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

α2-Macroglobulin (α2M) 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 α2M 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 α2M and trypsin-activated α2M 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 α2M and α2M-methylamine. The same differential pattern of unlabeled PDGF isoforms binding to α2M was observed by Western blotting of PDGF. Human lung fibroblasts secreted α2M as measured by Western blotting, and fibroblast-derived α2M possessed the same differential binding pattern for PDGF isoforms as did plasma-derived α2M. The specific binding of PDGF-AB and -BB to these fibroblasts was inhibited by native bovine α2M, although PDGF-AA binding was not affected. Native α2M 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 α2M and that PDGF-AA produced by fibroblasts and smooth muscle cells is not controlled by this cytokine-binding protein. α2-Macroglobulin (α2M) 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 α2M 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 α2M and trypsin-activated α2M 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 α2M and α2M-methylamine. The same differential pattern of unlabeled PDGF isoforms binding to α2M was observed by Western blotting of PDGF. Human lung fibroblasts secreted α2M as measured by Western blotting, and fibroblast-derived α2M possessed the same differential binding pattern for PDGF isoforms as did plasma-derived α2M. The specific binding of PDGF-AB and -BB to these fibroblasts was inhibited by native bovine α2M, although PDGF-AA binding was not affected. Native α2M 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 α2M and that PDGF-AA produced by fibroblasts and smooth muscle cells is not controlled by this cytokine-binding protein. Platelet-derived growth factor (PDGF)1( 1The abbreviations used are: PDGFplatelet-derived growth factorPDGF-Rplatelet-derived growth factor receptorα2Mα2-macroglobulinLRPlow density lipoprotein receptor-related proteinSFDMserum-free defined mediumFPLCfast protein liquid chromatographyDMEMDulbecco's modified Eagle's mediumTGF-βtransforming growth factor βBSAbovine serum albuminPBSphosphate-buffered salineHPFhigh power fieldSPARCsecreted protein, rich in cysteinePBSTphosphate-buffered saline with Tween 20.) is a cationic polypeptide that stimulates mesenchymal cell mitogenesis and chemotaxis(1Grotendorst G.R. Chang T. Seppa H.E.J. Kleinman K.H. 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Coin P.G. Lindroos P.M. Ostrowski L.E. Brody A.R. Bonner J.C. Am. J. Respir. Cell Mol. Biol. 1995; 12: 162-170Crossref PubMed Scopus Google Scholar). The PDGF-B chain dimers preferentially bound to α2M as by Western blotting for PDGF and the results obtained with the PDGF isoforms gel of plasma-derived native and trypsin-activated fast bovine α2M with -AB, and of bovine α2M or was with -AB, or -BB in of binding for to on a gel as and and BB) was in the of α2M as a or the of native α2M or protein the of and fast of α2M. B, of the gel binding of and -BB to and fast of α2M binding of specific binding of all three isoforms was observed in binding with human lung fibroblasts blotting of PDGF isoforms bound to native bovine α2M. α2M was in the or of human PDGF-AA, -AB, or -BB in of binding for to nondenaturing gel and Western blotting for PDGF as and A PDGF that A and B chain PDGF molecules was used in the Western These data the with 125I-PDGF isoforms binding α2M in and the differential binding of PDGF isoforms to α2M. was for α2M in the of PDGF that macrophages secrete a of human plasma-derived α2M that serves as a binding protein for the produced by these J.C. M. Brody A.R. Am. J. Respir. Cell Mol. Biol. 1989; PubMed Scopus Google Scholar). the produced by fibroblasts is Y. Hammacher A. Heldin C.-H. Westermark B. Nature. 