TY - JOUR
T1 - Regulation of Insulin-Like Growth Factor (IGF)-I Action by Matrix Metalloproteinase-3 Involves Selective Disruption of IGF-I/IGF-Binding Protein-3 Complexes
AU - Fowlkes, John L.
AU - Serra, Delila M.
AU - Bunn, R. Clay
AU - Thrailkill, Kathryn M.
AU - Enghild, Jan J.
AU - Nagase, Hideaki
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/2
Y1 - 2004/2
N2 - 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 (TEMP-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.
AB - 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 (TEMP-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.
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U2 - 10.1210/en.2003-0636
DO - 10.1210/en.2003-0636
M3 - Article
C2 - 14605000
AN - SCOPUS:0842313088
SN - 0013-7227
VL - 145
SP - 620
EP - 626
JO - Endocrinology
JF - Endocrinology
IS - 2
ER -