CD47

CD47
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2JJS, 2JJT, 2VSC, 4CMM, 4KJY, 5IWL
Identifiers
Aliases	CD47 , IAP, MER6, OA3, CD47 molecule
External IDs	OMIM: 601028; MGI: 96617; HomoloGene: 1346; GeneCards: CD47; OMA:CD47 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) [1] Band 3q13.12 Start 108,043,091 bp [1] End 108,091,862 bp [1]
Gene location (Mouse) Chr. Chromosome 16 (mouse) [2] Band 16|16 B5 Start 49,620,896 bp [2] End 49,735,373 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gingival epithelium palpebral conjunctiva germinal epithelium visceral pleura right uterine tube pancreatic epithelial cell epithelium of nasopharynx Brodmann area 23 tibia pancreatic ductal cell Top expressed in fetal liver hematopoietic progenitor cell tibiofemoral joint blood medial dorsal nucleus cingulate gyrus lateral geniculate nucleus sciatic nerve cerebellar vermis gastrula spleen More reference expression data BioGPS More reference expression data
Gene ontology Molecular function thrombospondin receptor activity protein binding protein binding involved in heterotypic cell-cell adhesion cell-cell adhesion mediator activity Cellular component integral component of membrane plasma membrane integral component of plasma membrane membrane specific granule membrane tertiary granule membrane extracellular exosome cell surface Biological process integrin-mediated signaling pathway positive regulation of phagocytosis cell adhesion extracellular matrix organization positive regulation of inflammatory response positive regulation of T cell activation response to bacterium leukocyte migration positive regulation of cell population proliferation opsonization positive regulation of cell-cell adhesion neutrophil degranulation cell migration regulation of interferon-gamma production regulation of interleukin-10 production regulation of interleukin-12 production regulation of interleukin-6 production regulation of tumor necrosis factor production heterotypic cell-cell adhesion monocyte extravasation regulation of nitric oxide biosynthetic process positive regulation of stress fiber assembly cellular response to interferon-gamma cellular response to interleukin-1 cellular response to interleukin-12 cell-cell adhesion negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 961 16423 Ensembl ENSG00000196776 ENSMUSG00000055447 UniProt Q08722 Q61735 RefSeq (mRNA) NM_001025079 NM_001025080 NM_001777 NM_198793 NM_001382306 NM_010581 NM_001368415 NM_001368416 NM_001368417 NM_001368418 RefSeq (protein) NP_001768 NP_942088 NP_001369235 NP_034711 NP_001355344 NP_001355345 NP_001355346 NP_001355347 Location (UCSC) Chr 3: 108.04 – 108.09 Mb Chr 16: 49.62 – 49.74 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

CD47 (Cluster of Differentiation 47) also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily ^[5] and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). ^[6] CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis. ^[7]

CD47 is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a role in insulin secretion, as well as immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells. ^{[6] [8]} Expression in equine cutaneous tumors has been reported as well. ^[9]

Structure

CD47 is a 50 kDa membrane receptor that has extracellular N-terminal IgV domain, five transmembrane domains, and a short C-terminal intracellular tail. There are four alternatively spliced isoforms of CD47 that differ only in the length of their cytoplasmic tail. ^[10]

Form 2 is the most widely expressed form that is found in all circulating and immune cells. The second most abundant isoform is form 4, which is predominantly expressed in the brain and in the peripheral nervous system. Only keratinocytes expressed significant amounts of form 1. Little is known about the functional significance of this alternative splicing. However, these isoforms are highly conserved between mouse and man, suggesting an important role for the cytoplasmic domains in CD47 function. ^{[6] [10] [11]}

Interactions

Thrombospondin (TSP)

CD47 is a high affinity receptor for thrombospondin-1 (TSP-1), a secreted glycoprotein that plays a role in vascular development and angiogenesis, and in this later capacity the TSP1-CD47 interaction inhibits nitric oxide signaling at multiple levels in vascular cells. ^[12] Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation. ^[6]

Signal-regulatory protein (SIRP)

CD47 interacts with signal-regulatory protein alpha (SIRPα), an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation. ^{[6] [13] [14]}

Integrins

CD47 interacts with several membrane integrins, most commonly integrin α_Vβ₃. These interactions result in CD47/integrin complexes that affect a range of cell functions including adhesion, spreading and migration. ^{[6] [14]}

Function

Tumor cells

Due to the ubiquitous expression of CD47, signaling differs according to cell type. It is likely that intracellular and membrane-associated partners are crucial in determining the cellular response of CD47 signaling.

