Signal-regulatory protein alpha explained

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein CD47 also called the "don't eat me" signal. This interaction negatively controls effector function of innate immune cells such as host cell phagocytosis. SIRPα diffuses laterally on the macrophage membrane and accumulates at a phagocytic synapse to bind CD47 and signal 'self', which inhibits the cytoskeleton-intensive process of phagocytosis by the macrophage.^[1] This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors.^{[2] [3]} NB. Protein shown to the right is CD47 not SIRP α.

Structure

The cytoplasmic region of SIRPα is highly conserved between rats, mice and humans. Cytoplasmic region contains a number of tyrosine residues, which likely act as ITIMs. Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and SHP2.^[4] The extracellular region contains three Immunoglobulin superfamily domains – single V-set and two C1-set IgSF domains. SIRP β and γ have the similar extracellular structure but different cytoplasmic regions giving contrasting types of signals. SIRP α polymorphisms are found in ligand-binding IgSF V-set domain but it does not affect ligand binding. One idea is that the polymorphism is important to protect the receptor of pathogens binding.^{[2] [5]}

Ligands

SIRPα recognizes CD47, an anti-phagocytic signal that distinguishes live cells from dying cells. CD47 has a single Ig-like extracellular domain and five membrane spanning regions. The interaction between SIRPα and CD47 can be modified by endocytosis or cleavage of the receptor, or interaction with surfactant proteins. Surfactant protein A and D are soluble ligands, highly expressed in the lungs, that bind to the same region of SIRPα as CD47 and can therefore competitively block binding.^{[5] [6]}

Signalling

The extracellular domain of SIRP α binds to CD47 and transmits intracellular signals through its cytoplasmic domain. CD47-binding is mediated through the NH2-terminal V-like domain of SIRP α. The cytoplasmic region contains four ITIMs that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinase SHP2. SIRP α has been shown to bind also phosphatase SHP1, adaptor protein SCAP2 and FYN-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition of myosin accumulation at the cell surface and results in the inhibition of phagocytosis.^{[5] [6]}

Cancer

Cancer cells highly expressed CD47 that activate SIRP α and inhibit macrophage-mediated destruction. In one study, they engineered high-affinity variants of SIRP α that antagonized CD47 on cancer cells and caused increase phagocytosis of cancer cells.^[7] Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.^{[8] [9]}

