Signal-regulatory protein alpha: Difference between revisions

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{{Infobox_gene}}
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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.
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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 system|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.<ref name="pmid18332220">{{cite journal| vauthors=Tsai RK, Discher DE| title=Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. | journal=J Cell Biol | year= 2008 | volume= 180 | issue= 5 | pages= 988–1003 | pmid=18332220 | doi= 10.1083/jcb.200708043| pmc= | url=https://www.ncbi.nlm.nih.gov/pubmed/18332220  }}</ref> This is analogous to the self signals provided by [[MHC class I]] molecules to [[NK cells]] via Ig-like or [[Ly49]] receptors.<ref name="pmid19223164">{{cite journal| author=Barclay AN| title=Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function. | journal=Curr Opin Immunol | year= 2009 | volume= 21 | issue= 1 | pages= 47–52 | pmid=19223164 | doi=10.1016/j.coi.2009.01.008 | pmc=3128989 }}</ref><ref name="pmid18524990">{{cite journal| vauthors=Stefanidakis M, Newton G, Lee WY, Parkos CA, Luscinskas FW| title=Endothelial CD47 interaction with SIRPgamma is required for human T-cell transendothelial migration under shear flow conditions in vitro. | journal=Blood | year= 2008 | volume= 112 | issue= 4 | pages= 1280–9 | pmid=18524990 | doi=10.1182/blood-2008-01-134429 | pmc=2515120 }}</ref> NB. Protein shown to the right is CD47 not SIRP α.
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==Structure==
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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 [[Immunoreceptor tyrosine-based inhibitory motif|ITIMs]].  Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and [[PTPN11|SHP2]].<ref>{{Cite journal|last=Okazawa|first=Hideki|last2=Motegi|first2=Sei-ichiro|last3=Ohyama|first3=Naoko|last4=Ohnishi|first4=Hiroshi|last5=Tomizawa|first5=Takeshi|last6=Kaneko|first6=Yoriaki|last7=Oldenborg|first7=Per-Arne|last8=Ishikawa|first8=Osamu|last9=Matozaki|first9=Takashi|date=2005-02-15|title=Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system|url=https://www.ncbi.nlm.nih.gov/pubmed/15699129|journal=Journal of Immunology|volume=174|issue=4|pages=2004–2011|issn=0022-1767|pmid=15699129}}</ref> The extracellular region contains three [[Immunoglobulin superfamily]] domains – single V-set and two C1-set [[Immunoglobulin superfamily|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 [[Immunoglobulin superfamily|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.<ref name="pmid19223164"/><ref name="pmid16691243">{{cite journal| vauthors=Barclay AN, Brown MH| title=The SIRP family of receptors and immune regulation. | journal=Nat Rev Immunol | year= 2006 | volume= 6 | issue= 6 | pages= 457–64 | pmid=16691243 | doi=10.1038/nri1859 | pmc= | url=https://www.ncbi.nlm.nih.gov/pubmed/16691243  }}</ref>
}}
 
== Ligands ==
SIRPα recognizes [[CD47]], that is an antiphagocytic signal distinguished live cells from dying. CD47 has a single Ig-like extracellular domain and five membrane spanning regions.  Their interaction can be modified also by [[endocytosis]] of the receptor, cleavage or interaction with [[Surfactant protein A|surfactant proteins]]. SIRP α recognize soluble ligands such as [[surfactant protein A]] and [[Surfactant protein D|D]] that bind to the same region as [[CD47]] and block binding of this ligand.<ref name="pmid16691243"/><ref name="pmid16339510">{{cite journal| vauthors=van Beek EM, Cochrane F, Barclay AN, van den Berg TK| title=Signal regulatory proteins in the immune system. | journal=J Immunol | year= 2005 | volume= 175 | issue= 12 | pages= 7781–7 | pmid=16339510 | doi= 10.4049/jimmunol.175.12.7781| pmc= | url=https://www.ncbi.nlm.nih.gov/pubmed/16339510  }}</ref>
 
