METALLOPROTEINASE INHIBITION AND ERYTHROID POTENTIATION ARE INDEPENDENT ACTIVITIES OF TISSUE INHIBITOR OF METALLOPROTEINASES-1

Tissue inhibitor of metalloproteinases-1 (TIMP-1), the major physiolog ical matrix metalloproteinase inhibitor and a potent antimetastatic fa ctor, also stimulates the growth of erythroid progenitors (erythroid-p otentiating activity). We analyzed the relationship between the growth factor activity and protease inhibition by preparing purified TIMP-1 ''knock-out'' proteins lacking in vitro antiproteolytic activity. The growth-stimulatory effect of these N-terminal TIMP-1 point mutants, as tested in an in vitro assay using erythroid precursors (erythroid bur st-forming units) was equal to that of unmutated TIMP-1. A fully antip roteolytic C-terminal TIMP-1 truncation also stimulated growth in the erythroid burst-forming unit assay, The results indicate that the infl uence of TIMP-1 on erythroid precursor growth is independent of its ab ility to inhibit metalloproteinases. TIMP-1 is analogous to proteins t hat have both proteolytic and growth factor activity, such as plasmin, thrombin, and urokinase. However, TIMP-1 is novel in this regard beca use It is a metalloproteinase inhibitor. We show that the antiproteoly tic and growth factor activities of the TIMP-1 molecule are physically and functionally distinct. (C) 1995 by The American Society of Hemato logy.