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
CD47 also called the "don't eat me" signal. This interaction negatively controls effector function of
innate immune cells such as host cell
phagocytosis. SIRPα diffuses laterally on the
macrophage 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 by
MHC class I molecules to
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
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.[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]
Seiffert M, Cant C, Chen Z, et al. (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): 3633–43.
doi:
10.1182/blood.V94.11.3633.
PMID10572074.
S2CID11033417.