Signal-regulatory protein alpha

Source: Wikipedia, the free encyclopedia.
SIRPA
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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: 129.43 – 129.47 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[citation needed] or neurons.

SIRPα acts as inhibitory receptor and interacts with a broadly expressed transmembrane protein

NK cells via Ig-like or Ly49 receptors.[6][7]
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 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

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]

Signalling

The extracellular domain of SIRP α binds to

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

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

  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:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 18332220
    .
  6. ^ .
  7. .
  8. .
  9. ^ .
  10. ^ .
  11. .
  12. ^ Potential new cancer treatment activates cancer-engulfing cells. Feb 2017
  13. PMID 28097229
    .

Further reading

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