CD47
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Location (UCSC) | Chr 3: 108.04 – 108.09 Mb | Chr 16: 49.62 – 49.74 Mb | |||||||
PubMed search | [3] | [4] |
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
Structure
CD47 is a 50 kDa membrane receptor that has
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
Signal-regulatory protein (SIRP)
CD47 interacts with
Integrins
CD47 interacts with several membrane integrins, most commonly integrin αVβ3. 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
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.
Similarly, CD47 ligation rapidly induces apoptosis in
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
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.
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 by macrophages can initiate an antitumor T-cell immune response. Noteworthy, anti-CD47 antibody treatment not only enables macrophage phagocytosis of cancer, but also 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) and follicular lymphoma (FL).[35]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000196776 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055447 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: CD47 CD47 molecule".
- ^ PMID 22774848.
- ^ "Fibrosis reversed when 'don't eat me' signal blocked, study finds". medicalxpress.com.
- ^ PMID 22310103.
- PMID 27154320.
- ^ PMID 8586654.
- doi:10.1038/mp.a002870.01 (inactive 2024-03-25).)
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- ^ PMID 19360900.
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- ^ Furlow B (December 2018). "Researchers Report Early Clinical Promise for Macrophage Checkpoint Blockade". Cancer Therapy Advisor. Haymarket Media, Inc.
Gholamin S, Youssef OA, Rafat M, et al. Irradiation or temozolomide chemotherapy enhances anti-CD47 treatment of glioblastoma. Innate Immun. 2020;26(2):130‐137. doi:10.1177/1753425919876690
Further reading
- Oldenborg, P. A. (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
- Soto Pantoja, D. R., Kaur, S., Miller, T. W., et al. & Roberts, D. D. (2013) Leukocyte surface antigen CD47. UCSD Molecule Pages, 2(1), 19-36.
- Brown EJ, Frazier WA (March 2001). "Integrin-associated protein (CD47) and its ligands". Trends in Cell Biology. 11 (3): 130–135. PMID 11306274.
- Oldenborg PA (July 2004). "Role of CD47 in erythroid cells and in autoimmunity". Leukemia & Lymphoma. 45 (7): 1319–1327. S2CID 12642148.
- Kaczorowski DJ, Billiar TR (March 2007). "Targeting CD47: NO limit on therapeutic potential". Circulation Research. 100 (5): 602–603. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. PMID 10549293.
- Erb L, Liu J, Ockerhausen J, Kong Q, Garrad RC, Griffin K, et al. (April 2001). "An RGD sequence in the P2Y(2) receptor interacts with alpha(V)beta(3) integrins and is required for G(o)-mediated signal transduction". The Journal of Cell Biology. 153 (3): 491–501. PMID 11331301.
- Rebres RA, Vaz LE, Green JM, Brown EJ (September 2001). "Normal ligand binding and signaling by CD47 (integrin-associated protein) requires a long range disulfide bond between the extracellular and membrane-spanning domains". The Journal of Biological Chemistry. 276 (37): 34607–34616. PMID 11454874.
- Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. (April 2012). "The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors". Proceedings of the National Academy of Sciences of the United States of America. 109 (17): 6662–6667. PMID 22451913.
- Edris B, Weiskopf K, Volkmer AK, Volkmer JP, Willingham SB, Contreras-Trujillo H, et al. (April 2012). "Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma". Proceedings of the National Academy of Sciences of the United States of America. 109 (17): 6656–6661. PMID 22451919.
- Soto-Pantoja DR, Stein EV, Rogers NM, Sharifi-Sanjani M, Isenberg JS, Roberts DD (January 2013). "Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47". Expert Opinion on Therapeutic Targets. 17 (1): 89–103. PMID 23101472.
- Jiang H, Fu R, Wang H, Li L, Liu H, Shao Z (August 2013). "CD47 is expressed abnormally on hematopoietic cells in myelodysplastic syndrome". Leukemia Research. 37 (8): 907–910. PMID 23642736.
- Zhang Y, Sime W, Juhas M, Sjölander A (October 2013). "Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration". European Journal of Cancer. 49 (15): 3320–3334. PMID 23810249.
- Starr JS, Jiang L, Li Z, Qiu Y, Menke DM, Tun HW (October 2013). "CD47 and osteopontin expression in diffuse large B-cell lymphoma with nodal and intravascular involvement". Clinical Lymphoma, Myeloma & Leukemia. 13 (5): 597–601. PMID 23810243.
- Venkatraman L, Tucker-Kellogg L (October 2013). "The CD47-binding peptide of thrombospondin-1 induces defenestration of liver sinusoidal endothelial cells". Liver International. 33 (9): 1386–1397. PMID 23799952.
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.