Abstract
Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor-mediated proliferation of lymphocytes. However, we show that Cbl-b-deficient DT40 B cells display reduced phospholipase C (PLC)-gamma2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-gamma2 and helped the association of PLC-gamma2 with Bruton's tyrosine kinase (Btk), as well as B cell linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH(2)-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-gamma2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-gamma2 complex formation.
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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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / metabolism*
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Calcium Signaling / physiology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cells, Cultured
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Chickens
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Precursors / metabolism
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Gene Targeting
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / metabolism*
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Macromolecular Substances
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Mice
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Phospholipase C gamma
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Protein Binding / physiology
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Protein Structure, Tertiary / physiology
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Protein Transport / physiology
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-cbl
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Receptors, Antigen, B-Cell / metabolism*
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Signal Transduction / physiology
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Spleen / cytology
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Syk Kinase
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Type C Phospholipases / metabolism*
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Ubiquitin-Protein Ligases*
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src-Family Kinases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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B cell linker protein
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Carrier Proteins
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Cblb protein, mouse
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Enzyme Precursors
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Macromolecular Substances
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Phosphoproteins
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Receptors, Antigen, B-Cell
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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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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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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lyn protein-tyrosine kinase
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src-Family Kinases
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Type C Phospholipases
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Phospholipase C gamma