Trends in Cell Biology
ReviewFunctions and molecular mechanisms of the CD47–SIRPα signalling pathway
Section snippets
CD47 and SIRPα form an intercellular communication relay
Cells in a multicellular organism need to communicate with one another to regulate their development and organization into tissues, to control their growth and death and to coordinate their functions. Animal cells communicate with each other in two principal ways: (i) they secrete chemicals that signal to cells at some distance; and (ii) they express a signalling molecule at the cell surface that binds to a cognate receptor on adjacent cells. The latter system is more suitable for precise and
SIRPα
SIRPα, also known as SHPS-1, SIRPA, p84 and BIT (see Box 1 for discussion of SIRP family nomenclature), is a transmembrane protein that contains three immunoglobulin (Ig)-like domains in its extracellular region and putative tyrosine phosphorylation sites in its cytoplasmic region 1, 2, 3, 4, 5. Various growth factors and events such as integrin-mediated cell adhesion to extracellular matrix (ECM) proteins induce the tyrosine phosphorylation of SIRPα 1, 6. The tyrosine-phosphorylated sites of
CD47
CD47 is a ligand for the extracellular region of SIRPα [17] (Figure 1a). This protein, which was originally identified in association with the integrin αvβ3 (hence its alternative name ‘integrin-associated protein’ [IAP]), is also a member of the Ig superfamily, possessing a V-type Ig-like extracellular domain, five putative membrane-spanning segments and a short cytoplasmic tail [18]. The extracellular region of CD47 is also responsible for its association with the integrin β3 subunit [19].
Regulation of phagocytosis in macrophages by the CD47–SIRPα signalling complex
The best-characterized function of the CD47–SIRPα signalling complex in vivo is the prevention of phagocytosis of RBCs or platelets by macrophages (Figure 2a). Macrophages are ‘professional’ phagocytes that have an important role in preservation of tissue integrity and function by engulfing old cells or apoptotic bodies 41, 42. The rate of clearance of CD47-deficient RBCs from the bloodstream was found to be markedly increased compared with that found for wild-type cells [28]. This
Regulation of the immune system by signalling downstream of the CD47–SIRPα complex
Similarly to its regulation of phagocytosis in macrophages, SIRPα, through its interaction with CD47, was also thought to have a negative role in the immune system 13, 53. Ligation of SIRPα by CD47-Fc fusion proteins was thus found to suppress the phenotypic and functional maturation of immature dendritic cells (DCs) and to inhibit cytokine production by mature DCs [13], indicating that SIRPα (on DCs), through its interaction with CD47 (on T cells), prevents activation of DCs. By contrast,
Functions of the CD47–SIRPα pairing in the central nervous system
SIRPα is abundant throughout the brain, especially in synapse-rich areas such as the stratum lucidum of the cornus ammonis 3 (CA3) region in the hippocampus, the molecular layer and synaptic glomeruli of the cerebellum, and the plexiform layers of the retina 3, 17, 27. CD47 is also expressed throughout the brain and the regions in which it is most abundant overlap with those enriched with SIRPα 3, 27 (Figure 3a). In addition, the expression of both SIRPα and CD47 in the brain increases markedly
Emerging roles for SIRPα in insulin secretion and muscle formation
SIRPα and CD47 have been recently shown to be highly expressed in pancreatic β-cells [74]. Furthermore, SIRPα mutant mice manifest a low plasma insulin level and impaired glucose tolerance, indicating that SIRPα promotes insulin secretion from β-cells. Glucose-stimulated insulin secretion was found to be similar for pancreatic islets isolated from wild-type or SIRPα mutant mice, but with the impaired glucose tolerance of SIRPα mutant mice being ameliorated by treatment with an α2-adrenergic
Concluding remarks and future perspectives
Almost one decade has passed since the discovery of CD47 as a ligand for SIRPα, but the functions of and molecular mechanism for the CD47–SIRPα signalling pathway still seem to be attractive for researchers and the knowledge regarding this cell–cell signalling system is steadily increasing. Graft failure in the transplantation of hematopoietic stem cells (HSCs) occurs despite donor–host genetic identity of human leukocyte antigens, indicating that additional factors modulate engraftment. With
Acknowledgements
The work in the authors’ laboratory was supported by a Grant-in-Aid for Scientific Research on Priority Areas Cancer, a Grant-in-Aid for Scientific Research (B), a Grant-in-Aid for Young Scientists, a grant of the 21st Century COE Program and a Global Center of Excellence Program grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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