Signal-regulatory protein alpha

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 is_associated_with::CD47 called also don´t eat me signal. This interaction negatively controls effector function of innate immune cells such as host cell is_associated_with::phagocytosis. This is analogous to the self signals provided by is_associated_with::MHC class I molecules to is_associated_with::NK cells via Ig-like or is_associated_with::Ly49 receptors.

Structure
The cytoplasmic region of SIRP α is highly conserved between rats, mice and humans. Cytoplasmic region concists of is_associated_with::tyrosine residues conform to inhibitory ITIMs that associates with phosphataseSHP2. The extracellular region contains three is_associated_with::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.

Ligands
SIRP α recognize is_associated_with::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 – is_associated_with::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 is_associated_with::endocytosis of the receptor, cleavage or interaction with surfactant proteins. SIRP α recognize soluble ligands such as is_associated_with::surfactant protein A and D that bind to the same region as is_associated_with::CD47 and block binding of this ligand.

Signalization
The extracellular domain of SIRP α binds to is_associated_with::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 is_associated_with::FYN-binding protein. Recruitment of SHP phosphatases to the membrane leads to the inhibition of is_associated_with::myosin accumulation at the cell surface and results in the inhibition of is_associated_with::phagocytosis.

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