Integrins initiate signaling pathways that impact tissue organization, inflammation, blood clotting, oncogenesis and angiogenesis upon binding of extracellular matrix proteins, in the regulation of biological processes. In this proposal, the role of integrin-associated protein (IAP, CD47), a co-receptor in mediating integrin signaling, will be studied by manipulation of both the receptor apparatus and the ligand structure. The C- terminal cell-binding domain (CBD) of thrombospondin (TS) is a ligand of IAP, and peptides derived from the CBD stimulate integrin-dependent processes via heterotrimeric G proteins. To define the mechanism of G protein coupling to the integrin-IAP complex, 1) a model expression system will be established for integrins, IAP and G protein subunits to evaluate receptor function in cellular assays upon treatment with IAP agonists; 2) direct measurements of G protein coupling will be carried out in the transfected cells and correlated with functional assays to identify the role of each component in the signaling complex; and 3) expression and mutagenesis of TS and CBD will be carried out to identify the determinants for IAP activation. By correlating changes in the interactions of the receptor and G protein components with downstream or """"""""read-out"""""""" cellular functions, these studies should begin to define the molecular basis for the role of IAP in integrin-regulated biological processes such as angiogenesis, tumorigenesis and wound healing.
| McDonald, John F; Zheleznyak, Alex; Frazier, William A (2004) Cholesterol-independent interactions with CD47 enhance alphavbeta3 avidity. J Biol Chem 279:17301-11 |
| McDonald, J F; Dimitry, J M; Frazier, W A (2003) An amyloid-like C-terminal domain of thrombospondin-1 displays CD47 agonist activity requiring both VVM motifs. Biochemistry 42:10001-11 |
