Signal-regulatory protein alpha

SIRPA
Available structures
PDBOrtholog 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




More reference expression data
Orthologs
Species Human Mouse
Entrez

140885

19261

Ensembl

ENSG00000198053

ENSMUSG00000037902

UniProt

P78324

P97797

RefSeq (mRNA)

NM_001040022
NM_001040023
NM_080792

RefSeq (protein)

NP_001035111.1
NP_001035112.1
NP_542970.1

NP_001171118.1
NP_001277948.1
NP_001277949.1
NP_031573.2

Location (UCSC) Chr 20: 1.89 – 1.94 Mb Chr 2: 129.59 – 129.63 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

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 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]

Structure

The cytoplasmic region of SIRP α is highly conserved between rats, mice and humans. Cytoplasmic region consists 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.[3][5]

Ligands

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.[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]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 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. 1 2 3 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. 1 2 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 3810306Freely accessible. PMID 23722425.

Further reading

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

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