== 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 [[Immunoreceptor tyrosine-based inhibitory motif|ITIMs]] that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinase [[PTPN11|SHP2]]. SIRP α has been shown to bind also phosphatase [[PTPN6|SHP1]], adaptor protein [[SREBP|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]].<ref name="pmid16691243"/><ref name="pmid16339510"/>
 
== 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.<ref name="pmid23722425">{{cite journal |vauthors=Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, etal | title=Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. | journal=Science | year= 2013 | volume= 341 | issue= 6141 | pages= 88–91 | pmid=23722425 | doi=10.1126/science.1238856 | pmc=3810306 }}</ref> Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.<ref>[https://www.sciencedaily.com/releases/2017/02/170206084054.htm Potential new cancer treatment activates cancer-engulfing cells. Feb 2017]</ref><ref name=Yanagita2017>{{cite journal |title=Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy. |journal=JCI Insight, 2017; 2 (1) |doi=10.1172/jci.insight.89140 |year=2017 |url=https://insight.jci.org/articles/view/89140 |volume=2}}</ref>


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==References==
{{GNF_Protein_box
{{reflist | refs =
| image = 
| image_source = 
| PDB =  
| Name = Signal-regulatory protein alpha
| HGNCid = 9662
| Symbol = SIRPA
| AltSymbols =; P84; BIT; CD172A; MFR; MYD-1; PTPNS1; SHPS-1; SHPS1; SIRP; SIRP-ALPHA-1; SIRPalpha; SIRPalpha2
| OMIM = 602461
| ECnumber = 
| Homologene = 7246
| MGIid = 108563
| GeneAtlas_image1 = PBB_GE_SIRPA_202896_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_SIRPA_202895_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_SIRPA_202897_at_tn.png
| Function =
| Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0007155 |text = cell adhesion}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 140885
    | Hs_Ensembl = ENSG00000198053
    | Hs_RefseqProtein = NP_001035111
    | Hs_RefseqmRNA = NM_001040022
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 20
    | Hs_GenLoc_start = 1823425
    | Hs_GenLoc_end = 1868543
    | Hs_Uniprot = P78324
    | Mm_EntrezGene = 19261
    | Mm_Ensembl = ENSMUSG00000037902
    | Mm_RefseqmRNA = NM_007547
    | Mm_RefseqProtein = NP_031573
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 129284355
    | Mm_GenLoc_end = 129323669
    | Mm_Uniprot = P97797
  }}
}}
'''Signal-regulatory protein alpha''', also known as '''SIRPA''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SIRPA signal-regulatory protein alpha| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=140885| accessdate = }}</ref>  SIRPA has also recently been designated '''CD172A''' ([[cluster of differentiation]] 172A).


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by this gene is a member of the signal-regulatory-protein (SIRP) family, and also belongs to the immunoglobulin superfamily. SIRP family members are receptor-type transmembrane glycoproteins known to be involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. This protein can be phosphorylated by tyrosine kinases. The phospho-tyrosine residues of this PTP have been shown to recruit SH2 domain containing tyrosine phosphatases (PTP), and serve as substrates of PTPs. This protein was found to participate in signal transduction mediated by various growth factor receptors. CD47 has been demonstrated to be a ligand for this receptor protein. This gene and its product share very high similarity with several other members of the SIRP family. These related genes are located in close proximity to each other on chromosome 20p13. Multiple alternatively spliced transcript variants have been determined for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: SIRPA signal-regulatory protein alpha| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=140885| accessdate = }}</ref>
}}
}}


