid, the overall tyrosine phosphorylation of Btk is significantly enhanced in PKCbeta-deficient B cells. We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. These findings provide a novel mechanism whereby reversible translocation of Btk/Tec kinases regulates the threshold for immunoreceptor signaling and thereby modulates lymphocyte activation.
- Publication
The EMBO journal, 2001, Vol 20, Issue 20, p5692
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1093/emboj/20.20.5692