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 proteinCD47 also called the "don't eat me" signal. This interaction negatively controls effector function ofinnate immune cells such as host cellphagocytosis. SIRPα diffuses laterally on themacrophage 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 byMHC class I molecules toNK cells via Ig-like orLy49 receptors.[6][7] NB. Protein shown to the right is CD47 not SIRP α.
The cytoplasmic region of SIRPα is highly conserved between rats, mice and humans. Cytoplasmic region contains a number oftyrosine residues, which likely act asITIMs. Upon CD47 ligation, SIRPα is phosphorylated and recruits phosphatases like SHP1 andSHP2.[8] The extracellular region contains threeImmunoglobulin superfamily domains – single V-set and two C1-setIgSF 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-bindingIgSF 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]
SIRPα recognizesCD47, 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 byendocytosis or cleavage of the receptor, or interaction withsurfactant proteins.Surfactant protein A andD are soluble ligands, highly expressed in the lungs, that bind to the same region of SIRPα asCD47 and can therefore competitively block binding.[9][10]
The extracellular domain of SIRP α binds toCD47 and transmits intracellular signals through its cytoplasmic domain. CD47-binding is mediated through theNH2-terminalV-like domain of SIRP α. The cytoplasmic region contains fourITIMs that become phosphorylated after binding of ligand. The phosphorylation mediates activation of tyrosine kinaseSHP2. SIRP α has been shown to bind also phosphataseSHP1, adaptor proteinSCAP2 andFYN-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition ofmyosin accumulation at the cell surface and results in the inhibition ofphagocytosis.[9][10]
Cancer cells highly expressedCD47 that activate SIRP α and inhibitmacrophage-mediated destruction. In one study, they engineered high-affinity variants of SIRP α that antagonizedCD47 on cancer cells and caused increasephagocytosis 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]
Margolis RL, Breschel TS, Li SH, Kidwai AS, Antonarakis SE, McInnis MG, et al. (July 1995). "Characterization of cDNA clones containing CCA trinucleotide repeats derived from human brain".Somatic Cell and Molecular Genetics.21 (4):279–284.doi:10.1007/BF02255782.PMID8525433.S2CID22174220.
Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, et al. (December 1999). "Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47".Blood.94 (11):3633–3643.doi:10.1182/blood.V94.11.3633.PMID10572074.S2CID11033417.