Cell proliferation

The role of CD47 in promoting cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation.

Activation of CD47 with TSP-1 increases proliferation of human U-87 MG and U373 astrocytoma cells but not normal astrocytes. Additionally, CD47 blocking antibodies inhibit proliferation of unstimulated astrocytoma cells but not normal astrocytes. Though the exact mechanism is unclear, it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells. ^[15]

Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. Expression of several stem cell markers, including c-Myc, is elevated in CD47-null endothelial cells and a human T cell line lacking CD47. Activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors. ^[16]

Cell death

CD47 ligation leads to cell death in many normal and tumor cell lines via apoptosis or autophagy. The activation of CD47 induces rapid apoptosis of T cells. Jurkat cells and peripheral blood mononuclear cells (PBMC) incubated with the monoclonal antibody Ad22 results in apoptosis within 3 hours. However, apoptosis was not observed following culture with other anti-CD47 antibodies. The apoptosis inducing function of CD47 appears to be dependent on activation of specific epitopes on the extracellular domain. ^[17]

Similarly, CD47 ligation rapidly induces apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells. Treatment with a disulfide-linked antibody dimer induces apoptosis of CD47-positive primary B-CLL and leukemic cells (MOLT-4 and JOK-1). In addition, administration of the antibody prolonged survival of SCID mice implanted with JOK-1 cells. Apoptosis induction appears to be regulated by the hypoxia inducible factor 1α (HIF-1α) pathway. ^[18]

The RAS-transformed cell lines MDFB6 and B6ras show near complete loss of TSP-1 expression. Activation of CD47 with TSP-1 results in loss of viability in these RAS-expressing cells. Affected cells do not exhibit hallmarks of apoptosis but rather autophagy as seen by staining with acridine orange and immunoreactivity for LC3. ^[19]

Migration

Cell migration appears to be universally stimulated by CD47 ligation and activation. The role of CD47 in cell migration was first demonstrated for neutrophils, where CD47 blocking antibodies inhibited transmigration of neutrophils and monocytes through the endothelium. These effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. ^{[6] [14]}

Originally discovered by Irving Weissman’s group at Stanford University, blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanoma, prostate cancer and ovarian cancer-derived cells. ^[20] In a mouse model of multiple myeloma, tumor metastasis to bone was decreased in CD47-deficient mice compared with wild type controls. ^[21] In work led by Mark Chao and Ash Alizadeh, at Stanford, mice were xenografted with human non-Hodgkin lymphoma (NHL) cells; blocking CD47 function with shRNA or antibodies led to a dramatic reduction in metastasis to major organs. ^[22]

Stromal cells

Angiogenesis

Loss of CD47 promotes proliferation and increases asymmetric division of primary murine endothelial cells. ^[16] Additionally, activation of CD47 with TSP-1 in wild-type primary mouse cerebral endothelial cells induces cytotoxicity, which is significantly decreased in cerebral endothelial cells derived from CD47 knockout mice. ^[23]

CD47 signaling may suppress angiogenesis as TSP-1 activation significantly inhibited endothelial cell migration and tube formation in vitro. ^[23] In vivo, injections of TSP-1 in mice after hindlimb ischemia induces a significant decrease of blood flow recovery. ^[24] The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells. ^[12] CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis. ^[24]

Inflammatory response

Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 knockout mice show reduced recruitment of blood T cells as well as neutrophils and monocytes in areas of inflammation. ^[25] CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Red blood cells that lack CD47 are rapidly cleared from the bloodstream by macrophages, a process that is mediated by interaction with SIRPα. ^[26] Mouse hematopoietic stem cells (HSCs) and progenitors transiently upregulate CD47 during their migratory phase, which reduces macrophage engulfment in vivo. ^[27]

Tumor cells can also evade macrophage phagocytosis through the expression of CD47. ^[8] CD47 is highly expressed in bladder tumor initiating cells (T-ICs) compared with the rest of the tumor. Blockade of CD47 with a monoclonal antibody results in macrophage engulfment of bladder cancer cells in vitro. ^[28] CD47 is also upregulated in mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line allows these cells to evade phagocytosis. ^[27]

Insulin secretion

CD47 receptor signaling inhibits insulin release from human as well as mouse pancreatic β cells and that it can be pharmacologically blocked to boost insulin secretion in both models. ^[29]

Clinical significance

CD47 was first identified as a tumor antigen on human ovarian cancer in the 1980s. Since then, CD47 has been found to be expressed on multiple human tumor types including acute myeloid leukemia (AML), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, and other solid tumors. ^[8] CD47 is also highly expressed on pediatric and adult brain tumors. ^[30]

High levels of CD47 allows cancer cells to avoid phagocytosis despite having a higher level of calreticulin - the dominant pro-phagocytic signal. ^[31] This is due to engagement of the SIRP-α of macrophage by CD47. Engagement of SIRP-α leads to inhibition of phagocytosis. Thus blocking CD47 with antibody turns off “don’t eat me” signal and favors phagocytosis.

