Integrin-associated protein (CD47): an unusual activator of G protein signaling

This is the authors' abstract. We don't add key points for this paper.

Integrin-associated protein (IAP), also known as CD47, was first discovered as a protein physically and functionally associated with the integrin αvβ3 but now is known to associate with additional integrins, such as α2β1 and αIIbβ3, and also to have ligands of its own. This very unusual member of the immunoglobulin (Ig) superfamily includes a single Ig domain, followed by a very hydrophobic region that spans the membrane five times, and a short cytoplasmic tail that demonstrates tissue-specific expression of four alternatively spliced isoforms. IAP binds both the large plasma and ECM glycoprotein thrombospondin (TSP) and a cell-based ligand, SIRPα, independent of its association with integrins. Ligation of the integrin/IAP complex on a variety of cells can induce adhesion, chemotaxis, spreading, secretion, and other sequelae of cell activation. The work by Brittain et al., reported in this issue of the JCI (1), suggests that IAP-mediated activation may extend to circulating reticulocytes, cells not normally thought to respond to environmental cues by changing adhesive behavior. IAP may therefore play an important role in sickle-cell disease, in which large numbers of reticulocytes circulate and can adhere within small blood vessels. This work not only has implications for the pathophysiology and treatment of sickle cell anemia, but also raises important questions about the mechanisms of IAP signal transduction. The IAP/integrin complex initiates signaling by an unusual mechanism. Ligand engagement of the integrin/IAP complex can activate heterotrimeric G protein signal transduction (2). To date, the only Gα subunit identified that is associated with this membrane complex is Gαi, and indeed, most of the identified functions of the complex are sensitive to pertussis toxin, which targets this subunit.