Trends in Cell Biology
Volume 19, Issue 2, February 2009, Pages 72-80
Journal home page for Trends in Cell Biology

Review
Functions and molecular mechanisms of the CD47–SIRPα signalling pathway

https://doi.org/10.1016/j.tcb.2008.12.001Get rights and content

Signal regulatory protein (SIRP)α, also known as SHPS-1 or SIRPA, is a transmembrane protein that binds to the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is predominantly expressed in neurons, dendritic cells and macrophages. CD47, a widely expressed transmembrane protein, is a ligand for SIRPα, with the two proteins constituting a cell–cell communication system. The interaction of SIRPα with CD47 is important for the regulation of migration and phagocytosis. Recent studies have implicated the CD47–SIRPα signalling pathway in immune homeostasis and in regulation of neuronal networks. Advances in the structural and functional analyses of the CD47–SIRPα signalling pathway now provide exciting hints of the therapeutic benefits of manipulating this signalling system in autoimmune diseases and neurological disorders.

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.

References (85)

  • X. Han

    CD47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation

    J. Biol. Chem.

    (2000)
  • Y. Liu

    Functional elements on SIRPα IgV domain mediate cell surface binding to CD47

    J. Mol. Biol.

    (2007)
  • D. Hatherley

    The structure of the macrophage signal regulatory protein α (SIRPα) inhibitory receptor reveals a binding face reminiscent of that used by T cell receptors

    J. Biol. Chem.

    (2007)
  • A. Nakaishi

    Structural insight into the specific interaction between murine SHPS-1/SIRPα and its ligand CD47

    J. Mol. Biol.

    (2008)
  • D. Hatherley

    Paired receptor specificity explained by structures of signal regulatory proteins alone and complexed with CD47

    Mol. Cell

    (2008)
  • T. Takada

    Roles of the complex formation of SHPS-1 with SHP-2 in insulin-stimulated mitogen-activated protein kinase activation

    J. Biol. Chem.

    (1998)
  • R. Sato

    Regulation of multiple functions of SHPS-1, a transmembrane glycoprotein, by its cytoplasmic region

    Biochem. Biophys. Res. Commun.

    (2003)
  • Y. Liu

    The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47

    J. Biol. Chem.

    (2001)
  • Y. Liu

    Signal regulatory protein (SIRPα), a cellular ligand for CD47, regulates neutrophil transmigration

    J. Biol. Chem.

    (2002)
  • S.J. Gardai

    By binding SIRPα or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation

    Cell

    (2003)
  • S. Greenberg et al.

    Phagocytosis and innate immunity

    Curr. Opin. Immunol.

    (2002)
  • P.A. Oldenborg

    Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic (NOD) mice

    Blood

    (2002)
  • T. Ishikawa-Sekigami

    SHPS-1 promotes the survival of circulating erythrocytes through inhibition of phagocytosis by splenic macrophages

    Blood

    (2006)
  • T. Ishikawa-Sekigami

    Enhanced phagocytosis of CD47-deficient red blood cells by splenic macrophages requires SHPS-1

    Biochem. Biophys. Res. Commun.

    (2006)
  • T. Yamao

    Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1

    J. Biol. Chem.

    (2002)
  • M. Olsson

    Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia

    Blood

    (2005)
  • S.J. Gardai

    Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte

    Cell

    (2005)
  • C. Okuzawa

    Resistance to collagen-induced arthritis in SHPS-1 mutant mice

    Biochem. Biophys. Res. Commun.

    (2008)
  • S. Motegi

    Essential roles of SHPS-1 in induction of contact hypersensitivity of skin

    Immunol. Lett.

    (2008)
  • C.T. Weaver

    Th17: an effector CD4 T cell lineage with regulatory T cell ties

    Immunity

    (2006)
  • K. Kikly

    The IL-23/Th17 axis: therapeutic targets for autoimmune inflammation

    Curr. Opin. Immunol.

    (2006)
  • J.C. Fiala

    Dendritic spine pathology: cause or consequence of neurological disorders?

    Brain Res. Brain Res. Rev.

    (2002)
  • H. Taniguchi

    Cold exposure induces tyrosine phosphorylation of BIT through NMDA receptors in the rat hypothalamus

    Biochem. Biophys. Res. Commun.

    (2004)
  • H. Taniguchi

    Regulation of sympathetic and parasympathetic nerve activities by BIT/SHPS-1

    Neurosci. Lett.

    (2006)
  • Y. Liu

    SIRPβ1 is expressed as a disulfide-linked homodimer in leukocytes and positively regulates neutrophil transepithelial migration

    J. Biol. Chem.

    (2005)
  • A. Hayashi

    Positive regulation of phagocytosis by SIRPβ and its signaling mechanism in macrophages

    J. Biol. Chem.

    (2004)
  • L. Piccio

    Adhesion of human T cells to antigen-presenting cells through SIRPβ2-CD47 interaction costimulates T-cell proliferation

    Blood

    (2005)
  • Y. Fujioka

    A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion

    Mol. Cell. Biol.

    (1996)
  • A. Kharitonenkov

    A family of proteins that inhibit signalling through tyrosine kinase receptors

    Nature

    (1997)
  • Z.P. Mi

    Expression of a synapse-associated membrane protein, P84/SHPS-1, and its ligand, IAP/CD47, in mouse retina

    J. Comp. Neurol.

    (2000)
  • H. Ohnishi

    Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins

    J. Neurochem.

    (1999)
  • T.K. van den Berg

    A nomenclature for signal regulatory protein family members

    J. Immunol.

    (2005)
  • Cited by (349)

    View all citing articles on Scopus
    View full text