As a potential drug target

Anti-CD47 antibody–mediated phagocytosis of cancer fosters the activation of cancer-specific lymphocytes: cancer cells display mutant proteins to which the immune system can now react. ^{[32] [33]} Based on significant activity in preclinical models and in synergistic combinations with other antibodies, ^[34] Humanized anti-CD47 antibody is being evaluated for the treatment of various cancers, e.g. diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) ^[35] , Primary Effusion Lymphoma ^[36] and acute myeloid leukemia (AML). ^[37]

See also

• Cluster of differentiation
• Anti-CD47 therapy

References

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18. Sagawa M, Shimizu T, Fukushima N, Kinoshita Y, Ohizumi I, Uno S, et al. (June 2011). "A new disulfide-linked dimer of a single-chain antibody fragment against human CD47 induces apoptosis in lymphoid malignant cells via the hypoxia inducible factor-1α pathway". Cancer Science. 102 (6): 1208–1215. doi: 10.1111/j.1349-7006.2011.01925.x . PMID   21401803. S2CID   205236897.
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20. Shahan TA, Fawzi A, Bellon G, Monboisse JC, Kefalides NA (February 2000). "Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca(2+)-dependent mechanism requiring CD47 and the integrin alpha(V)beta(3)". The Journal of Biological Chemistry. 275 (7): 4796–4802. doi: 10.1074/jbc.275.7.4796 . PMID   10671513.
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23. Xing C, Lee S, Kim WJ, Wang H, Yang YG, Ning M, et al. (August 2009). "Neurovascular effects of CD47 signaling: promotion of cell death, inflammation, and suppression of angiogenesis in brain endothelial cells in vitro". Journal of Neuroscience Research. 87 (11): 2571–2577. doi:10.1002/jnr.22076. PMC   3712846 . PMID   19360900.
24. Smadja DM, d'Audigier C, Bièche I, Evrard S, Mauge L, Dias JV, et al. (March 2011). "Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (3): 551–559. doi: 10.1161/ATVBAHA.110.220624 . PMID   21148423.
25. Azcutia V, Stefanidakis M, Tsuboi N, Mayadas T, Croce KJ, Fukuda D, et al. (September 2012). "Endothelial CD47 promotes vascular endothelial-cadherin tyrosine phosphorylation and participates in T cell recruitment at sites of inflammation in vivo". Journal of Immunology. 189 (5): 2553–2562. doi:10.4049/jimmunol.1103606. PMC   3424398 . PMID   22815286.
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34. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, et al. (September 2010). "Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma". Cell. 142 (5): 699–713. doi:10.1016/j.cell.2010.07.044. PMC   2943345 . PMID   20813259.
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Further reading

