Cells regulate their mitogenic response to thrombin through release of protease nexin

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Abstract
We previously reported that human and mouse fibroblast-like cells release into their growth medium a protein that we termed protease nexin. Protease nexin forms a covalent acyl linkage with thrombin and certain other serine proteases via the protease active site1 and mediates their binding, internalization and degradation by cells2. Binding of thrombin-protease nexin to cells is mediated by the protease nexin portion of the complex to a high-affinity cellular binding site2. As thrombin is a potent mitogen for a variety of fibroblast-like cells in culture3–5, we examined whether protease nexin itself regulates thrombin-stimulated cell division. Recently, we showed that heparin virtually blocked the binding of thrombin–protease nexin complexes to both mouse and human cells without affecting the ability of these cells to respond to thrombin6. Thus, protease nexin does not appear to be a positive modulator in thrombin-induced cell division. Here, we show that protease nexin negatively regulates the mitogenic response of cells in culture to thrombin.