Signal-regulatory protein alpha

From Wikipedia, the free encyclopedia
Jump to: navigation, search
SIRPA
Protein CD47 PDB 2JJS.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SIRPA, BIT, CD172A, MFR, MYD-1, P84, PTPNS1, SHPS1, SIRP, Signal-regulatory protein alpha, signal regulatory protein alpha
External IDs MGI: 108563 HomoloGene: 7246 GeneCards: SIRPA
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
Species Human Mouse
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 Mb Chr 2: 129.59 – 129.63 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/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. This is analogous to the self signals provided by MHC class I molecules to NK cells via Ig-like or Ly49 receptors.[3][4] 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.[5] 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.[3][6]

Ligands[edit]

SIRPα recognizes CD47, that is an antiphagocytic signal distinguished live cells from dying. It has 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.[6][7]

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.[6][7]

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.[8] Another study (in mice) found anti-SIRPα antibodies helped macrophages to reduce cancer growth and metastasis, alone and in synergy with other cancer treatments.[9][10]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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 (Baltimore, Md.: 1950). 174 (4): 2004–2011. ISSN 0022-1767. PMID 15699129. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
  10. ^ "Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy.". JCI Insight, 2017; 2 (1). 2017. doi:10.1172/jci.insight.89140. 

Further reading[edit]

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