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.
ARTICLES|
December 15, 1995
Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1
L Chesler,
L Chesler
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
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DW Golde,
DW Golde
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
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N Bersch,
N Bersch
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
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MD Johnson
MD Johnson
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
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Blood (1995) 86 (12): 4506–4515.
Citation
L Chesler, DW Golde, N Bersch, MD Johnson; Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood 1995; 86 (12): 4506–4515. doi: https://doi.org/10.1182/blood.V86.12.4506.bloodjournal86124506
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