SIRP

Signal-regulatory protein (SIRP) refers to a family of cell-surface receptors in the immunoglobulin superfamily, primarily expressed on myeloid cells. The best characterized member is SIRPα (also called CD172a). Other family members include SIRPβ and SIRPγ, with species-specific differences in expression.

Structure and signaling: SIRP proteins are type I transmembrane glycoproteins with two (or three) extracellular immunoglobulin-like domains and cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon engagement, ITIMs recruit SHP-1 and SHP-2 phosphatases, modulating signaling pathways that affect phagocytosis, adhesion, and migration.

Function and interaction with CD47: The extracellular interaction with CD47 serves as a "don't eat me" signal. When CD47 on a target cell binds SIRPα on myeloid cells, phagocytosis is inhibited, and antigen presentation may be altered. This axis helps maintain self-tolerance and tissue homeostasis but can be exploited by cancer cells that overexpress CD47.

Clinical relevance: Disruption of the CD47-SIRPα interaction is being explored as a cancer therapy to promote macrophage-mediated clearance of tumor cells. Therapeutic approaches include anti-CD47 antibodies, SIRPα-Fc fusion proteins, and CD47 blockade in combination with other immunotherapies. Potential adverse effects include anemia and thrombocytopenia due to phagocytosis of aged red blood cells and platelets.

Genetic and species variation: SIRP family shows species- and cell-type differences in expression and function. In humans, SIRPA encodes SIRPα; other family members show distinct signaling capabilities. SIRP signaling is regulated by inflammatory cues and alternative splicing.