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Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner.

Src-like adaptor protein (SLAP) and c-Cbl recently have been shown to cooperate in regulating T cell receptor (TCR) levels in developing T cells. SLAP also is expressed in developing B cells, and its deficiency leads to alterations in B cell receptor (BCR) levels and B cell development. Hence, we hypothesized that SLAP and c-Cbl may cooperate during B cell development to regulate BCR levels. In mice deficient in both SLAP and c-Cbl, we found that B cell development is altered, suggesting that they function through intersecting pathways. To study the mechanism by which SLAP and c-Cbl alter BCR levels, we coexpressed them in a mature mouse B cell line (Bal-17). First we determined that SLAP associates with proximal components of the BCR complex after stimulation and internalization. Coexpression of SLAP and c-Cbl in Bal-17 led to decreased surface and total BCR levels. This decrease in BCR levels depended on intact Src homology 2 (SH2) and C-terminal domains of SLAP. In addition, a mutation in the SH2 domain of SLAP blocked its colocalization with c-Cbl and the BCR complex, whereas deletion of the C terminus did not affect its localization. Last, coexpression of SLAP and c-Cbl altered BCR complex recycling. This alteration in BCR complex recycling depended on enzymatically active c-Cbl and Src family kinases, as well as the intact SH2 and C-terminal domains of SLAP. These data suggest that SLAP has a conserved function in B and T cells by adapting c-Cbl to the antigen-receptor complex and targeting it for degradation.

Pubmed ID: 17110436

Authors

  • Dragone LL
  • Myers MD
  • White C
  • Gadwal S
  • Sosinowski T
  • Gu H
  • Weiss A

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 28, 2006

Associated Grants

  • Agency: NIAID NIH HHS, Id: 5K08AI055873-04
  • Agency: NCI NIH HHS, Id: CA72531

Mesh Terms

  • Animals
  • B-Lymphocytes
  • Cell Differentiation
  • Cell Line, Tumor
  • Down-Regulation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins pp60(c-src)
  • Receptors, Antigen, B-Cell