Alternative titles; symbols
HGNC Approved Gene Symbol: SIRPA
Cytogenetic location: 20p13 Genomic coordinates (GRCh38): 20:1,894,167-1,940,592 (from NCBI)
PTPNS1, or SIRP-alpha-1, is a transmembrane glycoprotein primarily expressed on myeloid cells. Binding of CD47 (601028) on red blood cells to the extracellular domain of PTPNS1 on macrophages prevents unwanted phagocytosis. PTPNS1 also plays an important role in regulating the homeostasis of T cells, natural killer cells, and dendritic cells (summary by Li et al., 2012).
Fujioka et al. (1996) used expression screening of a v-src (190090)-transformed rat fibroblast library to clone the cDNA encoding rat Shps1, which encodes a 115- to 120-kD tyrosine-phosphorylated protein. The rat Shps1 sequence contains a single putative transmembrane domain, a secretory signal sequence, 3 immunoglobulin domains, 15 potential glycosylation sites, and 4 potential tyrosine phosphorylation sites.
Yamao et al. (1997) cloned an SHPS1 cDNA by screening a human brain cDNA library with a P-labeled rat SHPS1 cDNA probe. The SHPS1 gene encodes a predicted 503-amino acid polypeptide that contains the same domains as the rat protein, but it has only 4 potential glycosylation sites. Northern blot analysis revealed that human SHPS1 was expressed as a 4.2-kb mRNA in all tissues examined, with highest abundance in brain. Smaller transcripts were observed in heart, muscle, testis, and leukocytes, suggesting that multiple alternatively spliced forms of the primary transcript may exist. Immunohistochemical staining showed that SHPS1 was localized in neuronal cells. Yamao et al. (1997) detected 17 CCA repeats in the 3-prime untranslated region of the SHPS1 gene. They noted that the human SHPS1 cDNA appeared to be the same as the CC53 clone identified from a human brain cDNA library by Margolis et al. (1995) as part of a screen for cDNAs containing CCA trinucleotide repeats.
Kharitonenkov et al. (1997) also cloned SHPS1, which they called SIRP-alpha-1. They also cloned 3 closely related genes: SIRP-alpha-2, which differs from alpha-1 in the first immunoglobulin domain; SIRP-alpha-3, which has amino acid substitutions relative to SIRP-alpha-1 throughout the polypeptide; and SIRP-beta-1 (SIRPB1; 603889). They identified sequence fragments of 11 other putative SIRP family members.
Brooke et al. (1998) identified MYD1 (SHPS1), a surface antigen associated with dendritic cells that activate T lymphocytes, and cloned the corresponding cDNA.
Fujioka et al. (1996) showed that rat Shps1 bound SHP1 (176883) and SHP2 (176876). Mitogens induced tyrosine phosphorylation of SHPS1 and its subsequent association with SHP2.
Kharitonenkov et al. (1997) found that expression of SIRP-alpha-1 in NIH-3T3 cells blocked growth factor-induced DNA synthesis, reduced activation of MAP kinase, and suppressed oncogene-mediated transformation by v-fms (164770). SIRP-alpha-1, in its tyrosine phosphorylated form, bound SHP1, SHP2, and GRB2 (108355) in vitro.
Brooke et al. (1998) showed that COS cells transfected with MYD1 acquired the ability to bind CD4 (186940)-positive T cells.
The immune system recognizes invaders as foreign because they express determinants that are absent on host cells or because they lack 'markers of self' that are normally present. Oldenborg et al. (2000) demonstrated that CD47 functions as a marker of self on murine red blood cells. Red blood cells that lack CD47 were rapidly cleared from the bloodstream by splenic red pulp macrophages. CD47 on normal red blood cells prevented this elimination by binding to the inhibitory receptor signal SIRP-alpha. Thus, Oldenborg et al. (2000) concluded that macrophages may use a number of nonspecific activating receptors and rely on the presence or absence of CD47 to distinguish self from foreign. Oldenborg et al. (2000) suggested that CD47-SIRP-alpha may represent a potential pathway for the control of hemolytic anemia.
Takenaka et al. (2007) found that nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice supported human hematopoietic stem cell (HSC) grafts better than immune-deficient mice of other strains. Using positional genetics and in vitro and in vivo assays, they identified variation in the Sirpa gene as the molecular basis for the strain differences, and showed that the NOD Sirpa allele conferred enhanced binding to human CD47 and that Sirpa was a potent regulator of interactions between HSCs and the bone marrow microenvironment. Takenaka et al. (2007) concluded that a Sirpa-dependent, macrophage-mediated mechanism is critical in HSC xenotransplantation and possibly in human transplantation. They suggested that SIRPA polymorphism may represent a new axis of genetically regulated HSC engraftment.
