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

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A common theme in the development of hematological malignancies is the aberrant activation of receptor tyrosine kinases (RTKs) which, in the normal physiological state, bind to and transduce signals received from growth factors. The mechanism by which aberrant RTK activation leads to leukemia is complex and cell type-specific, however, it has become apparent that regulators of receptor activation and degradation may also be involved.

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. Studies on SLAP-2 and a closely related family member, SLAP, suggest that these adaptor proteins negatively regulate T-cell signaling through the recruitment of the E3 ubiquitin ligase, c-Cbl to the receptor. c-Cbl has an established role in the ubiquitination and degradation of many RTKs, for example the Epidermal Growth Factor Receptor (EGFR) and the colony-stimulating factor-1 receptor (CSF-1R). To study whether SLAP-2 promotes the recruitment of c-Cbl to the activated CSF-1R, receptor activation and ubiquitination were examined in a myeloid cell line, FD/Fms cells, stably expressing SLAP-2 and a dominant-negative mutant of SLAP-2. Here we show that SLAP-2 interacts with the CSF-1R in both FD/Fms cells and primary bone marrow derived macrophages (BMDM). Our data show that the dominant-negative (DN) form of SLAP-2 impairs c- Cbl association with CSF-1R and receptor ubiquitination. FD/Fms cells expressing DN SLAP-2 also display an enhancement in their ability to differentiate in response to CSF-1. Our ongoing research focuses on whether SLAP-2-deficient mice have similar defects in CSF-1R down regulation.