Differential Binding and Regulation of Platelet-derived Growth Factor A and B Chain Isoforms by α2-Macroglobulin

Abstract

Alpha 2-Macroglobulin (alpha 2M) is a multifunctional secreted glycoprotein that serves as a ubiquitous proteinase inhibitor and as a binding protein for platelet-derived growth factor (PDGF) BB and homologues of PDGF-BB secreted in culture by macrophages. The interaction of alpha 2M 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 125I-PDGF-B chain molecules (AB and BB) bound to plasma-derived, native human, or bovine alpha 2M and trypsin-activated alpha 2M on Superose 6 fast protein liquid chromatography gel filtration and on nondenaturing polyacrylamide gel electrophoresis, whereas 125I-PDGF-AA did not. Similar results were obtained with 125I-PDGF isoforms binding to immobilized bovine alpha 2M and alpha 2M-methylamine. The same differential pattern of unlabeled PDGF isoforms binding to alpha 2M was observed by Western blotting of PDGF. Human lung fibroblasts secreted alpha 2M as measured by Western blotting, and fibroblast-derived alpha 2M possessed the same differential binding pattern for PDGF isoforms as did plasma-derived alpha 2M. The specific binding of PDGF-AB and -BB to these fibroblasts was inhibited by native bovine alpha 2M, although PDGF-AA binding was not affected. Native alpha 2M 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 2M and that PDGF-AA produced by fibroblasts and smooth muscle cells is not controlled by this cytokine-binding protein.

Role of platelet-derived growth factors in physiology and medicine

“…Binding of PDGF-B has been demonstrated to ␣-2-macroglobulin (Bonner and Osornio-Vargas 1995), possibly acting as a scavenger for PDGF-B through low-density lipoprotein (LDL) receptor-related protein (LRP) receptors on macrophages and other cells . PDGF-B also binds to SPARC and adiponectin, which may trap the growth factor in the extracellular space Arita et al 2002).…”

Growth factors from bovine milk and colostrum: composition, extraction and biological activities

“…These PDGF family members differ from the others in that they are secreted as an inactive form. PDGFs interact with proteins of the extracellular matrix (ECM), but also with soluble proteins such as α 2 -M. This latter interaction involves PDGF-BB but not PDGF-AA [18]. Binding of PDGF with proteins modulates the interaction with receptors.…”

Native and Activated Forms of α2-Macroglobulin Increase Expression of Platelet-derived Growth Factor α-Receptor in Vascular Smooth Muscle Cells

“…TGF-␤2 binds with equal affinity to native ␣ 2 M and activated ␣ 2 M, while TGF-␤1 and PDGF-BB bind with higher affinity to activated ␣ 2 M (30). In contrast, PDGF-AA does not bind to ␣ 2 M at all (31). In the rat, there are two homologues of human ␣ 2 M, a constitutively expressed protein, ␣ 1 M, and an acute-phase reactant, ␣ 2 M (24).…”