==References==
{{reflist|2}}
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal |doi= 10.1155/2013/614619 | pmc=3564380 | pmid=23401787 | volume=2013 | title=CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease | journal=ISRN Hematol | page=614619 | vauthors=Oldenborg PA}}
| citations =
* {{cite journal | vauthors = Yamauchi T, Takenaka K, Urata S ''et al'' | year = | title = & Akashi, K. (2013). Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment | url = | journal = Blood | volume = 121 | issue = 8| pages = 1316–1325 }}
*{{cite journal  | author=Oldenborg PA |title=Role of CD47 in erythroid cells and in autoimmunity. |journal=Leuk. Lymphoma |volume=45 |issue= 7 |pages= 1319-27 |year= 2004 |pmid= 15359629 |doi= 10.1080/1042819042000201989 }}
*{{cite journal |author = Oldenborg PA |title = Role of CD47 in erythroid cells and in autoimmunity. |journal = Leuk. Lymphoma |volume = 45 |issue = 7 |pages = 1319–27 |year = 2004 |pmid = 15359629 |doi = 10.1080/1042819042000201989 }}
*{{cite journal | author=Margolis RL, Breschel TS, Li SH, ''et al.'' |title=Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. |journal=Somat. Cell Mol. Genet. |volume=21 |issue= 4 |pages= 279-84 |year= 1996 |pmid= 8525433 |doi= }}
*{{cite journal  |vauthors=Margolis RL, Breschel TS, Li SH, etal |title = Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain. |journal = Somat. Cell Mol. Genet. |volume = 21 |issue = 4 |pages = 279–84 |year = 1996 |pmid = 8525433 |doi = 10.1007/BF02255782 }}
*{{cite journal  | author=Ohnishi H, Kubota M, Ohtake A, ''et al.'' |title=Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule. |journal=J. Biol. Chem. |volume=271 |issue= 41 |pages= 25569-74 |year= 1996 |pmid= 8810330 |doi= }}
*{{cite journal  |vauthors=Ohnishi H, Kubota M, Ohtake A, etal |title = Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule. |journal = J. Biol. Chem. |volume = 271 |issue = 41 |pages = 25569–74 |year = 1996 |pmid = 8810330 |doi = 10.1074/jbc.271.41.25569 }}
*{{cite journal  | author=Fujioka Y, Matozaki T, Noguchi T, ''et al.'' |title=A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. |journal=Mol. Cell. Biol. |volume=16 |issue= 12 |pages= 6887-99 |year= 1997 |pmid= 8943344 |doi= }}
*{{cite journal  |vauthors=Fujioka Y, Matozaki T, Noguchi T, etal |title = A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. |journal = Mol. Cell. Biol. |volume = 16 |issue = 12 |pages = 6887–99 |year = 1997 |pmid = 8943344 |doi = |pmc = 231692 }}
*{{cite journal  | author=Kharitonenkov A, Chen Z, Sures I, ''et al.'' |title=A family of proteins that inhibit signalling through tyrosine kinase receptors. |journal=Nature |volume=386 |issue= 6621 |pages= 181-6 |year= 1997 |pmid= 9062191 |doi= 10.1038/386181a0 }}
*{{cite journal  |vauthors=Sano S, Ohnishi H, Omori A, etal |title = BIT, an immune antigen receptor-like molecule in the brain. |journal = FEBS Lett. |volume = 411 |issue = 2–3 |pages = 327–34 |year = 1997 |pmid = 9271230 |doi = 10.1016/S0014-5793(97)00724-2 }}
*{{cite journal  | author=Yamao T, Matozaki T, Amano K, ''et al.'' |title=Mouse and human SHPS-1: molecular cloning of cDNAs and chromosomal localization of genes. |journal=Biochem. Biophys. Res. Commun. |volume=231 |issue= 1 |pages= 61-7 |year= 1997 |pmid= 9070220 |doi= 10.1006/bbrc.1996.6047 }}
*{{cite journal |vauthors = Brooke GP, Parsons KR, Howard CJ |title = 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. |journal = Eur. J. Immunol. |volume = 28 |issue = 1 |pages = 1–11 |year = 1998 |pmid = 9485180 |doi = 10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V }}
*{{cite journal | author=Sano S, Ohnishi H, Omori A, ''et al.'' |title=BIT, an immune antigen receptor-like molecule in the brain. |journal=FEBS Lett. |volume=411 |issue= 2-3 |pages= 327-34 |year= 1997 |pmid= 9271230 |doi= }}
