View source for Signal-regulatory protein alpha

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
'''Signal regulatory protein α''' (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells{{Citation needed|reason=SIRPα seems to be a marker for non-stem cell (ie matured) identity in cardiomyocyte maturation, see pubmed 22020386|date=May 2022}} 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 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 = The Journal of Cell Biology | volume = 180 | issue = 5 | pages = 989–1003 | date = March 2008 | pmid = 18332220 | pmc = 2265407 | doi = 10.1083/jcb.200708043 }}</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 | vauthors = Barclay AN | title = Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function | journal = Current Opinion in Immunology | volume = 21 | issue = 1 | pages = 47–52 | date = February 2009 | pmid = 19223164 | pmc = 3128989 | doi = 10.1016/j.coi.2009.01.008 }}</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 | volume = 112 | issue = 4 | pages = 1280–1289 | date = August 2008 | pmid = 18524990 | pmc = 2515120 | doi = 10.1182/blood-2008-01-134429 }}</ref> 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 [[Immunoreceptor tyrosine-based inhibitory motif|ITIMs]].  Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 and [[PTPN11|SHP2]].<ref>{{cite journal | vauthors = Okazawa H, Motegi S, Ohyama N, Ohnishi H, Tomizawa T, Kaneko Y, Oldenborg PA, Ishikawa O, Matozaki T | title = Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system | journal = Journal of Immunology | volume = 174 | issue = 4 | pages = 2004–2011 | date = February 2005 | pmid = 15699129 | doi = 10.4049/jimmunol.174.4.2004 | doi-access = free }}</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 = Nature Reviews. Immunology | volume = 6 | issue = 6 | pages = 457–464 | date = June 2006 | pmid = 16691243 | doi = 10.1038/nri1859 | s2cid = 7915923 }}</ref>

== 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 protein A|surfactant proteins]]. [[Surfactant protein A]] and [[Surfactant protein D|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.<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 = Journal of Immunology | volume = 175 | issue = 12 | pages = 7781–7787 | date = December 2005 | pmid = 16339510 | doi = 10.4049/jimmunol.175.12.7781 | doi-access = free }}</ref>

