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IGF-I and IGF-II play important roles in growth and development via interactions with cell-surface receptors; however, in nature, IGFs are sequestered by at least six soluble, high-affinity IGF-binding proteins (IGFBPs), namely IGFBPs 1-6. Herein, we demonstrate that the stromal cell-derived extracellular matrix-degrading metalloproteinase stromelysin 1 (matrix metalloproteinase 3) disrupts IGF/IGFBP-3 complexes and liberates free, intact IGFs, leading to phosphorylation of cell surface type 1 IGF receptors and cellular proliferation. Tissue inhibitor of metalloproteinases (TIMP-1) or an antibody to the type 1 IGF receptor mitigates IGF-mediated cellular proliferation. Thus, these studies suggest that matrix metalloproteinases, beyond their effects on extracellular matrix turnover, regulate cellular proliferation by modulating the bioavailability of IGFs, an event critical for such diverse phenomena as embryo development, morphogenesis, angiogenesis, and tumorigenesis.

Original publication

DOI

10.1210/en.2003-0636

Type

Journal article

Journal

Endocrinology

Publication Date

02/2004

Volume

145

Pages

620 - 626

Addresses

Division of Pediatric Endocrinology and Diabetes, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Arkansas Children's Hospital Research Institute, 800 Marshall Street, Slot 512-6, Little Rock, AR 72202, USA. fowlkesjohnl@uams.edu

Keywords

3T3 Cells, Fibroblasts, Animals, Humans, Mice, Receptor, IGF Type 1, Tyrosine, Insulin-Like Growth Factor I, Peptide Fragments, Insulin-Like Growth Factor Binding Protein 3, Tissue Inhibitor of Metalloproteinase-1, Transfection, Cell Division, Gene Expression, Glycosylation, Phosphorylation, Homeostasis, Matrix Metalloproteinase 3