Alternative titles; symbols
HGNC Approved Gene Symbol: CD47
Cytogenetic location: 3q13.12 Genomic coordinates (GRCh38): 3:108,043,091-108,091,031 (from NCBI)
By testing hybrids containing various deletions of chromosome 3, Miller et al. (1987) described an IgM monoclonal antibody, 1D8, that recognized an antigen coded by a gene located in the region 3cen-q22. The monoclonal antibody was designated MER6. The antigen was absent in the Rh deficiency syndrome, Rh-null hemolytic anemia (268150). However, this antigen probably had no pathogenetic role in the Rh deficiency, which was shown by Cherif-Zahar et al. (1996) to be due to mutation in the Rh50 gene (180297) on chromosome 6. Cherif-Zahar et al. (1996) noted that many cell membrane components are missing from the multisubunit Rh complex when the RH50A gene is mutant.
Lindberg et al. (1994) stated that IAP is a 50-kD membrane protein with an N-terminal immunoglobulin domain and a C-terminal multiple membrane-spanning region. IAP is identical to the ovarian tumor marker OA3 (Mawby et al., 1994). It is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix. IAP is also expressed on erythrocytes, which have no known integrins. Lindberg et al. (1994) found that IAP expression was reduced on Rh(null) erythrocytes. Using FISH, Lindberg et al. (1994) mapped IAP within a region of chromosome 3 known to contain the gene encoding the Rh-associated 1D8 antigen. By expression studies on human erythrocytes and IAP transfectants, IAP was found to be identical to the 1D8 antigen and to CD47, a cell surface protein with broad tissue distribution and reduced expression on Rh(null) erythrocytes. Lindberg et al. (1994) stated that these studies demonstrated an unexpected link between integrin signal transduction and erythrocyte membrane structure.
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) found that Cd47 functioned as a marker of self on murine red blood cells. Red blood cells lacking 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 regulatory protein (SIRP)-alpha (PTPNS1; 602461). 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. They suggested that CD47-SIRP-alpha may represent a potential pathway for the control of hemolytic anemia.
Osteoclasts and giant cells are multinucleated and resorb the substrate onto which they adhere. They are thought to originate from the fusion of mononuclear phagocytes. Han et al. (2000) used immunofluorescence microscopy to show that at the onset of fusion macrophages express not only the macrophage fusion receptor (MFR, or SIRP-alpha) but also, at a lower level than MFR, the hemopoietic form of CD47. Immunoprecipitation and immunoblot experiments confirmed the association of the CD47 variable domain and the MFR immunoglobulin V1 domain. Macrophage fusion could be blocked by either anti-CD47 monoclonal antibodies or a CD47 fusion protein.
Type III, or necrosis-like, programmed cell death (PCD) is defined exclusively by cytoplasmic features and seems to operate in a caspase-independent manner. Bras et al. (2007) showed that ligation of CD47 triggered type III PCD in B cells from healthy volunteers and patients with chronic lymphocytic leukemia (CLL; 151400), and they identified DRP1 (DNM1L; 603850) as a key mediator of this PCD. CD47 ligation induced DRP1 translocation from the cytosol to mitochondria. In mitochondria, DRP1 provoked impairment of the mitochondrial electron transport chain, resulting in dissipation of mitochondrial transmembrane potential, generation of reactive oxygen species, and a drop in ATP levels. Responsiveness of cells to CD47 ligation increased following DRP1 overexpression, while resistance to CD47-mediated death was observed following DRP1 downregulation. In CLL B cells, DRP1 mRNA levels strongly correlated with death sensitivity.
CD47 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.
Berkovits and Mayr (2015) showed that in human cell lines, alternative 3-prime UTRs differentially regulate the localization of membrane proteins. The long 3-prime UTR of CD47 enables efficient cell surface expression of CD47 protein, whereas the short 3-prime UTR primarily localizes CD47 protein in the endoplasmic reticulum (ER). CD47 protein localization occurs posttranslationally and independently of RNA localization. Berkovits and Mayr (2015) described a model of 3-prime UTR-dependent protein localization in which the long 3-prime UTR of CD47 acts as a scaffold to recruit a protein complex containing the RNA-binding protein HuR (ELAVL1; 603466) and SET (600960) to the site of translation. This facilitates interaction of SET with the newly translated cytoplasmic domains of CD47 and results in subsequent translocation of CD47 to the plasma membrane via activated RAC1 (602048). Berkovits and Mayr (2015) also showed that CD47 protein has different functions depending on whether it was generated by the short or long 3-prime UTR isoforms. Thus, alternative cleavage and polyadenylation contributes to the functional diversity of the proteome without changing the amino acid sequence. 3-prime UTR-dependent protein localization has the potential to be a widespread trafficking mechanism for membrane proteins since ELAVL1 binds to thousands of mRNAs, and Berkovits and Mayr (2015) showed that the long 3-prime UTRs of CD44 (107269), ITGA1 (192968), and TNFRSF13C (606269), which are bound by ELAVL1, increase surface protein expression compared to their corresponding short 3-prime UTRs. Berkovits and Mayr (2015) proposed that during translation, the scaffold function of 3-prime UTRs facilitates binding of proteins to nascent proteins to direct their transport or function, and that this role of 3-prime UTRs can be regulated by alternative cleavage and polyadenylation.
