Metalloproteinase Inhibition and Erythroid Potentiation Are Independent Activities of Tissue Inhibitor of Metalloproteinases - l

Tissue inhibitor of metalloproteinases-l (TIMP-l), the major physiological matrix metalloproteinase inhibitor and a potent antimetastatic factor, also stimulates the growth of erythroid progenitors (erythroid-potentiating activity). We analyzed the relationship between the growth factor activity and protease inhibition by preparing purified TIMP-1 “knockout” 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 burst-forming units) was equal to that of unmutated TIMP-1. A fully antiproteolytic C-terminal TIMP-