Linking Receptor Signaling and Endocytosis

Abstract

Upon binding to foreign antigen, the B cell receptor (BCR) propagates an intracellular signaling cascade to mount an effective antibody response. The BCR is then rapidly internalized to down-regulate signaling and to transport the antigen to internal compartments for processing and presentation to other lymphocytes. Signal initiation requires localization of BCRs to lipid rafts at the cell surface, where signaling molecules concentrate. However, BCR endocytosis is thought to occur through clathrin-coated pits. What coordinates these two events has not been so clear. Stoddart et al. report that crosstalk between signaling molecules and transport machinery unites these two processes in a single location. Activation of BCRs in lipid rafts induced the phosphorylation of clathrin by Src-family kinases. This phosphorylation correlated with BCR internalization. Clathrin also appeared to be constitutively associated with lipid rafts. Treatment of B cells with Src-family kinase inhibitors or agents that disrupt lipid rafts prevented clathrin phosphorylation and BCR internalization in response to receptor activation. Lipid rafts may thus serve as a platform that unites signaling and endocytosis machinery to regulate BCR internalization. The authors discuss various models by which phosphorylation of clathrin may facilitate coated pit formation.A. Stoddart, M. L. Dykstra, B. K. Brown, W. Song, S. K. Pierce, F. M Brodsky, Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. Immunity 17, 451-462 (2002). [Online Journal]