Further reading

• 10.1155/2013/614619 . 3564380 . 23401787 . 2013 . CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease . ISRN Hematol . 614619 . Oldenborg PA . 2013. free .
• Yamauchi T, Takenaka K, Urata S et al . 2013. & Akashi, K. (2013). Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment . Blood . 121 . 8. 1316–1325 . 10.1182/blood-2012-06-440354 . 23293079. free .
• Oldenborg PA . Role of CD47 in erythroid cells and in autoimmunity. . Leuk. Lymphoma . 45 . 7 . 1319–27 . 2004 . 15359629 . 10.1080/1042819042000201989 . 12642148 .
• Margolis RL, Breschel TS, Li SH, etal . Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. . Somat. Cell Mol. Genet. . 21 . 4 . 279–84 . 1996 . 8525433 . 10.1007/BF02255782 . 22174220 .
• Ohnishi H, Kubota M, Ohtake A, etal . Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule. . J. Biol. Chem. . 271 . 41 . 25569–74 . 1996 . 8810330 . 10.1074/jbc.271.41.25569 . free .
• Fujioka Y, Matozaki T, Noguchi T, etal . 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. . 16 . 12 . 6887–99 . 1997 . 8943344 . 10.1128/MCB.16.12.6887. 231692 .
• Sano S, Ohnishi H, Omori A, etal . BIT, an immune antigen receptor-like molecule in the brain. . FEBS Lett. . 411 . 2–3 . 327–34 . 1997 . 9271230 . 10.1016/S0014-5793(97)00724-2 . 39554802 . free .
• Brooke GP, Parsons KR, Howard CJ . Cloning of two members of the SIRP alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells. . Eur. J. Immunol. . 28 . 1 . 1–11 . 1998 . 9485180 . 10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V . free .
• Timms JF, Carlberg K, Gu H, etal . Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. . Mol. Cell. Biol. . 18 . 7 . 3838–50 . 1998 . 9632768 . 10.1128/mcb.18.7.3838. 108968 .
• Veillette A, Thibaudeau E, Latour S . High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. . J. Biol. Chem. . 273 . 35 . 22719–28 . 1998 . 9712903 . 10.1074/jbc.273.35.22719 . free .
• Jiang P, Lagenaur CF, Narayanan V . Integrin-associated protein is a ligand for the P84 neural adhesion molecule. . J. Biol. Chem. . 274 . 2 . 559–62 . 1999 . 9872987 . 10.1074/jbc.274.2.559 . free .
• Ohnishi H, Yamada M, Kubota M, etal . Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. . J. Neurochem. . 72 . 4 . 1402–8 . 1999 . 10098842 . 10.1046/j.1471-4159.1999.721402.x . 83600875 . free .
• Timms JF, Swanson KD, Marie-Cardine A, etal . SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. . Curr. Biol. . 9 . 16 . 927–30 . 1999 . 10469599 . 10.1016/S0960-9822(99)80401-1 . 16056124 . free .
• Seiffert M, Cant C, Chen Z, etal . Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. . Blood . 94 . 11 . 3633–43 . 1999 . 10572074 . 10.1182/blood.V94.11.3633. 11033417 .
• Sano S, Ohnishi H, Kubota M . Gene structure of mouse BIT/SHPS-1. . Biochem. J. . 344 . 3. 667–75 . 2000 . 10585853 . 10.1042/0264-6021:3440667. 1220688 .
• Yang J, Cheng Z, Niu T, etal . Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1. . J. Biol. Chem. . 275 . 6 . 4066–71 . 2000 . 10660565 . 10.1074/jbc.275.6.4066 . free .
• Stofega MR, Argetsinger LS, Wang H, etal . Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha. . J. Biol. Chem. . 275 . 36 . 28222–9 . 2000 . 10842184 . 10.1074/jbc.M004238200 . free .
• Wu CJ, Chen Z, Ullrich A, etal . Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs). . Oncogene . 19 . 35 . 3999–4010 . 2000 . 10962556 . 10.1038/sj.onc.1203748 . 9020984 .
• Latour S, Tanaka H, Demeure C, etal . Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation. . J. Immunol. . 167 . 5 . 2547–54 . 2001 . 11509594 . 10.4049/jimmunol.167.5.2547. free .
• Deloukas P, Matthews LH, Ashurst J, etal . The DNA sequence and comparative analysis of human chromosome 20. . Nature . 414 . 6866 . 865–71 . 2002 . 11780052 . 10.1038/414865a . free . 2001Natur.414..865D .

Notes and References

1. Tsai RK, Discher DE. Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. . J Cell Biol . 2008 . 180 . 5 . 988–1003 . 10.1083/jcb.200708043. 2265407. 18332220 .
2. Barclay AN. Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function. . Curr Opin Immunol . 2009 . 21 . 1 . 47–52 . 19223164 . 10.1016/j.coi.2009.01.008 . 3128989 .
3. Stefanidakis M, Newton G, Lee WY, Parkos CA, Luscinskas FW. Endothelial CD47 interaction with SIRPgamma is required for human T-cell transendothelial migration under shear flow conditions in vitro. . Blood . 2008 . 112 . 4 . 1280–9 . 18524990 . 10.1182/blood-2008-01-134429 . 2515120 .
4. Okazawa. Hideki. Motegi. Sei-ichiro. Ohyama. Naoko. Ohnishi. Hiroshi. Tomizawa. Takeshi. Kaneko. Yoriaki. Oldenborg. Per-Arne. Ishikawa. Osamu. Matozaki. Takashi. 2005-02-15. Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. Journal of Immunology. 174. 4. 2004–2011. 0022-1767. 15699129. 10.4049/jimmunol.174.4.2004. free.
5. Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. . Nat Rev Immunol . 2006 . 6 . 6 . 457–64 . 10.1038/nri1859 . 16691243 . 7915923 .
6. van Beek EM, Cochrane F, Barclay AN, van den Berg TK. Signal regulatory proteins in the immune system. . J Immunol . 2005 . 175 . 12 . 7781–7 . 10.4049/jimmunol.175.12.7781. 16339510 . free .
7. Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, etal . Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. . Science . 2013 . 341 . 6141 . 88–91 . 23722425 . 10.1126/science.1238856 . 3810306 . 2013Sci...341...88W .
8. https://www.sciencedaily.com/releases/2017/02/170206084054.htm Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
9. Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy . JCI Insight. 10.1172/jci.insight.89140 . 2017 . 2 . 1. e89140. Yanagita T. 5214103 . 28097229.