The Src-like adaptor protein 2 regulates colony-stimulating factor-1 receptor signaling and down-regulation.

Src-like adaptor protein 2 (SLAP-2) is a hematopoietic adaptor protein previously implicated as a negative regulator of T-cell antigen receptor (TCR)-mediated signaling. SLAP-2 contains an SH3 and an SH2 domain, followed by a unique carboxyl-terminal tail, which is important for c-Cbl binding. Here we describe a novel role for SLAP-2 ...
in regulation of the colony-stimulating factor 1 receptor (CSF-1R), a receptor tyrosine kinase important for growth and differentiation of myeloid cells. SLAP-2 co-immunoprecipitates with c-Cbl and CSF-1R in primary bone marrow-derived macrophages. Using murine myeloid cells expressing CSF-1R (FD-Fms cells), we show that SLAP-2 is tyrosine-phosphorylated upon stimulation with CSF-1 and associates constitutively with both c-Cbl and CSF-1R. In addition, we show that expression of a dominant negative form of SLAP-2 impairs c-Cbl association with the CSF-1R and receptor ubiquitination. Impaired c-Cbl recruitment also correlated with changes in the kinetics of CSF-1R down-regulation and trafficking. CSF-1-mediated differentiation of FD-Fms cells and activation of downstream signaling events was also enhanced in cells stably expressing dominant negative SLAP-2. Together, these results demonstrate that SLAP-2 plays a role in c-Cbl-dependent down-regulation of CSF-1R signaling.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Bone Marrow Cells, Down-Regulation, Gene Expression Regulation, Macrophages, Mice, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins pp60(c-src), Receptor, Macrophage Colony-Stimulating Factor, Signal Transduction, Ubiquitin, src Homology Domains
J. Biol. Chem.
Date: Jun. 22, 2007
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