Regulation of insulin-like growth factor (IGF)-I action by matrix metalloproteinase-3 involves selective disruption of IGF-I/IGF-binding protein-3 complexes.
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.
Fowlkes
John L
JL
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
Serra
Delila M
DM
Bunn
R Clay
RC
Thrailkill
Kathryn M
KM
Enghild
Jan J
JJ
Nagase
Hideaki
H
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division; D005347:Fibroblasts; D015870:Gene Expression; D006031:Glycosylation; D006706:Homeostasis; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D018972:Insulin-Like Growth Factor Binding Protein 3; D010446:Peptide Fragments; D019715:Tissue Inhibitor of Metalloproteinase-1; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D019278:Matrix Metalloproteinase 3