Casey et al. (2016) demonstrated that MYC (190080) regulates the expression of 2 immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 and the adaptive immune checkpoint programmed death ligand-1 (PDL1; 605402). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PDL1 mRNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pdl1 genes. MYC inactivation in mouse tumors downregulated CD47 and PDL1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PDL1, the immune response was suppressed, and tumors continued to grow. Thus, Casey et al. (2016) concluded that MYC appears to initiate and maintain tumorigenesis, in part through the modulation of immune regulatory molecules.
Kojima et al. (2016) showed that atherogenesis is associated with upregulation of CD47, a key antiphagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or efferocytosis. Kojima et al. (2016) found that administration of CD47-blocking antibodies reversed this defect in efferocytosis, normalized the clearance of diseased vascular tissue, and ameliorated atherosclerosis in multiple mouse models. Mechanistic studies implicated the proatherosclerotic factor TNF-alpha (191160) as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.
By testing hybrids containing various deletions of chromosome 3, Miller et al. (1987) described an IgM monoclonal antibody, 1D8, that recognized an antigen coded by a gene, CD47, on chromosome 3cen-q22.
By FISH, Lindberg et al. (1994) mapped the CD47 gene to chromosome 3q13.1-q13.2.
Lindberg et al. (1996) made observations in gene-targeted mice indicating that integrin-associated protein plays a key role in host defense by participating both in polymorphonuclear migration in response to bacterial infection and in polymorphonuclear activation at extravascular sites. Mice homozygous for knockout of the Iap gene succumbed to Escherichia coli peritonitis at inoccula survived by heterozygous littermates. In vivo, they had an early defect in PMN accumulation at the site of infection. In vivo, they showed deficiency of several manifestations of PMN activation.
Berkovits, B. D., Mayr, C. Alternative 3-prime UTRs act as scaffolds to regulate membrane protein localization. Nature 522: 363-367, 2015. [PubMed: 25896326] [Full Text: https://doi.org/10.1038/nature14321]
Bras, M., Yuste, V. J., Roue, G., Barbier, S., Sancho, P., Virely, C., Rubio, M., Baudet, S., Esquerda, J. E., Merle-Beral, H., Sarfati, M., Susin, S. A. Drp1 mediates caspase-independent type III cell death in normal and leukemic cells. Molec. Cell. Biol. 27: 7073-7088, 2007. [PubMed: 17682056] [Full Text: https://doi.org/10.1128/MCB.02116-06]
Casey, S. C., Tong, L., Li, Y., Do, R., Walz, S., Fitzgerald, K. N., Gouw, A. M., Baylot, V., Gutgemann, I., Eilers, M., Felsher, D. W. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352: 227-231, 2016. Note: Erratum: 352: Apr 8, 2016. [PubMed: 26966191] [Full Text: https://doi.org/10.1126/science.aac9935]
Cherif-Zahar, B., Raynal, V., Gane, P., Mattei, M.-G., Bailly, P., Gibbs, B., Colin, Y., Cartron, J.-P. Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency. Nature Genet. 12: 168-173, 1996. [PubMed: 8563755] [Full Text: https://doi.org/10.1038/ng0296-168]
Han, X., Sterling, H., Chen, Y., Saginario, C., Brown, E. J., Frazier, W. A., Lindberg, F. P., Vignery, A. CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J. Biol. Chem. 275: 37984-37992, 2000. [PubMed: 10964914] [Full Text: https://doi.org/10.1074/jbc.M002334200]
Kojima, Y., Volkmer, J.-P., McKenna, K., Civelek, M., Lusis, A. J., Miller, C. L., Direnzo, D., Nanda, V., Ye, J., Connolly, A. J., Schadt, E. E., Quertermous, T., Betancur, P., Maegdefessel, L., Matic, L. P., Hedin, U., Weissman, I. L., Leeper, N. J. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536: 86-90, 2016. [PubMed: 27437576] [Full Text: https://doi.org/10.1038/nature18935]
Lindberg, F. P., Bullard, D. C., Caver, T. E., Gresham, H. D., Beaudet, A. L., Brown, E. J. Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice. Science 274: 795-798, 1996. [PubMed: 8864123] [Full Text: https://doi.org/10.1126/science.274.5288.795]
Lindberg, F. P., Lublin, D. M., Telen, M. J., Veile, R. A., Miller, Y. E., Donis-Keller, H., Brown, E. J. Rh-related antigen CD47 is the signal-transducer integrin-associated protein. J. Biol. Chem. 269: 1567-1570, 1994. [PubMed: 8294396]
Mawby, W. J., Holmes, C. H., Anstee, D. J., Spring, F. A., Tanner, M. J. A. Isolation and characterization of CD47 glycoprotein: a multispanning membrane protein which is the same as integrin-associated protein (IAP) and the ovarian tumour marker OA3. Biochem. J. 304: 525-530, 1994. [PubMed: 7998989] [Full Text: https://doi.org/10.1042/bj3040525]
Miller, Y. E., Daniels, G. L., Jones, C., Palmer, D. K. Identification of a cell-surface antigen produced by a gene on human chromosome 3 (cen-q22) and not expressed by Rh(null) cells. Am. J. Hum. Genet. 41: 1061-1070, 1987. [PubMed: 3120581]
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]
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]