CD47

Official Full Name

CD47 molecule

Organism

Homo sapiens

GeneID

961

Background

This gene encodes a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix. The encoded protein is also a receptor for the C-terminal cell binding domain of thrombospondin, and it may play a role in membrane transport and signal transduction. This gene has broad tissue distribution, and is reduced in expression on Rh erythrocytes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2010]

Synonyms

IAP; OA3; MER6;

Bio Chemical Class

Osteoclast fusion complex

Protein Sequence

MWPLVAALLLGSACCGSAQLLFNKTKSVEFTFCNDTVVIPCFVTNMEAQNTTEVYVKWKFKGRDIYTFDGALNKSTVPTDFSSAKIEVSQLLKGDASLKMDKSDAVSHTGNYTCEVTELTREGETIIELKYRVVSWFSPNENILIVIFPIFAILLFWGQFGIKTLKYRSGGMDEKTIALLVAGLVITVIVIVGAILFVPGEYSLKNATGLGLIVTSTGILILLHYYVFSTAIGLTSFVIAILVIQVIAYILAVVGLSLCIAACIPMHGPLLISGLSILALAQLLGLVYMKFVASNQKTIQPPRKAVEEPLNAFKESKGMMNDE

Open

Disease

Acute myeloid leukaemia, B-cell lymphoma, Colorectal cancer, Diffuse large B-cell lymphoma, Leukaemia, Lymphoma, Malignant haematopoietic neoplasm, Melanoma, Multiple myeloma, Mycosis fungoides, Myelodysplastic syndrome, Neuroendocrine carcinoma, Non-small-cell lung cancer, Ovarian cancer, Solid tumour/cancer, Squamous cell carcinoma, Stomach cancer

Approved Drug

Clinical Trial Drug

16 +

Discontinued Drug

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Detailed Information

Cluster of differentiation 47 (CD47) was first observed on stem cells. It is a transmembrane protein that inhibits phagocytosis by binding to its receptor, signal regulatory protein α (SIRPα), which is expressed on phagocytes. Lack of CD47 on erythrocytes, platelets and lymphohematopoietic cells causes rapid clearance of these cells by macrophages, due to the elimination of the CD47-SIRPα-mediated antiphagocytic signal. Binding of CD47 to SIRPα leads to phosphorylation of immunoreceptor tyrosine based inhibitory motifs (ITIMs) on SIRPα and the recruitment of SHP-1 and SHP-2, both of which inhibit the accumulation of myosin-IIA at the phagocytic synapse. Once phosphorylated ITIM of SIRPα interacts with the SH2 domains of phosphatase, the activity of the enzyme is triggered. This cancels out an activating signaling pathway producing a "do not eat me" signal triggered by CD47, suppressing phagocytosis by macrophages. CD47-SIRPα interactions play a role in healthy and pathological conditions, such as infection, red blood cell (RBC) homeostasis, autoimmunity, and inflammation.

CD47 and Disease

The upregulation of CD47 inhibits macrophage phagocytosis of normal, healthy hematopoietic stem cells (HSC) and allows these cells to migrate to the periphery in response to inflammatory insults. The up-regulation of CD47 is an especially important mechanism for cancer stem cells to bypass the immune system, which plays an important role in cancer recurrence. Studies have shown overexpression of CD47 in nearly all types of tumors, some of which include acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, and bladder cancer. While CD47 is implicated in the regulation of cancer cell invasion and metastasis, its most important and in-depth function related to tumor development is to prevent phagocytosis by ligating with SIRPα on the surrounding phagocytes. Besides, CD47 expression on cancer stem cells (CSCs) implies its role in cancer recurrence. Particularly, a study has demonstrated that CSCs have increased CD47 expression to protect themselves from immune-mediated elimination during conventional anti-tumor therapies. This increases the chance of CSC survival, which in turn could repopulate a new tumor mass and cause a tumor relapse. Recent research found that high levels of CD47 are not only expressed in cutaneous T-cell lymphomas (CTCL), but also on fibroblasts following activation of transcription factor c-Jun, leading to the development of diseases such as idiopathic pulmonary fibrosis and scleroderma. Compared with non-atherosclerotic vascular tissue, atherosclerosis is another disease process involving the upregulation of CD47, indicating a pathological commonality in both cardiovascular disease and cancer.

Targeting CD47 as A Therapeutic Strategy

CD47 signaling induced by increased expression of TSP1 may play an important role in the pathophysiology of several major diseases of aging. Therefore, CD47 could be an effective therapeutic target in cardiovascular disease to increase blood flow to ischemic tissues. Animal studies further show that targeting CD47 could improve healing in diet-induced vasculopathy and ameliorate the effects of cardiac hypertrophy. The protective effect of antibodies targeting CD47 in liver and kidney ischemia-reperfusion injury models indicates applications in organ transplantation. Antibodies targeting CD47 that block SIRPa signaling are entering clinical testing to enhance macrophage-mediated clearance of cancers, but the same humanized antibody may also block TSP1-induced signaling through CD47. In cancer, such antibodies could also enhance cytotoxic CD8 T cell antitumor responses when combined with radiation therapy.

Figure 1. CD47 regulates nitric oxide signaling in vascular cells. (Soto-Pantoja D R, et al., 2015)

Currently, CD47 blocking antibodies are the most advanced towards clinical testing. Used systemically for cancer therapy, these antibodies will encounter a vast reservoir of CD47 on red blood cells and on other critical vascular cells such as platelets and endothelium where CD47 plays crucial physiological roles by limiting NO signaling. Therefore, anemia, hypertension and thrombosis are all predicted side effects of therapeutic CD47 antibodies. Indeed, acute increases in mean arterial and diastolic blood pressure were demonstrated when mice were injected intravenously with a function-blocking mouse CD47 antibody. Local application of CD47 antibodies to prevent or treat ischemia and ischemia/reperfusion injuries may avoid these complications, which seems to be more promising.

References:

Liu X, et al. Is CD47 an innate immune checkpoint for tumor evasion?. Journal of hematology & oncology, 2017, 10(1): 1-7.
Folkes A S, et al. Targeting CD47 as a cancer therapeutic strategy–the cutaneous T cell lymphoma experience. Current opinion in oncology, 2018, 30(5): 332.
Huang Y, et al. Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy. Journal of thoracic disease, 2017, 9(2): E168.
Liu X, et al. CD47 blockade triggers T cell–mediated destruction of immunogenic tumors. Nature medicine, 2015, 21(10): 1209-1215.
Soto-Pantoja D R, et al. CD47 signaling pathways controlling cellular differentiation and responses to stress. Critical reviews in biochemistry and molecular biology, 2015, 50(3): 212-230.
Kojima Y, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature, 2016, 536(7614): 86-90.

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