Signal-regulatory protein alpha

Signal-regulatory protein alpha
Rendering based on PDB 2JJS​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2JJS​, 2JJT​, 2UV3​, 2WNG​, 4CMM​
Identifiers
Symbols	SIRPA ; BIT; CD172A; MFR; MYD-1; P84; PTPNS1; SHPS1; SIRP
External IDs	OMIM: 602461 MGI: 108563 HomoloGene: 7246 GeneCards: SIRPA Gene
EC number	3.1.3.48
Gene ontology Molecular function • SH3 domain binding Cellular component • plasma membrane • membrane • integral component of membrane • extracellular exosome Biological process • cell adhesion • blood coagulation • leukocyte migration Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	140885	19261
Ensembl	ENSG00000198053	ENSMUSG00000037902
UniProt	P78324	P97797
RefSeq (mRNA)	NM_001040022	NM_001177646
RefSeq (protein)	NP_001035111	NP_001171118
Location (UCSC)	Chr 20: 1.89 – 1.94 Mb	Chr 2: 129.59 – 129.63 Mb
PubMed search

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

SIRP α 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. This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors.^{[1] [2]}

Structure

The cytoplasmic region of SIRP α is highly conserved between rats, mice and humans. Cytoplasmic region consists of tyrosine residues conform to inhibitory ITIMs that associates with phosphataseSHP2. 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.^{[1] [3]}

Ligands

SIRP α recognize CD47, that is an antiphagocytic signal distinguished live cells from dying. It has single Ig-like extracellular domain and five membrane spanning regions. CD47 can interact also with other ligands which affect the outcome of interaction SIRP α – CD47. Beside this both proteins can be present on the same cell and the levels of their expression is crucial in regulation. Their interaction can be modified also by endocytosis of the receptor, cleavage or interaction with surfactant proteins. SIRP α recognize soluble ligands such as surfactant protein A and D that bind to the same region as CD47 and block binding of this ligand. ^{[4] [3]}

Signalization

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.^{[4] [3]}

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.^[5]

References

1. Barclay AN (2009). "Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function.". Curr Opin Immunol 21 (1): 47–52. doi:10.1016/j.coi.2009.01.008. PMC 3128989. PMID 19223164.
2. Stefanidakis M, Newton G, Lee WY, Parkos CA, Luscinskas FW (2008). "Endothelial CD47 interaction with SIRPgamma is required for human T-cell transendothelial migration under shear flow conditions in vitro.". Blood 112 (4): 1280–9. doi:10.1182/blood-2008-01-134429. PMC 2515120. PMID 18524990.
3. Barclay AN, Brown MH (2006). "The SIRP family of receptors and immune regulation.". Nat Rev Immunol 6 (6): 457–64. doi:10.1038/nri1859. PMID 16691243.
4. van Beek EM, Cochrane F, Barclay AN, van den Berg TK (2005). "Signal regulatory proteins in the immune system.". J Immunol 175 (12): 7781–7. doi:10.4049/jimmunol.175.12.7781. PMID 16339510.
5. Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, et al. (2013). "Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.". Science 341 (6141): 88–91. doi:10.1126/science.1238856. PMC 3810306. PMID 23722425.

Further reading

• Oldenborg, P. A. (2013). CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN hematology, ; 2013: 614619. . doi: 10.1155/2013/614619
• Yamauchi, T., Takenaka, K., Urata, S., et al. & 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
• Oldenborg PA (2004). "Role of CD47 in erythroid cells and in autoimmunity.". Leuk. Lymphoma 45 (7): 1319–27. doi:10.1080/1042819042000201989. PMID 15359629.
• Margolis RL, Breschel TS, Li SH, et al. (1996). "Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain.". Somat. Cell Mol. Genet. 21 (4): 279–84. doi:10.1007/BF02255782. PMID 8525433.
• Ohnishi H, Kubota M, Ohtake A, et al. (1996). "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. doi:10.1074/jbc.271.41.25569. PMID 8810330.
• Fujioka Y, Matozaki T, Noguchi T, et al. (1997). "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. PMC 231692. PMID 8943344.
• Sano S, Ohnishi H, Omori A, et al. (1997). "BIT, an immune antigen receptor-like molecule in the brain.". FEBS Lett. 411 (2–3): 327–34. doi:10.1016/S0014-5793(97)00724-2. PMID 9271230.
• Brooke GP, Parsons KR, Howard CJ (1998). "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. doi:10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V. PMID 9485180.
• Timms JF, Carlberg K, Gu H, et al. (1998). "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. PMC 108968. PMID 9632768.
• Veillette A, Thibaudeau E, Latour S (1998). "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. doi:10.1074/jbc.273.35.22719. PMID 9712903.
• Jiang P, Lagenaur CF, Narayanan V (1999). "Integrin-associated protein is a ligand for the P84 neural adhesion molecule.". J. Biol. Chem. 274 (2): 559–62. doi:10.1074/jbc.274.2.559. PMID 9872987.
• Ohnishi H, Yamada M, Kubota M, et al. (1999). "Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins.". J. Neurochem. 72 (4): 1402–8. doi:10.1046/j.1471-4159.1999.721402.x. PMID 10098842.
• Timms JF, Swanson KD, Marie-Cardine A, et al. (1999). "SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages.". Curr. Biol. 9 (16): 927–30. doi:10.1016/S0960-9822(99)80401-1. PMID 10469599.
• Seiffert M, Cant C, Chen Z, et al. (1999). "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. PMID 10572074.
• Sano S, Ohnishi H, Kubota M (2000). "Gene structure of mouse BIT/SHPS-1.". Biochem. J. 344 (3): 667–75. doi:10.1042/0264-6021:3440667. PMC 1220688. PMID 10585853.
• Yang J, Cheng Z, Niu T, et al. (2000). "Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1.". J. Biol. Chem. 275 (6): 4066–71. doi:10.1074/jbc.275.6.4066. PMID 10660565.
• Stofega MR, Argetsinger LS, Wang H, et al. (2000). "Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha.". J. Biol. Chem. 275 (36): 28222–9. doi:10.1074/jbc.M004238200. PMID 10842184.
• Wu CJ, Chen Z, Ullrich A, et al. (2000). "Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs).". Oncogene 19 (35): 3999–4010. doi:10.1038/sj.onc.1203748. PMID 10962556.
• Latour S, Tanaka H, Demeure C, et al. (2001). "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. doi:10.4049/jimmunol.167.5.2547. PMID 11509594.
• Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20.". Nature 414 (6866): 865–71. doi:10.1038/414865a. PMID 11780052.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.