title: Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk.
abstract: Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b-deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Igalpha, Syk, and phospholipase C (PLC)-gamma2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b-deficient B cells in contrast to the BCRs in Cbl-b-expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination.
authors.affiliation: The Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Sohn
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D003432:Cross-Linking Reagents; D004792:Enzyme Precursors / Q000378:metabolism*; D007137:Immunoglobulin alpha-Chains / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D051567:Proto-Oncogene Proteins c-vav; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase; D010738:Type C Phospholipases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D004792:Enzyme Precursors; D007137:Immunoglobulin alpha-Chains; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; D025801:Ubiquitin; C496619:Vav1 protein, mouse; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma