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 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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3T3 Cells
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Agammaglobulinaemia Tyrosine Kinase
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Agammaglobulinemia / genetics
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Alleles
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Amino Acid Sequence
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Animals
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B-Lymphocytes / enzymology
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B-Lymphocytes / immunology
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Calcium Signaling / drug effects
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Feedback
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / physiology*
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Lymphocyte Activation / physiology*
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Mast Cells / enzymology
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Mast Cells / immunology
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Peptide Mapping
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Phosphorylation
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Phosphoserine / chemistry
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / deficiency
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Protein Kinase C / genetics
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Protein Kinase C / physiology*
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Protein Kinase C beta
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Protein Processing, Post-Translational
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Protein Structure, Tertiary
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Protein Transport
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism*
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Receptors, Antigen, B-Cell / physiology*
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Receptors, IgE / physiology
Substances
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Enzyme Inhibitors
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Isoenzymes
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Membrane Proteins
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Receptors, Antigen, B-Cell
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Receptors, IgE
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Phosphoserine
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Tec protein-tyrosine kinase
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Btk protein, mouse
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Protein Kinase C
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Protein Kinase C beta