CD47 (Cluster of Differentiation 47)

Abstract

CD47, also known as integrin-associated protein, is a constitutively and ubiquitously expressed transmembrane receptor. CD47 is conserved across amniotes including mammals, reptiles, and birds. Expression is increased in many cancers and, in non-malignant cells, by stress and with aging. The up-regulation of CD47 expression is generally epigenetic, whereas gene amplification occurs with low frequency in some cancers. CD47 is a high affinity signaling receptor for the secreted protein thrombospondin-1 (THBS1) and the counter-receptor for signal regulatory protein-α (SIRPA, SIRPα) and SIRPγ (SIRPG). CD47 interaction with SIRPα serves as a marker of self to innate immune cells and thereby protects cancer cells from phagocytic clearance. Consequently, higher CD47 correlates with a poor prognosis in some cancers, and therapeutic blockade can suppress tumor growth by enhancing innate antitumor immunity. CD47 expressed on cytotoxic T cells, dendritic cells, and NK cells mediates inhibitory THBS1 signaling that further limits antitumor immunity. CD47 laterally associates with several integrins and thereby regulates cell adhesion and migration. CD47 has additional lateral binding partners in specific cell types, and ligation of CD47 in some cases modulates their function. THBS1-CD47 signaling in non-malignant cells inhibits nitric oxide/cGMP, calcium, and VEGF signaling, mitochondrial homeostasis, stem cell maintenance, protective autophagy, and DNA damage response, and promotes NADPH oxidase activity. CD47 signaling is a physiological regulator of platelet activation, angiogenesis and blood flow. THBS1/CD47 signaling is frequently dysregulated in chronic diseases.

Keywords: CD47; KLF4; MYC; OCT3/4; SOX2; THBS1; blood flow; chemotherapy; metabolism; nitric oxide; radiation; reactive oxygen species; regulation of genotoxic stress; self-renewal.

Figure 1.

Chromosomal location of human CD47. Position of the gene on chromosome 3 is indicated in red.

Figure 2.

Human CD47 transcripts and intron organization. Two of the six identified CD47 gene transcripts (CD47–201 and CD47–202) encode functional CD47 proteins. Coding exons 1–3 encode the extracellular immunoglobulin-like domain, and exons 3–7 encode the transmembrane domain. Alternative splicing produces CD47 isoforms with short and long forms of the C-terminal cytoplasmic tail with the sequences shown. Short and long forms of the 3’-UTR differentially direct subcellular localization of CD47 isoforms. (adapted from http://useast.ensembl.org/Homo_sapiens/Gene/Splice?db=core;g=ENSG00000196776;r=3:108043091-108091862).

Figure 3.

Structure and posttranslational modifications of CD47 protein. The left panel shows the orientation of CD47 in the plasma membrane. The extracellular IgV domain is modified by several asparagine-linked oligosaccharides and by heparan and chondroitin sulfate glycosaminoglycans at Ser-64 and Ser-79 (Kaur et al., 2011). Ser-64 modification is required for THBS1 signaling. Gln-19 is enzymatically modified to a pyroglutamyl residue required for binding to SIRPA, and Lys-317 can be ubiquitinylated. The right panel shows a space filling model of the IgV domain bound to the extracellular region of SIRPA (Hatherley et al., 2008). Direct binding assays demonstrated that THBS1 blocks SIRPA binding to CD47, but the location of the THBS1 binding site on CD47 remains to be determined (Isenberg et al., 2009).

Figure 4.

The distribution of observed synonymous, missense and loss of function (LoF) mutations in the exons of CD47 is presented in the upper panel. The lower panel presents the expected and observed numbers of each variant type. The lower than expected number of LoF mutations indicates an 89% probability that the CD47 gene is loss-intolerant (pLI).

Figure 5.

Locations of identified mutations in CD47 from cancers in the TCGA PanCancer Atlas (analysis of samples from 10,953 individuals). The upper panel represents the frequency of CD47 gene alterations in TCGA Pan-Cancer data (10,953 individuals/10967 samples from 32 studies) classified by cancer type using cBioPortal tools. Green = mutation, purple = fusion, blue = deletion, red = amplification, grey = multiple alterations. The lower panel presents associations of mutation and copy number variation with CD47 mRNA expression. Data is from The Cancer Genome Atlas (TCGA) using cBioPortal tools to analyze data from 10,953 individuals (Cerami et al., 2012; Gao et al., 2013).

Figure 6.

Distribution of mutations in CD47 identified in human cancers sequenced in The Cancer Genome Atlas.