DIFFERENTIAL BINDING AND REGULATION OF PLATELET-DERIVED GROWTH-FACTOR A-CHAIN AND B-CHAIN ISOFORMS BY ALPHA(2)-MACROGLOBULIN

alpha(2)Macroglobulin (alpha(2)M) is a multifunctional secreted glycoprotein that serves as a ubiquitous proteinase inhibitor and as a binding protein for platelet-derived growth factor (PDGF) BE and homologues of PDGF-BB secreted in culture by macrophages. The interaction of alpha(2)M with PDGF-A chain molecules has not been addressed. This is a potentially important issue because fibroblasts and smooth muscle cells produce PDGF-AA, whereas macrophages produce mainly PDGF-BB. Recombinant human I-125-PDGF-B chain molecules (AB and BE) bound to plasma-derived, native human, or bovine alpha(2)M and trypsin-activated alpha(2)M on Superose 6 fast protein liquid chromatography gel filtration and on nondenaturing polyacrylamide gel electrophoresis, whereas I-125-PDGF-AA did not. Similar results were obtained with I-125-PDGF isoforms binding to immobilized bovine alpha(2)M and alpha(2)M-methylamine. The same differential pattern of unlabeled PDGF isoforms binding to alpha(2)M was observed by Western blotting of PDGF. Human lung fibroblasts secreted alpha(2)M as measured by Western blotting, and fibroblast-derived alpha(2)M possessed the same differential binding pattern for PDGF isoforms as did plasma-derived alpha(2)M. The specific binding of PDGF-AB and -BB to these fibroblasts was inhibited by native bovine alpha(2)M, although PDGF-AA binding was not affected. Native alpha(2)M preferentially blocked fibroblast chemotaxis to the PDGF-B chain dimers. These data suggest that only PDGF-B chain dimers, such as those produced by macrophages or released from platelets, are regulated by alpha(2)M and that PDGF-AA produced by fibroblasts and smooth muscle cells is not controlled by this cytokine-binding protein.