Signal-regulatory protein alpha

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SIRPA
Protein CD47 PDB 2JJS.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSIRPA, BIT, CD172A, MFR, MYD-1, P84, PTPNS1, SHPS1, SIRP, Signal-regulatory protein alpha, signal regulatory protein alpha
External IDsMGI: 108563 HomoloGene: 7246 GeneCards: SIRPA
Gene location (Human)
Chromosome 20 (human)
Chr.Chromosome 20 (human)[1]
Chromosome 20 (human)
Genomic location for SIRPA
Genomic location for SIRPA
Band20p13Start1,894,167 bp[1]
End1,940,592 bp[1]
RNA expression pattern
PBB GE SIRPA 202897 at fs.png

PBB GE SIRPA 202896 s at fs.png

PBB GE SIRPA 202895 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001040022
NM_001040023
NM_080792
NM_001330728

RefSeq (protein)

NP_001035111
NP_001035112
NP_001317657
NP_542970

Location (UCSC)Chr 20: 1.89 – 1.94 MbChr 2: 129.59 – 129.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors.[6][7] NB. Protein shown to the right is CD47 not SIRP α.

Structure[edit]

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.[8] 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.[6][9]

Ligands[edit]

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.[9][10]

Signalization[edit]

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.[9][10]

Cancer[edit]

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.[11] Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.[12][13]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198053 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000037902 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ 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. PMC 2265407Freely accessible. PMID 18332220. 
  6. ^ a b 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 3128989Freely accessible. PMID 19223164. 
  7. ^ 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 2515120Freely accessible. PMID 18524990. 
  8. ^ 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. doi:10.4049/jimmunol.174.4.2004. ISSN 0022-1767. PMID 15699129. 
  9. ^ a b c 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. 
  10. ^ a b 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. 
  11. ^ 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 3810306Freely accessible. PMID 23722425. 
  12. ^ Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
  13. ^ Yanagita T (2017). "Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy". JCI Insight, 2017; 2 (1). 2. doi:10.1172/jci.insight.89140. PMC 5214103Freely accessible. 

Further reading[edit]

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