Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells.

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Calcium Signaling, Carrier Proteins, Cells, Cultured, Chickens, Enzyme Activation, Enzyme Precursors, Gene Targeting, Intracellular Signaling Peptides and Proteins, Isoenzymes, Macromolecular Substances, Mice, Phospholipase C gamma, Phosphoproteins, Protein Binding, Protein Structure, Tertiary, Protein Transport, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Receptors, Antigen, B-Cell, Signal Transduction, Spleen, Type C Phospholipases, Ubiquitin-Protein Ligases, src-Family Kinases
J. Exp. Med.
Date: Jul. 01, 2002
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