1987; 328: 715-717Crossref PubMed Scopus (138) Google Scholar), to in and that PDGF-AA not to α2M produced by fibroblasts in human lung fibroblasts secreted of in culture as by that specific for human α2M not The human did not with bovine α2M, and did not α2M from bovine serum that was used in the of these This fibroblast α2M the of plasma-derived α2M on a Superose 6 not The human fibroblast-derived α2M was by Western blotting and all of the protein as the native form on a nondenaturing gel and not 125I-PDGF-AA bound to native and trypsin-activated of human fibroblast-derived α2M immobilized α2M was to the specific binding of PDGF isoforms to native and bovine α2M. binding was in the of of the PDGF bound immobilized α2M and in a whereas specific binding was than PDGF-BB and 125I-PDGF-AA binding was specific binding of this was than of the bound only and -BB specific binding results specific to immobilized α2M. that the PDGF-AA was binding on of fibroblasts in with the immobilized α2M with the same of 125I-PDGF-AA and observed specific binding for all isoforms to fibroblast of PDGF isoforms were with in the immobilized α2M PDGF-BB was the of for binding to immobilized α2M, by PDGF-AB and PDGF-AA in of did not to that were with binding was in the or of not of specific 125I-PDGF binding to immobilized bovine α2M and human lung fibroblasts in the activity of PDGF isoforms, were with human fibroblasts or immobilized α2M as and binding was in the of PDGF and binding was in the of PDGF for binding to fibroblasts or PDGF for immobilized α2M binding three PDGF isoforms possessed specific binding for fibroblast only PDGF-B chain dimers bound immobilized α2M specific The specific binding data are the of separate in of PDGF isoforms for the binding of to immobilized α2M. of PDGF isoforms to immobilized α2M was as and was with of PDGF-AA PDGF-AB or PDGF-BB for PDGF-BB and inhibited binding in a that was of PDGF. PDGF-AA inhibited binding by and as as PDGF-AA were to binding by The data are of a in of the and separate for to the binding of PDGF isoforms for α2M by and binding data from a Superose 6 and were as J.C. J.A. J. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). the by L.E. Cell A on and Scholar), is the is the on and is the and is the of the is the on and is the of by The of PDGF is by and that of α2M is by in the the the of PDGF. of and for binding native bovine α2M are in A of was on these A binding was on human lung fibroblasts of the three PDGF isoforms a of three PDGF isoforms bound to these cells with specific binding this PDGF was with of α2M for to on for and to of fibroblasts in native bovine α2M blocked the binding of and binding 125I-PDGF-AA binding was not inhibited by α2M. fibroblasts were to to a of PDGF that a PDGF-AB and three isoforms were also and a in as to not chemotaxis defined a chemotaxis for of the PDGF A.R. Bonner J.C. Badgett A. Brody A.R. Am. J. 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Full Text PDF PubMed Google Scholar). that α2M binds PDGF isoforms with differential PDGF-BB is bound than which is bound than that the of the PDGF by α2M is to of the by α2M native and of the binding protein preferentially to growth factor in the obtained a of for binding to native α2M through of and data The obtained for PDGF-BB binding α2M was to by and in the J. Biol. Chem. Full Text PDF PubMed Google Scholar). were not to a for PDGF-AB binding to α2M, although binding was of the data in a and 6 for PDGF-AB binding α2M. PDGF-AA binding α2M was not the gel filtration and nondenaturing gel in this specific binding of 125I-PDGF-AA to immobilized was this was a of the binding PDGF-AA for the binding of to immobilized α2M of PDGF-AA bound by that PDGF-AA and for PDGF-BB binding to J.C. J.A. J. 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The produced by fibroblasts and smooth muscle cells is not regulated by either of these binding that PDGF-AB and PDGF-BB not PDGF-AA to native and of α2M from or from lung fibroblast PDGF-AB and -BB binding to cell on fibroblasts and the chemotaxis of these cells is inhibited by α2M, whereas PDGF-AA binding and chemotaxis are not by α2M. macrophages secrete mainly PDGF-B chain dimers and mesenchymal cells (fibroblasts and smooth muscle produce PDGF-AA, that the α2M and receptor for of and mesenchymal cell PDGF signals or the of