Proteinases are isoform-specific regulators of the binding of transforming growth factor beta to alpha 2-macroglobulin.

Webb DJ, Weaver AM, Atkins-Brady TL, Gonias SL
Biochem J. 1996 320 ( Pt 2): 551-5

PMID: 8973565 · PMCID: PMC1217964 · DOI:10.1042/bj3200551

alpha 2-Macroglobulin (alpha 2M) regulates growth and gene expression in many cell types by binding and neutralizing transforming growth factor beta (TGF-beta). In this study we characterized the effects of the serine proteinase, plasmin, on the interaction of alpha 2M with TGF-beta 1 and TGF-beta 2. Binding of both TGF-beta isoforms to purified alpha 2M-plasmin complex was primarily non-covalent and reversible. The binding affinity of alpha 2M for TGF-beta 1 was increased by plasmin; the Kd values were 320 and 84 nM for native alpha 2M and alpha 2M-plasmin respectively. In contrast the affinity of alpha 2M for TGF-beta 2 was decreased by plasmin; the Kd values were 14 and 80 nM for native alpha 2M and alpha 2M-plasmin respectively. Thrombin decreased the affinity of alpha 2M for TGF-beta 2 in a similar manner to plasmin. In assays of DNA synthesis in fetal bovine heart endothelial cells, native alpha 2M neutralized the activity of exogenously added TGF-beta 2, whereas alpha 2M-plasmin, at equivalent concentrations, had almost no effect. Native alpha 2M and methylamine-modified alpha 2M increased platelet-derived growth factor alpha-receptor expression in vascular smooth-muscle cells, an activity attributed to the neutralization of autocrine TGF-beta activity, whereas alpha 2M-plasmin was less effective at the same concentration. These studies demonstrate that the effects of proteinases on the cytokine-binding and cytokine-neutralizing activities of alpha 2M are cytokine-dependent. By reacting with alpha 2M, proteinases might regulate not only the availability of cytokines in the extracellular spaces but also the composition of the cytokine milieu.

MeSH Terms (21)

alpha-Macroglobulins Animals Aorta Cattle Cell Division Cells, Cultured DNA Endothelium, Vascular Fibrinolysin Heart Humans Kinetics Muscle, Smooth, Vascular Platelet-Derived Growth Factor Protein Binding Rats Rats, Sprague-Dawley Receptor, Platelet-Derived Growth Factor alpha Receptors, Platelet-Derived Growth Factor Thrombin Transforming Growth Factor beta

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