*{{cite journal  |vauthors=Timms JF, Carlberg K, Gu H, etal |title = Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. |journal = Mol. Cell. Biol. |volume = 18 |issue = 7 |pages = 3838–50 |year = 1998 |pmid = 9632768 |doi =  |pmc = 108968 }}
*{{cite journal  | author=Brooke GP, Parsons KR, Howard CJ |title=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. |journal=Eur. J. Immunol. |volume=28 |issue= 1 |pages= 1-11 |year= 1998 |pmid= 9485180 |doi=  }}
*{{cite journal |vauthors = Veillette A, Thibaudeau E, Latour S |title = High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. |journal = J. Biol. Chem. |volume = 273 |issue = 35 |pages = 22719–28 |year = 1998 |pmid = 9712903 |doi = 10.1074/jbc.273.35.22719 }}
*{{cite journal | author=Timms JF, Carlberg K, Gu H, ''et al.'' |title=Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages. |journal=Mol. Cell. Biol. |volume=18 |issue= 7 |pages= 3838-50 |year= 1998 |pmid= 9632768 |doi= }}
*{{cite journal |vauthors = Jiang P, Lagenaur CF, Narayanan V |title = Integrin-associated protein is a ligand for the P84 neural adhesion molecule. |journal = J. Biol. Chem. |volume = 274 |issue = 2 |pages = 559–62 |year = 1999 |pmid = 9872987 |doi = 10.1074/jbc.274.2.559 }}
*{{cite journal | author=Veillette A, Thibaudeau E, Latour S |title=High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. |journal=J. Biol. Chem. |volume=273 |issue= 35 |pages= 22719-28 |year= 1998 |pmid= 9712903 |doi= }}
*{{cite journal  |vauthors=Ohnishi H, Yamada M, Kubota M, etal |title = Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. |journal = J. Neurochem. |volume = 72 |issue = 4 |pages = 1402–8 |year = 1999 |pmid = 10098842 |doi = 10.1046/j.1471-4159.1999.721402.x }}
*{{cite journal  | author=Jiang P, Lagenaur CF, Narayanan V |title=Integrin-associated protein is a ligand for the P84 neural adhesion molecule. |journal=J. Biol. Chem. |volume=274 |issue= 2 |pages= 559-62 |year= 1999 |pmid= 9872987 |doi= }}
*{{cite journal  |vauthors=Timms JF, Swanson KD, Marie-Cardine A, etal |title = SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. |journal = Curr. Biol. |volume = 9 |issue = 16 |pages = 927–30 |year = 1999 |pmid = 10469599 |doi = 10.1016/S0960-9822(99)80401-1 }}
*{{cite journal  | author=Ohnishi H, Yamada M, Kubota M, ''et al.'' |title=Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. |journal=J. Neurochem. |volume=72 |issue= 4 |pages= 1402-8 |year= 1999 |pmid= 10098842 |doi= }}
*{{cite journal  |vauthors=Seiffert M, Cant C, Chen Z, etal |title = Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. |journal = Blood |volume = 94 |issue = 11 |pages = 3633–43 |year = 1999 |pmid = 10572074 |doi = }}
*{{cite journal  | author=Timms JF, Swanson KD, Marie-Cardine A, ''et al.'' |title=SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. |journal=Curr. Biol. |volume=9 |issue= 16 |pages= 927-30 |year= 1999 |pmid= 10469599 |doi= }}
*{{cite journal |vauthors = Sano S, Ohnishi H, Kubota M |title = Gene structure of mouse BIT/SHPS-1. |journal = Biochem. J. |volume = 344 |issue = 3|pages = 667–75 |year = 2000 |pmid = 10585853 |doi =  10.1042/0264-6021:3440667|pmc = 1220688 }}
*{{cite journal | author=Seiffert M, Cant C, Chen Z, ''et al.'' |title=Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. |journal=Blood |volume=94 |issue= 11 |pages= 3633-43 |year= 1999 |pmid= 10572074 |doi=  }}
*{{cite journal  |vauthors=Yang J, Cheng Z, Niu T, etal |title = Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1. |journal = J. Biol. Chem. |volume = 275 |issue = 6 |pages = 4066–71 |year = 2000 |pmid = 10660565 |doi = 10.1074/jbc.275.6.4066 }}
*{{cite journal  | author=Sano S, Ohnishi H, Kubota M |title=Gene structure of mouse BIT/SHPS-1. |journal=Biochem. J. |volume=344 Pt 3 |issue= |pages= 667-75 |year= 2000 |pmid= 10585853 |doi= }}
