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J. Biol. Chem., Vol. 282, Issue 25, 17953-17963, June 22, 2007

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The Src-like Adaptor Protein 2 Regulates Colony-stimulating Factor-1 Receptor Signaling and Down-regulation^*

Benjamin Pakuts, Christophe Debonneville¹, Larissa M. Liontos², Michael P. Loreto, and C. Jane McGlade³

From the Department of Medical Biophysics, University of Toronto and The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada

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.

Received for publication, February 7, 2007

^* This work was supported in part by the Canadian Institutes of Health Research (to C. J. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of fellowships from the Swiss National Science Foundation and the Hospital for Sick Children Foundation.

² Recipient of an MD/PhD studentship from the Canadian Institutes of Health Research.

³ To whom correspondence should be addressed: The Hospital for Sick Children, 101 College St. TMDT 11-601, Toronto, Ontario M5G 1L7, Canada. Tel.: 416-813-8457; Fax: 416-813-8456; E-mail: jmcglade{at}sickkids.ca.

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