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Vol. 16, Issue 5, 2339-2348, May 2005
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* G. W. Hooper Foundation, University of California San Francisco, San Francisco, CA 94143;
Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom
Submitted January 18, 2005;
Accepted February 7, 2005
Monitoring Editor: Sandra Schmid
B cell antigen receptor (BCR) association with lipid rafts, the actin cytoskeleton, and clathrin-coated pits influences B cell signaling and antigen presentation. Although all three cellular structures have been separately implicated in BCR internalization, the relationship between them has not been clearly defined. In this study, internalization pathways were characterized by specifically blocking each potential mechanism of internalization. BCR uptake was reduced by 
70% in B cells conditionally deficient in clathrin heavy chain expression. Actin or raft antagonists were both able to block the residual, clathrin-independent BCR internalization. These agents also affected clathrin-dependent internalization, indicating that clathrin-coated pits, in concert with mechanisms dependent on rafts and actin, mediate the majority of BCR internalization. Clustering GM1 gangliosides enhanced clathrin-independent BCR internalization, and this required actin. Thus, although rafts or actin independently did not mediate BCR internalization, they apparently cooperate to promote some internalization even in the absence of clathrin. Simultaneous inhibition of all BCR uptake pathways resulted in sustained tyrosine phosphorylation and activation of the extracellular signal-regulated kinase (ERK), strongly suggesting that downstream BCR signaling can occur without receptor translocation to endosomes and that internalization leads to signal attenuation.
Abbreviations used: BCR, B cell antigen receptor; CHC, clathrin heavy chain; CCV, clathrin-coated vesicle; CTB, cholera toxin B; DMSO, dimethyl sulfoxide; ERK, extracellular signal-regulated kinase; FITC, fluorescein isothiocyanate; FCS, fetal calf serum; Ig, immunoglobulin; MAP, mitogen-activated protein; PBS, phosphatebuffered saline; TfR, transferrin receptor.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Present address: Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637.
Address correspondence to: Frances Brodsky (fmarbro{at}itsa.ucsf.edu).
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