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¹ The Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
² The Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Address correspondence to Susan K. Pierce, NIAID/NIH/Twinbrook II, 12441 Parklawn Dr., Rm. 200B, MSC 8180, Rockville, MD 20852. Phone: 301-496-9589; Fax: 301-402-0259; E-mail: spierce{at}nih.gov

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 Ig, Syk, and phospholipase C (PLC)-2, 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.

Key Words: B cells • antigen receptor • ubiquitination • tyrosine kinase • capping

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