CD47 (601028) is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Weiskopf et al. (2013) modified the binding domain of human SIRP-alpha, the receptor for CD47, for use as a CD47 antagonist. Weiskopf et al. (2013) engineered high-affinity SIRP-alpha variants with about a 50,000-fold increased affinity for human CD47 relative to wildtype SIRP-alpha As high-affinity SIRP-alpha monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This 'one-two punch' directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.
By use of a monochromosomal human-rodent hybrid cell line, Margolis et al. (1995) mapped the CCA53 clone to human chromosome 20. Yamao et al. (1997) used fluorescence in situ hybridization (FISH) to map the SHPS1 gene to chromosome 20p13. By direct R-banding FISH with a mouse cDNA fragment as a probe, they mapped the mouse shps1 gene to chromosome 2. Eckert et al. (1997) used FISH and database analysis to refine the mapping of the SHPS1/P84 gene to a 1-Mb region between STS markers IB255 and WI-9632, close to polymorphic marker D20S199.
Li et al. (2012) found that Sirpa -/- mice infected with Salmonella typhimurium exhibited significantly higher mortality and bacterial loads in spleen and liver, as well as reduced Salmonella-specific antibody production and Cd4 T-cell responses, compared with wildtype mice. In vitro, Sirpa -/- dendritic cells were defective in antigen processing and presentation. Sirpa -/- mice had no defects in the control of Chlamydia muridarum infection and developed appropriate Cd4 T-cell responses. Li et al. (2012) concluded that SIRPA is indispensable for protective immunity against Salmonella infection.
Brooke, G. P., Parsons, K. R., Howard, C. J. Cloning of two members of the SIRP-alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells. Europ. J. Immun. 28: 1-11, 1998. [PubMed: 9485180] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V]
Eckert, C., Olinsky, S., Cummins, J., Stephan, D., Narayanan, V. Mapping of the human P84 gene to the subtelomeric region of chromosome 20p. Somat. Cell Molec. Genet. 23: 297-301, 1997. [PubMed: 9542532] [Full Text: https://doi.org/10.1007/BF02674421]
Fujioka, Y., Matozaki, T., Noguchi, T., Iwamatsu, A., Yamao, T., Takahashi, N., Tsuda, M., Takada, T., Kasuga, M. A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Molec. Cell. Biol. 16: 6887-6899, 1996. [PubMed: 8943344] [Full Text: https://doi.org/10.1128/MCB.16.12.6887]
Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., Ullrich, A. A family of proteins that inhibit signalling through tyrosine kinase receptors. Nature 386: 181-186, 1997. [PubMed: 9062191] [Full Text: https://doi.org/10.1038/386181a0]
Li, L.-X., Atif, S. M., Schmiel, S. E., Lee, S.-J., McSorley, S. J. Increased susceptibility to Salmonella infection in signal regulatory protein alpha-deficient mice. J. Immun. 189: 2537-2544, 2012. [PubMed: 22851710] [Full Text: https://doi.org/10.4049/jimmunol.1200429]
Margolis, R. L., Breschel, T. S., Li, S.-H., Kidwai, A. S., Antonarakis, S. E., McInnis, M. G., Ross, C. A. Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. Somat. Cell. Molec. Genet. 21: 279-284, 1995. [PubMed: 8525433] [Full Text: https://doi.org/10.1007/BF02255782]
Oldenborg, P.-A., Zheleznyak, A., Fang, Y.-F., Lagenaur, C. F., Gresham, H. D., Lindberg, F. P. Role of CD47 as a marker of self on red blood cells. Science 288: 2051-2054, 2000. [PubMed: 10856220] [Full Text: https://doi.org/10.1126/science.288.5473.2051]
Takenaka, K., Prasolava, T. K., Wang, J. C. Y., Mortin-Toth, S. M., Khalouei, S., Gan, O. I., Dick, J. E., Danska, J. S. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nature Immun. 8: 1313-1323, 2007. [PubMed: 17982459] [Full Text: https://doi.org/10.1038/ni1527]
Weiskopf, K., Ring, A. M., Ho, C. C. M., Volkmer, J.-P., Levin, A. M., Volkmer, A. K., Ozkan, E., Fernhoff, N. B., van de Rijn, M., Weissman, I. L., Garcia, K. C. Engineered SIRP-alpha variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341: 88-91, 2013. [PubMed: 23722425] [Full Text: https://doi.org/10.1126/science.1238856]
Yamao, T., Matozaki, T., Amano, K., Matsuda, Y., Takahashi, N., Ochi, F., Fujioka, Y., Kasuga, M. Mouse and human SHPS-1: molecular cloning of cDNAs and chromosomal localization of genes. Biochem. Biophys. Res. Commun. 231: 61-67, 1997. [PubMed: 9070220] [Full Text: https://doi.org/10.1006/bbrc.1996.6047]