== 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 [[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, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC | title = Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies | journal = Science | volume = 341 | issue = 6141 | pages = 88–91 | date = July 2013 | pmid = 23722425 | pmc = 3810306 | doi = 10.1126/science.1238856 | bibcode = 2013Sci...341...88W }}</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 | vauthors = Yanagita T, Murata Y, Tanaka D, Motegi SI, Arai E, Daniwijaya EW, Hazama D, Washio K, Saito Y, Kotani T, Ohnishi H, Oldenborg PA, Garcia NV, Miyasaka M, Ishikawa O, Kanai Y, Komori T, Matozaki T | title = Anti-SIRP<b>α</b> antibodies as a potential new tool for cancer immunotherapy | journal = JCI Insight | volume = 2 | issue = 1 | pages = e89140 | date = January 2017 | pmid = 28097229 | pmc = 5214103 | doi = 10.1172/jci.insight.89140 }}</ref>
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== References ==
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== Further reading ==
{{refbegin|30}}
* {{cite journal | vauthors = Oldenborg PA | title = CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease | journal = ISRN Hematology | volume = 2013 | pages = 614619 | year = 2013 | pmid = 23401787 | pmc = 3564380 | doi = 10.1155/2013/614619 | doi-access = free }}
* {{cite journal | vauthors = Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, Iwamoto C, Nishihara M, Iwasaki H, Miyamoto T, Honma N, Nakao M, Matozaki T, Akashi K | title = Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment | journal = Blood | volume = 121 | issue = 8 | pages = 1316–1325 | date = February 2013 | pmid = 23293079 | doi = 10.1182/blood-2012-06-440354 | doi-access = free }}
* {{cite journal | vauthors = Oldenborg PA | title = Role of CD47 in erythroid cells and in autoimmunity | journal = Leukemia & Lymphoma | volume = 45 | issue = 7 | pages = 1319–1327 | date = July 2004 | pmid = 15359629 | doi = 10.1080/1042819042000201989 | s2cid = 12642148 }}
* {{cite journal | vauthors = Margolis RL, Breschel TS, Li SH, Kidwai AS, Antonarakis SE, McInnis MG, Ross CA | title = Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain | journal = Somatic Cell and Molecular Genetics | volume = 21 | issue = 4 | pages = 279–284 | date = July 1995 | pmid = 8525433 | doi = 10.1007/BF02255782 | s2cid = 22174220 }}
* {{cite journal | vauthors = Ohnishi H, Kubota M, Ohtake A, Sato K, Sano S | title = Activation of protein-tyrosine phosphatase SH-PTP2 by a tyrosine-based activation motif of a novel brain molecule | journal = The Journal of Biological Chemistry | volume = 271 | issue = 41 | pages = 25569–25574 | date = October 1996 | pmid = 8810330 | doi = 10.1074/jbc.271.41.25569 | doi-access = free }}
* {{cite journal | vauthors = Fujioka Y, Matozaki T, Noguchi T, Iwamatsu A, Yamao T, Takahashi N, Tsuda M, Takada T, Kasuga M | 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 = Molecular and Cellular Biology | volume = 16 | issue = 12 | pages = 6887–6899 | date = December 1996 | pmid = 8943344 | pmc = 231692 | doi = 10.1128/MCB.16.12.6887 }}
* {{cite journal | vauthors = Sano S, Ohnishi H, Omori A, Hasegawa J, Kubota M | title = BIT, an immune antigen receptor-like molecule in the brain | journal = FEBS Letters | volume = 411 | issue = 2–3 | pages = 327–334 | date = July 1997 | pmid = 9271230 | doi = 10.1016/S0014-5793(97)00724-2 | s2cid = 39554802 | doi-access = free }}
* {{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 = European Journal of Immunology | volume = 28 | issue = 1 | pages = 1–11 | date = January 1998 | pmid = 9485180 | doi = 10.1002/(SICI)1521-4141(199801)28:01<1::AID-IMMU1>3.0.CO;2-V | doi-access = free }}
* {{cite journal | vauthors = Timms JF, Carlberg K, Gu H, Chen H, Kamatkar S, Nadler MJ, Rohrschneider LR, Neel BG | title = Identification of major binding proteins and substrates for the SH2-containing protein tyrosine phosphatase SHP-1 in macrophages | journal = Molecular and Cellular Biology | volume = 18 | issue = 7 | pages = 3838–3850 | date = July 1998 | pmid = 9632768 | pmc = 108968 | doi = 10.1128/mcb.18.7.3838 }}
* {{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 = The Journal of Biological Chemistry | volume = 273 | issue = 35 | pages = 22719–22728 | date = August 1998 | pmid = 9712903 | doi = 10.1074/jbc.273.35.22719 | doi-access = free }}
* {{cite journal | vauthors = Jiang P, Lagenaur CF, Narayanan V | title = Integrin-associated protein is a ligand for the P84 neural adhesion molecule | journal = The Journal of Biological Chemistry | volume = 274 | issue = 2 | pages = 559–562 | date = January 1999 | pmid = 9872987 | doi = 10.1074/jbc.274.2.559 | doi-access = free }}
* {{cite journal | vauthors = Ohnishi H, Yamada M, Kubota M, Hatanaka H, Sano S | title = Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins | journal = Journal of Neurochemistry | volume = 72 | issue = 4 | pages = 1402–1408 | date = April 1999 | pmid = 10098842 | doi = 10.1046/j.1471-4159.1999.721402.x | s2cid = 83600875 | doi-access = free }}
* {{cite journal | vauthors = Timms JF, Swanson KD, Marie-Cardine A, Raab M, Rudd CE, Schraven B, Neel BG | title = SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages | journal = Current Biology | volume = 9 | issue = 16 | pages = 927–930 | date = August 1999 | pmid = 10469599 | doi = 10.1016/S0960-9822(99)80401-1 | s2cid = 16056124 | doi-access = free | bibcode = 1999CBio....9..927T }}
* {{cite journal | vauthors = Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, Bühring HJ | 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 = 3633–3643 | date = December 1999 | pmid = 10572074 | doi = 10.1182/blood.V94.11.3633 | s2cid = 11033417 }}
* {{cite journal | vauthors = Sano S, Ohnishi H, Kubota M | title = Gene structure of mouse BIT/SHPS-1 | journal = The Biochemical Journal | volume = 344 | issue = Pt 3 | pages = 667–675 | date = December 1999 | pmid = 10585853 | pmc = 1220688 | doi = 10.1042/0264-6021:3440667 }}
* {{cite journal | vauthors = Yang J, Cheng Z, Niu T, Liang X, Zhao ZJ, Zhou GW | title = Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 6 | pages = 4066–4071 | date = February 2000 | pmid = 10660565 | doi = 10.1074/jbc.275.6.4066 | doi-access = free }}
* {{cite journal | vauthors = Stofega MR, Argetsinger LS, Wang H, Ullrich A, Carter-Su C | title = Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha | journal = The Journal of Biological Chemistry | volume = 275 | issue = 36 | pages = 28222–28229 | date = September 2000 | pmid = 10842184 | doi = 10.1074/jbc.M004238200 | doi-access = free }}
* {{cite journal | vauthors = Wu CJ, Chen Z, Ullrich A, Greene MI, O'Rourke DM | 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 | date = August 2000 | pmid = 10962556 | doi = 10.1038/sj.onc.1203748 | s2cid = 9020984 | doi-access =  }}
* {{cite journal | vauthors = Latour S, Tanaka H, Demeure C, Mateo V, Rubio M, Brown EJ, Maliszewski C, Lindberg FP, Oldenborg A, Ullrich A, Delespesse G, Sarfati M | 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 = Journal of Immunology | volume = 167 | issue = 5 | pages = 2547–2554 | date = September 2001 | pmid = 11509594 | doi = 10.4049/jimmunol.167.5.2547 | doi-access = free }}
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{{Clusters of differentiation}}

[[Category:Clusters of differentiation]]