The thrombospondin receptor integrin-associated protein (CD47) functionally couples to heterotrimeric G(i)

Integrin-associated protein (IAP; CD47) is a thrombospondin receptor that f orms a signaling complex with beta(3) integrins resulting in enhanced alpha (v)beta(3)-dependent cell spreading and chemotaxis and, in platelets, alpha (IIb)beta(3)-dependent spreading and aggregation. These actions of CD47 are all specifically abrogated by pertussis toxin treatment of cells. Here we report that CD47, its beta(3) integrin partner, and G(i) proteins form a st able, detergent-soluble complex that can be recovered by immunoprecipitatio n and affinity chromatography, G(i alpha) is released from this complex by treatment with GTP or AlF4. GTP and AlF4 also reduce the binding of CD47 to its agonist peptide (4N1K) derived from thrombospondin, indicating a direc t association of CD47 with G(i). 4N1K peptide causes a rapid decrease in in traplatelet cyclic AMP levels, a G(i)-dependent event necessary for aggrega tion. Finally, 4N1K stimulates the binding of GTP gamma(35)S to membranes f rom cells expressing IAP and alpha(v)beta(3). This functional coupling of C D47 to heterotrimeric G proteins provides a mechanistic explanation for the biological effects of CD47 in a wide variety of systems.