CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease

Abstract

Interactions between cells and their surroundings are important for proper function and homeostasis in a multicellular organism. These interactions can either be established between the cells and molecules in their extracellular milieu, but also involve interactions between cells. In all these situations, proteins in the plasma membranes are critically involved to relay information obtained from the exterior of the cell. The cell surface glycoprotein CD47 (integrin-associated protein (IAP)) was first identified as an important regulator of integrin function, but later also was shown to function in ways that do not necessarily involve integrins. Ligation of CD47 can induce intracellular signaling resulting in cell activation or cell death depending on the exact context. By binding to another cell surface glycoprotein, signal regulatory protein alpha (SIRPα), CD47 can regulate the function of cells in the monocyte/macrophage lineage. In this spotlight paper, several functions of CD47 will be reviewed, although some functions may be more briefly mentioned. Focus will be on the ways CD47 regulates hematopoietic cells and functions such as CD47 signaling, induction of apoptosis, and regulation of phagocytosis or cell-cell fusion.

Figure 1

Interactions of CD47 in cis and trans. CD47 interacts in cis with integrins, in trans with SIRPs, and can also bind the soluble protein TSP-1. The figure summarizes intracellular signaling events associated with CD47 upon binding to its interaction partners.

Figure 2

Mechanisms involved in mediating CD47-induced cell death. Ligation of CD47 by mAbs or TSP 1 induces apoptosis, which involves the activation of heterotrimeric Gi proteins, reduction in cAMP, and exposure of phosphatidylserine in the outer leaflet of the plasma membrane. It also induces the expression of the proapoptotic Bcl-2 family member BNIP3, its association with CD47, and subsequent translocation of BNIP3 to mitochondria. CD47-induced apoptosis may also involve ROS and F-actin.

Figure 3

Association of CD47 with the Rh and band 3 complexes in the erythrocyte membrane. CD47 interacts with the Rh/RhAG complex and also associates with protein 4.2, which links CD47 to the band 3/ankyrin complex and the spectrin cytoskeleton. It is important to note that not all CD47 appears to be associated with this multiprotein complex in erythrocyte membranes.

Figure 4

CD47 regulates phagocytosis of host cells by interacting with SIRPα. (a) CD47 on viable normal host cells can bind to SIRPα on a phagocytic cell (e.g., a macrophage (Mϕ)), which induces tyrosine phosphorylation of SIRPα ITIMS and recruitment of SHP-1. This can inhibit prophagocytic signaling through Fcγ receptors, complement receptors (CR), or LRP-1. Phagocytosis inhibition may involve signaling through Syk and PI3 kinase and inhibition of nonmuscle myosin type IIA (NMMIIA). (b) On apoptotic cells, CD47 becomes clustered in the plasma membrane and may be segregated away from domains containing ligands for prophagocytic receptors, here exemplified by calreticulin (crt) binding to LRP-1. However, most likely this principle involves also other prophagocytic receptors (receptor x). Clustered CD47 may also bind to SIRPα without inducing inhibition of phagocytosis, but may rather promote tethering of the apoptotic cell to the phagocyte. This function may also involve TSP-1 and so far uncharacterized mechanisms that can also promote phagocytosis. (c) Cancer cells may increase their expression of CD47 to strengthen the inhibitory signals through SIRPα and to more potently inhibit phagocytosis mediated by Fcγ receptors and other prophagocytic receptors (receptor x).