Signal-regulatory protein alpha

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Signal-regulatory protein alpha
Protein SIRPA PDB 2JJS.png
Rendering based on PDB 2JJS.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SIRPA ; BIT; CD172A; MFR; MYD-1; P84; PTPNS1; SHPS1; SIRP
External IDs OMIM602461 MGI108563 HomoloGene7246 GeneCards: SIRPA Gene
EC number 3.1.3.48
RNA expression pattern
PBB GE SIRPA 202896 s at tn.png
PBB GE SIRPA 202895 s at tn.png
PBB GE SIRPA 202897 at tn.png
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_001171117
Location (UCSC) Chr 20:
1.88 – 1.92 Mb
Chr 2:
129.59 – 129.63 Mb
PubMed search [1] [2]

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 called also 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[edit]

The cytoplasmic region of SIRP α is highly conserved between rats, mice and humans. Cytoplasmic region concists 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[edit]

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[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.[4] [3]

Cancer[edit]

Cancer cell highly expressed CD47 that activate SIRP α and inhibit macrophage-mediated destruction. There were engineered high-affinity variants of SIRP α that antagonized CD47 on cancer cells and can cause increase phagocytosis of cancer cells.[5]

References[edit]

  1. ^ 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 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. ^ 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. 
  4. ^ 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. 
  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[edit]

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