Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1.
Tissue inhibitor of metalloproteinases-1 (TIMP-1), 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-1 truncation also stimulated growth in the erythroid burst-forming unit assay. The results indicate that the influence of TIMP-1 on erythroid precursor growth is independent of its ability to inhibit metalloproteinases. TIMP-1 is analogous to proteins that have both proteolytic and growth factor activity, such as plasmin, thrombin, and urokinase. However, TIMP-1 is novel in this regard because it is a metalloproteinase inhibitor. We show that the antiproteolytic and growth factor activities of the TIMP-1 molecule are physically and functionally distinct.
Chesler
L
L
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
Golde
D W
DW
Bersch
N
N
Johnson
M D
MD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000235:genetics; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects / Q000502:physiology*; D016259:Genes, myc; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D019714:Tissue Inhibitor of Metalloproteinases
D018076:DNA, Complementary; D006023:Glycoproteins; D011993:Recombinant Fusion Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3