-Macroglobulin (M) is a potentially important regulator of platelet-derived growth factor-BB (PDGF-BB)-stimulated cell growth due to our previous observation that PDGF-BB binds to M noncovalently (Bonner, J. C., Goodell, A. L., Lasky, J. A., and Hoffman, M. R.(1992) J. Biol. Chem. 267, 12837-12844). We examined the in vitro effect of native and plasmin-activated (receptor-recognized) M on the PDGF-BB-induced proliferation of mouse Swiss 3T3 and rat lung fibroblasts. Nondenaturing polyacrylamide gel electrophoresis showed that plasmin converted M to its electrophoretically ``fast'' form at a 2:1 molar ratio and that I-PDGF-BB bound both M and M-plasmin. PDGF-BB-induced growth was not affected by native M (0.3 µM) or plasmin (0.6 µM). The combination of plasmin and M (2:1 molar ratio) inhibited PDGF-BB-induced cell proliferation 80-90%. Complexes of PDGF-BBM purified by gel filtration chromatography retained growth promoting activity, but the PDGF-BBM-plasmin complex did not. Preincubation of fibroblasts (37 °C for 24 h) with M-plasmin did not change I-PDGF-BB binding or affect gene expression of the 6.5-kilobase PDGF- receptor or 5.2-kilobase PDGF- receptor mRNA. However, preincubation with M-plasmin (0-4 °C for 4 h) increased I-PDGF-BB binding 2-fold, and this increase was blocked by a receptor-associated protein antagonist of the M-receptor/low density lipoprotein receptor-related protein. The receptor-associated protein antagonist blocked I-M-methylamine binding, inhibited PDGF-BB-M-plasmin uptake from fibroblast-cultured supernatants, and abolished the inhibitory effect of M-plasmin on PDGF-stimulated growth. These data suggest that inhibition of PDGF-stimulated proliferation by M-plasmin is mediated in part by clearance of PDGF-BB-M-plasmin through the lipoprotein receptor-related protein.

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