Publications (2)13.79 Total impact
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Article: B cell antigen receptor signaling and internalization are mutually exclusive events.
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ABSTRACT: Engagement of the B cell antigen receptor initiates two concurrent processes, signaling and receptor internalization. While both are required for normal humoral immune responses, the relationship between these two processes is unknown. Herein, we demonstrate that following receptor ligation, a small subpopulation of B cell antigen receptors are inductively phosphorylated and selectively retained at the cell surface where they can serve as scaffolds for the assembly of signaling molecules. In contrast, the larger population of non-phosphorylated receptors is rapidly endocytosed. Each receptor can undergo only one of two mutually exclusive fates because the tyrosine-based motifs that mediate signaling when phosphorylated mediate internalization when not phosphorylated. Mathematical modeling indicates that the observed competition between receptor phosphorylation and internalization enhances signaling responses to low avidity ligands.PLoS Biology 08/2006; 4(7):e200. · 11.45 Impact Factor -
Article: Spi-1 and Spi-B control the expression of the Grap2 gene in B cells.
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ABSTRACT: The Ets family members Spi-1 and Spi-B have been implicated in the regulation of genes important for B cell antigen receptor (BCR) signaling. Mice deficient in Spi-B exhibit reduced B cell proliferation in response to BCR cross-linking and impaired T cell-dependent immune responses. This defect is exacerbated in the presence of Spi-1 haplo-insufficiency (Spi1+/- SpiB-/-). Tyrosine phosphorylation and calcium mobilization induced by BCR engagement is diminished in Spi1+/- SpiB-/- B lymphocytes, although many key BCR signaling proteins are expressed, suggesting that Spi-1 and Spi-B regulate expression of additional, unidentified signaling molecules. We now demonstrate that expression of the adaptor protein Grap2 is impaired in Spi1+/- SpiB+/- and Spi1+/- SpiB-/- B lymphocytes. Analysis of two alternate murine Grap2 promoters revealed a functionally important Spi-1 and Spi-B DNA binding element located in the downstream promoter. Ectopic expression of Grap2 in Grap2-deficient B cells reduced the recruitment of BLNK to Igalpha and the phosphorylation of specific substrates. Regulation of BLNK recruitment was dependent upon the Grap2 proline-rich domain, while modulation of phosphorylation was dependent upon both the proline-rich and SH2 domains. These data indicate that Spi-1 and Spi-B directly regulate the expression of Grap2 and that Grap2 functions to modulate BCR signaling, but that reduced Grap2 expression is unlikely to account for the BCR signaling defects observed in Spi1+/- SpiB-/- B cells.Gene 07/2005; 353(1):134-46. · 2.34 Impact Factor
