Alternative titles; symbolsCD2-LIKE RECEPTOR ACTIVATING CYTOTOXIC CELLS; CRACCCS1CD319HGNC Approved Gene Symbol: SLAMF7Cytogenetic location: 1q23.3 Genomic c...
Alternative titles; symbols
HGNC Approved Gene Symbol: SLAMF7
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:160,739,056-160,754,820 (from NCBI)
Natural killer (NK)-cell function is regulated by a balance between signaling through inhibitory (e.g., KIR2DL1; 604936) and activating receptors. Some members of the CD2 (186990) family of activating receptors (e.g., CD244; 605554) stimulate cytotoxicity through the SLAM (603492)-associated protein (SAP; 300490). Mutations in the SH2 domain of SAP cause deficiencies in other CD2 family proteins that transduce signals through SAP, and these deficiencies lead to uncontrolled Epstein-Barr virus (EBV) infections and, ultimately, to X-linked lymphoproliferative disease (XLPD; 308240).
▼ Cloning and Expression
By searching an EST database for sequences encoding the TxYxxI/V/A tyrosine motif found in CD244 and SLAM, followed by PCR on an NK-cell cDNA library and library screening, Boles and Mathew (2001) isolated a cDNA encoding CS1 (CD2 subset 1). Sequence analysis predicted that the 335-amino acid transmembrane protein has a 225-residue extracellular domain, which has 7 putative N-linked glycosylation sites, and an 85-amino acid cytoplasmic domain, which contains 2 of the consensus tyrosine motifs and a third C-terminal tyrosine motif that has phe instead of thr. Northern blot analysis revealed expression of a 3.0-kb CS1 transcript that was highest in spleen, lymph node, and peripheral blood leukocytes and lowest in bone marrow. Expression was detected in an NK-cell line but not in promyelocytic, B-, or T-cell lines.
Bouchon et al. (2001) also cloned CS1, which they termed CRACC. They noted the presence of 2 CD2-like Ig folds in the extracellular domain of CRACC. RT-PCR analysis detected CRACC expression in NK and CD8 (see 186910)-positive cytotoxic cells. Flow cytometric analysis demonstrated expression of CRACC on nearly all NK cells, a large subset of CD8 cells, and few CD4 (186940) cells and B cells. Expression on B cells was upregulated upon CD40 (109535) activation, and expression on dendritic cells was upregulated by influenza virus, lipopolysaccharide, and CD40L (300386). Immunoprecipitation and SDS-PAGE analyses showed expression of a 66-kD protein and, after deglycosylation, a 37-kD protein. Functional analysis indicated that CRACC mediates lysis that is in addition to that mediated by NKP46 (604530) or CD16 (146740). Further analysis determined that, unlike CD244, cytotoxicity mediated by CRACC or NKP46 is SAP-independent and that CRACC triggers ERK (see 601335) activation. Immunoblot analysis showed that CRACC is tyrosine phosphorylated in activated NK cells and is associated with 19- and 39-kD proteins. Bouchon et al. (2001) proposed that CRACC may be particularly important in controlling pathogens other than EBV.
▼ Gene Function
Using flow cytometric analysis, Hagberg et al. (2013) found that stimulating peripheral blood mononuclear cells with RNA-containing immune complexes (RNA-ICs) resulted in increased expression of the SLAM family members CD229 (LY9; 600684) and CD319 on plasmacytoid dendritic cells (pDCs) and of CD319 on natural killer (NK) cells. Upregulation of CD229 and CD319 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines, such as GMCSF (CSF2; 138960) and IL3 (147740). IFNA (147660)-producing pDCs displayed higher SLAM molecule expression than IFNA-negative pDCs. The authors found that pDCs expressed the downstream signaling molecules SHIP1 (INPP5D; 601582), SHP1 (PTPN6; 176883), SHP2 (PTPN11; 176876), and CSK (124095), but lacked SAP and EAT2 (SH2D1B; 608510), suggesting that CD229 and CD319 act as inhibitory receptors on pDCs. Patients with systemic lupus erythematosus (SLE; 152700) showed decreased CD319 expression on pDCs and decreased CD229 expression on NK cells, and RNA-IC stimulation increased expression of both. Hagberg et al. (2013) concluded that expression of CD229 and CD319 is regulated on pDCs and NK cells by lupus immune complexes and that expression of these receptors is specifically altered in SLE.
Chen et al. (2017) found that macrophages are much more efficient at phagocytosis of hematopoietic tumor cells, compared with nonhematopoietic tumor cells, in response to SIRP-alpha (SIRPA; 602461)-CD47 (601028) blockade. Using a mouse lacking the SLAM family of homotypic hematopoietic cell-specific receptors, Chen et al. (2017) determined that phagocytosis of hematopoietic tumor cells during SIRPA-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7, expressed on macrophages and tumor cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of SLAM-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac1 (120980) and utilize signals involving immunoreceptor tyrosine-based activation motifs. Chen et al. (2017) concluded that their findings elucidated the mechanism by which macrophages engulf and destroy hematopoietic tumor cells, and revealed a novel SAP adaptor-independent function for a SLAM receptor.
▼ Gene Structure
By genomic sequence analysis, Boles and Mathew (2001) determined that the CS1 gene spans 13 kb, with a relatively small (8.7 kb) intron 1 compared with the 17-kb intron 1 of the CD244 gene.
By genomic sequence analysis, Boles and Mathew (2001) and Bouchon et al. (2001) mapped the CS1 gene to chromosome 1q23-q24, between the CD48 (109530) and CD229 (LY9; 600684) genes.