*{{cite journal  |vauthors=Stofega MR, Argetsinger LS, Wang H, etal |title = Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha. |journal = J. Biol. Chem. |volume = 275 |issue = 36 |pages = 28222–9 |year = 2000 |pmid = 10842184 |doi = 10.1074/jbc.M004238200 }}
*{{cite journal  | author=Yang J, Cheng Z, Niu T, ''et al.'' |title=Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1. |journal=J. Biol. Chem. |volume=275 |issue= 6 |pages= 4066-71 |year= 2000 |pmid= 10660565 |doi= }}
*{{cite journal  |vauthors=Wu CJ, Chen Z, Ullrich A, etal |title = Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs). |journal = Oncogene |volume = 19 |issue = 35 |pages = 3999–4010 |year = 2000 |pmid = 10962556 |doi = 10.1038/sj.onc.1203748 }}
*{{cite journal  | author=Stofega MR, Argetsinger LS, Wang H, ''et al.'' |title=Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha. |journal=J. Biol. Chem. |volume=275 |issue= 36 |pages= 28222-9 |year= 2000 |pmid= 10842184 |doi= 10.1074/jbc.M004238200 }}
*{{cite journal  |vauthors=Latour S, Tanaka H, Demeure C, etal |title = 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. |journal = J. Immunol. |volume = 167 |issue = 5 |pages = 2547–54 |year = 2001 |pmid = 11509594 |doi = 10.4049/jimmunol.167.5.2547}}
*{{cite journal  | author=Wu CJ, Chen Z, Ullrich A, ''et al.'' |title=Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs). |journal=Oncogene |volume=19 |issue= 35 |pages= 3999-4010 |year= 2000 |pmid= 10962556 |doi= 10.1038/sj.onc.1203748 }}
*{{cite journal  |vauthors=Deloukas P, Matthews LH, Ashurst J, etal |title = The DNA sequence and comparative analysis of human chromosome 20. |journal = Nature |volume = 414 |issue = 6866 |pages = 865–71 |year = 2002 |pmid = 11780052 |doi = 10.1038/414865a }}
*{{cite journal  | author=Latour S, Tanaka H, Demeure C, ''et al.'' |title=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. |journal=J. Immunol. |volume=167 |issue= 5 |pages= 2547-54 |year= 2001 |pmid= 11509594 |doi=  }}
*{{cite journal  | author=Deloukas P, Matthews LH, Ashurst J, ''et al.'' |title=The DNA sequence and comparative analysis of human chromosome 20. |journal=Nature |volume=414 |issue= 6866 |pages= 865-71 |year= 2002 |pmid= 11780052 |doi= 10.1038/414865a }}
}}
{{refend}}
{{refend}}


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Revision as of 22:38, 5 October 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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, that is an antiphagocytic signal distinguished live cells from dying. CD47 has a single Ig-like extracellular domain and five membrane spanning regions. 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.[5][6]

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.[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]

References

  1. ↑ Tsai RK, Discher DE (2008). "Inhibition of "self" engulfment through deactivation of myosin-II at the phagocytic synapse between human cells". J Cell Biol. 180 (5): 988–1003. doi:10.1083/jcb.200708043. PMID 18332220.
  2. ↑ 2.0 2.1 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.
  3. ↑ 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.
  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. ISSN 0022-1767. PMID 15699129.
  5. ↑ 5.0 5.1 5.2 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 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.
  8. ↑ Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
  9. ↑ "Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy". JCI Insight, 2017; 2 (1). 2. 2017. doi:10.1172/jci.insight.89140.

Further reading

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

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