Cloning and characterization of human Src-like adaptor protein 2 and a novel splice isoform, SLAP-2-v

Loreto, Michael P.; McGlade, C. Jane

doi:10.1038/sj.onc.1206114

Cited by 17 publications

(23 citation statements)

References 22 publications

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“…2A), was unable to associate with c-Cbl, consistent with previous studies that indicated the C-terminal region of SLAP-2 mediates its association with c-Cbl (Fig. 2B, second panel) (17,19,27). This form of SLAP-2 also showed a significant reduction in CSF-1R binding suggesting that this region also stabilizes SLAP-2 binding to the receptor.…”

Section: Slap-2-dependent Regulation Of Csf-1rsupporting

confidence: 77%

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

Pakuts

Debonneville

Liontos

et al. 2007

Journal of Biological Chemistry

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The colony-stimulating factor 1 receptor 4 is a member of the type III receptor tyrosine kinase (RTK) family, which includes c-Kit, platelet-derived growth factor receptor ␣ and ␤, and Flt3 (1). All of the functions of colony-stimulating factor-1 (CSF-1) are mediated by CSF-1R, which is the primary regulator of the common myeloid lineage consisting of osteoclasts and mononuclear phagocytes (monocytes and macrophages) in vivo (2-5).Ligand binding induces CSF-1R dimerization and autophosphorylation on tyrosine residues that regulate both kinase activity and mediate binding to downstream SH2 and PTB domain-containing proteins. Recruitment of such proteins leads to activation of signaling cascades involved in determining the biological outcomes of CSF-1R activation as well as receptor down-regulation (6 -8).A number of adaptor proteins, including Gads/Mona, FMIP, DOK-2, and c-Cbl, have been implicated as negative regulators of CSF-1R signaling. c-Cbl possesses a variant SH2 domain (TKB domain) that mediates binding to activated tyrosine kinases and a RING finger domain demonstrated to confer E3 ubiquitin ligase activity, which promotes the ubiquitination of activated tyrosine kinases (9, 10). In c-Cbl-deficient macrophages, both CSF-1R ubiquitination and endocytosis of the ubiquitinated receptor are impaired (11). Subsequent to CSF-1R ubiquitination, activated CSF-1R is degraded intralysosomally (12). The degradation of ligand-stimulated CSF-1R normally occurs rapidly, and the half-life of the CSF-1R decreases from 3 h to 5 min upon ligand binding (13,14). Mutation of the tyrosine residue within the c-Cbl binding site (Tyr-969 in human CSF-1R) has been frequently observed in myelodysplasia and acute myeloblastic leukemia (15). Similarly, the transforming viral homologue of CSF-1R, v-Fms, lacks the c-Cbl binding site. Importantly, re-addition of the c-Cbl binding site to v-Fms decreases its transforming activity (16).Src-like adaptor protein family proteins, SLAP and SLAP-2, have an amino-terminal myristoylation signal required for association with cell membranes, closely juxtaposed SH3 and SH2 domains, and a unique carboxyl-terminal region that mediates association with c-Cbl. Both SLAP and SLAP-2 have been demonstrated to function as negative regulators of T-cell antigen receptor (TCR) signaling via a mechanism requiring the c-Cbl binding region (17)(18)(19). In addition to c-Cbl, SLAP-2 associates with the Zap-70 and Syk cytoplasmic tyrosine kinases and promotes their degradation when co-expressed. Recent work has shown that SLAP functions as a negative regulator of the TCR by promoting c-Cbl-dependent ubiquitination of TCR chain and down-regulation of the CD3 complex (17,20,21). In addition, both SLAP and SLAP-2 have been implicated as negative regulators of B-cell receptor signaling (19,22), and avian SLAP has been demonstrated to interfere with erythropoietin signaling in erythroblasts (23).Although SLAP and SLAP-2 have been implicated in the regulation of antigen receptor signaling, SLAP was originally dis-* ...

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Section: Slap-2-dependent Regulation Of Csf-1rsupporting

confidence: 77%

“…Both SLAP and SLAP-2 are expressed in lymphoid tissues and cell lines, whereas SLAP-2 is also abundantly expressed in myeloid cell lines such as KG1a, OCI, AML-2, -3, and -5 (27). A recent study by Manes et al (28) demonstrated that SLAP-2 is expressed in murine bone marrow-derived macrophages and suggested a potential role for SLAP-2 in CSF-1 signaling.…”

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confidence: 99%