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

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 culture^3–5, 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.