• Oldenborg PA (2013). "CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease". ISRN Hematology. 2013: 614619. doi: 10.1155/2013/614619 . PMC   3564380 . PMID   23401787.
• Soto Pantoja DR, Kaur S, Miller TW, Isenberg JS, Roberts DD (2013). "Leukocyte surface antigen CD47". UCSD Molecule Pages. 2 (1): 19–36.
• Gholamin S, Youssef OA, Rafat M, Esparza R, Kahn S, Shahin M, et al. (February 2020). "Irradiation or temozolomide chemotherapy enhances anti-CD47 treatment of glioblastoma". Innate Immunity. 26 (2): 130–137. doi:10.1177/1753425919876690. PMC   7016411 . PMID   31547758.
• Brown EJ, Frazier WA (March 2001). "Integrin-associated protein (CD47) and its ligands". Trends in Cell Biology. 11 (3): 130–135. doi:10.1016/S0962-8924(00)01906-1. PMID   11306274.
• Oldenborg PA (July 2004). "Role of CD47 in erythroid cells and in autoimmunity". Leukemia & Lymphoma. 45 (7): 1319–1327. doi:10.1080/1042819042000201989. PMID   15359629. S2CID   12642148.
• Kaczorowski DJ, Billiar TR (March 2007). "Targeting CD47: NO limit on therapeutic potential". Circulation Research. 100 (5): 602–603. doi: 10.1161/01.RES.0000261609.44977.25 . PMID   17363705.
• Campbell IG, Freemont PS, Foulkes W, Trowsdale J (October 1992). "An ovarian tumor marker with homology to vaccinia virus contains an IgV-like region and multiple transmembrane domains". Cancer Research. 52 (19): 5416–5420. PMID   1394148.
• Brown E, Hooper L, Ho T, Gresham H (December 1990). "Integrin-associated protein: a 50-kD plasma membrane antigen physically and functionally associated with integrins". The Journal of Cell Biology. 111 (6 Pt 1): 2785–2794. doi:10.1083/jcb.111.6.2785. PMC   2116394 . PMID   2277087.
• Lindberg FP, Gresham HD, Schwarz E, Brown EJ (October 1993). "Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding". The Journal of Cell Biology. 123 (2): 485–496. doi:10.1083/jcb.123.2.485. PMC   2119833 . PMID   7691831.
• Mawby WJ, Holmes CH, Anstee DJ, Spring FA, Tanner MJ (December 1994). "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". The Biochemical Journal. 304 ( Pt 2) (Pt 2): 525–530. doi:10.1042/bj3040525. PMC   1137523 . PMID   7998989.
• Lindberg FP, Lublin DM, Telen MJ, Veile RA, Miller YE, Donis-Keller H, et al. (January 1994). "Rh-related antigen CD47 is the signal-transducer integrin-associated protein". The Journal of Biological Chemistry. 269 (3): 1567–1570. doi: 10.1016/S0021-9258(17)42058-8 . PMID   8294396.
• Gao AG, Lindberg FP, Finn MB, Blystone SD, Brown EJ, Frazier WA (January 1996). "Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin". The Journal of Biological Chemistry. 271 (1): 21–24. doi: 10.1074/jbc.271.1.21 . PMID   8550562.
• Cherif-Zahar B, Raynal V, Gane P, Mattei MG, Bailly P, Gibbs B, et al. (February 1996). "Candidate gene acting as a suppressor of the RH locus in most cases of Rh-deficiency". Nature Genetics. 12 (2): 168–173. doi:10.1038/ng0296-168. PMID   8563755. S2CID   1999844.
• Chung J, Gao AG, Frazier WA (June 1997). "Thrombspondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3". The Journal of Biological Chemistry. 272 (23): 14740–14746. doi: 10.1074/jbc.272.23.14740 . PMID   9169439.
• Jiang P, Lagenaur CF, Narayanan V (January 1999). "Integrin-associated protein is a ligand for the P84 neural adhesion molecule". The Journal of Biological Chemistry. 274 (2): 559–562. doi: 10.1074/jbc.274.2.559 . PMID   9872987.
• Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, et al. (February 1999). "The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23". The Journal of Cell Biology. 144 (4): 767–775. doi:10.1083/jcb.144.4.767. PMC   2132927 . PMID   10037797.
• Chung J, Wang XQ, Lindberg FP, Frazier WA (July 1999). "Thrombospondin-1 acts via IAP/CD47 to synergize with collagen in alpha2beta1-mediated platelet activation". Blood. 94 (2): 642–648. doi:10.1182/blood.V94.2.642. PMID   10397731.
• Longhurst CM, White MM, Wilkinson DA, Jennings LK (July 1999). "A CD9, alphaIIbbeta3, integrin-associated protein, and GPIb/V/IX complex on the surface of human platelets is influenced by alphaIIbbeta3 conformational states". European Journal of Biochemistry. 263 (1): 104–111. doi:10.1046/j.1432-1327.1999.00467.x. PMID   10429193.
• Mateo V, Lagneaux L, Bron D, Biron G, Armant M, Delespesse G, et al. (November 1999). "CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia". Nature Medicine. 5 (11): 1277–1284. doi:10.1038/15233. PMID   10545994. S2CID   8936080.
• Wu AL, Wang J, Zheleznyak A, Brown EJ (October 1999). "Ubiquitin-related proteins regulate interaction of vimentin intermediate filaments with the plasma membrane". Molecular Cell. 4 (4): 619–625. doi: 10.1016/S1097-2765(00)80212-9 . PMID   10549293.
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External links

• CD47+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• http://www.pathologyoutlines.com/topic/cdmarkerscd47.html
• Human CD47 genome location and CD47 gene details page in the UCSC Genome Browser .