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.
Yasuda
Tomoharu
T
Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Tezuka
Tohru
T
Maeda
Akito
A
Inazu
Tetsuya
T
Yamanashi
Yuji
Y
Gu
Hua
H
Kurosaki
Tomohiro
T
Yamamoto
Tadashi
T
D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D018390:Gene Targeting; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D046911:Macromolecular Substances; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma