Abstract
Bruton's tyrosine kinase (Btk) is required for human and mouse B cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice. Unlike Src proteins, Btk lacks a negative regulatory domain at the COOH terminus and may rely on cytoplasmic Btk-binding proteins to regulates its kinase activity by trans-inhibitor mechanisms. Consistent with this possibility, IBtk, which we identified as an inhibitor of Btk, bound to the PH domain of Btk. IBtk downregulated Btk kinase activity, Btk-mediated calcium mobilization and nuclear factor-kappaB-driven transcription. These results define a potential mechanism for the regulation of Btk function in B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Agammaglobulinaemia Tyrosine Kinase
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Amino Acid Sequence
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B-Lymphocytes / immunology*
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Calcium / metabolism
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Carrier Proteins / metabolism*
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Cell Line
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Humans
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Intracellular Signaling Peptides and Proteins
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Molecular Sequence Data
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NF-kappa B / antagonists & inhibitors
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / biosynthesis
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Tissue Distribution
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Transcription, Genetic
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Two-Hybrid System Techniques
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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IBtk protein, human
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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RNA, Messenger
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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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Calcium