Disease relevance of Cd47

• Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia [1].
• As platelets also express CD47, we asked whether inhibitory CD47/SIRPalpha signaling regulates normal platelet turnover and clearance of platelets in immune thrombocytopenic purpura (ITP) [1].
• Thus, IAP plays a key role in host defense by participating both in PMN migration in response to bacterial infection and in PMN activation at extravascular sites [2].
• Gene-targeted mice deficient for integrin-associated protein (IAP, also termed CD47) succumbed to Escherichia coli peritonitis at inoccula survived by heterozygous littermates [2].
• We have now investigated the role of the transmembrane protein CD47 in this process in N1E-115 neuroblastoma cells [3].

Psychiatry related information on Cd47

• We have previously demonstrated that integrin-associated protein is involved in memory consolidation of one-way inhibitory avoidance learning in rats and mice [4].

High impact information on Cd47

• Transcription of IAP endogenous retroviruses is constrained by cytosine methylation [5].
• In this case, as in XRPC24, c-mos was split by the insertion of a IAP genome [6].
• The two latter points suggest a correlation between the orientation of the long terminal repeat (LTR) of IAP relative to c-mos and its activity upon IAP integration [6].
• Decreased resistance to bacterial infection and granulocyte defects in IAP-deficient mice [2].
• We recently found that CD47 on unopsonized RBCs binds macrophage signal regulatory protein alpha (SIRPalpha), generating a negative signal that prevents phagocytosis of the unopsonized RBCs [7].

Biological context of Cd47

• This phenotype is at least partially due to a markedly increased rate of elimination of opsonized CD47(-/-) compared to CD47(+) RBCs [8].
• In vitro, macrophage phagocytosis of immunoglobulin G (IgG)-opsonized CD47(-/-) platelets was significantly higher than that for equally opsonized CD47(+/+) platelets [1].
• IAP also is functionally associated with signal transduction from the Leukocyte Response Integrin [9].
• In addition, SHPS-1 and its ligand CD47 constitute an intercellular recognition system that contributes to inhibition of cell migration by cell-cell contact [10].
• Furthermore, overexpression of SHPS-1 reduced the level of tyrosine phosphorylation of focal adhesion kinase, and this effect was reversed by CD47 binding [11].

Anatomical context of Cd47

• The glycoprotein CD47 (integrin-associated protein, IAP) is present on the surface of virtually all cells, including red blood cells (RBCs) [8].
• Because IAP has been implicated in cell signaling in cells of the immune system, P84 and IAP represent a heterophilic binding pair that is likely to be involved in bi-directional signaling at the synapse and in other tissues [12].
• P84 and integrin associated protein (IAP) are heterophilic binding partners that are expressed in the central nervous system in addition to a variety of other tissues [13].
• When CHO cells are transfected with human IAP, monoclonal anti-human antibody completely inhibits vitronectin bead binding [9].
• Furthermore, mouse CD47 expression on porcine cells markedly reduced their phagocytosis by mouse macrophages both in vitro and in vivo [14].

Associations of Cd47 with chemical compounds

• CD47 binding induced proteasome-mediated degradation of SHPS-1 in a tyrosine phosphorylation-independent manner [11].
• Conservation of Cys residues among CD47 homologues suggested the existence of a disulfide bond between the Ig and MMS domains that was confirmed by chemical digestion and mapped to Cys(33) and Cys(263) [15].
• Treatment of B16F10 cells with 1-deoxymannojirimycin, which prevents N-glycan processing, restored the ability of SHPS-1 derived from these cells to bind CD47-Fc in vitro, indicating that aberrant N-glycosylation of SHPS-1 impairs CD47 binding in B16F10 cells [11].
• Overexpression of integrin-associated protein (CD47) in rat kidney treated with a renal carcinogen, ferric nitrilotriacetate [16].
• Integrin-associated protein (IAP) is a 50-kDa intrinsic membrane protein that is involved in signal transduction during neutrophil activation by a variety of Arg-Gly-Asp-containing ligands [17].

Regulatory relationships of Cd47

• SHPS-1 also regulates intercellular communication in the neural and immune systems through its association with CD47 (integrin-associated protein) on adjacent cells [18].
• Inhibition of Rac or Cdc42 preferentially blocked CD47-induced formation of neurites and filopodia, respectively [3].
• These results suggest that the ligation of CD47 inhibits the migration of LCs and the expression of B7 costimulatory molecules, which results in inhibition of the contact hypersensitivity response [19].
• CD47 engagement in vivo significantly inhibits the emigration of LCs from the epidermis into draining lymph nodes following treatment with haptens and tumor necrosis factor-alpha [19].
• Neurite formation induced by CD47 was also inhibited by a mAb to the integrin beta3 subunit [3].

Other interactions of Cd47

• Thus, CD47-SIRPalpha signaling can have a profound influence on the severity of AIHA, making manipulation of this signaling pathway a theoretically appealing avenue in the treatment of the disease [8].
• Overexpression of CD47 resulted in the activation of both Rac and Cdc42 [3].
• Src homology 2 domain-containing protein tyrosine phosphatase substrate 1 (SHPS-1) is a member of the signal regulatory protein family in which the extracellular region interacts with its ligand, CD47 [20].
• Its extracellular region interacts with the transmembrane ligand CD47 expressed on the surface of adjacent cells, and its cytoplasmic region binds the protein tyrosine phosphatases SHP-1 and SHP-2 [21].
• Also, by transiently expressing mutant forms of this kinase, we demonstrated that Fyn is required for the integrin associated PI 3K activity [22].

Analytical, diagnostic and therapeutic context of Cd47

• Immunohistochemistry reveals a virtually identical distribution of P84 and IAP in a variety of adult brain regions [12].
• Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding [9].
• These effects on LCs and contact hypersensitivity response of CD47 ligation were reversed by treatment with pertussis toxin [19].
• Western blot analysis confirmed the lack of IAP protein in IAP-deficient mice, whereas IAP expression was similar in both the wild-type and heterozygote controls [23].
• Northern blots revealed that IAP was consistently overexpressed in non-tumorous parts of the kidney (2.4-fold increase, n = 9, P < 0.0001) as compared with matched controls 1 to 2 years after Fe-NTA treatment [16].

References