Insulin-like growth factor binding protein-5 is a target of matrix metalloproteinase-7: implications for epithelial-mesenchymal signaling.
Matrix metalloproteinase-7 (MMP-7) is localized to epithelial cells and is up-regulated in many cancers and in inflammation. We now report that MMP-7 targets a key mesenchymal cell type, the myofibroblast. Recombinant MMP-7 stimulated the proliferation and migration of human colonic myofibroblasts. These responses were partly attributable to activation of other MMPs, notably MMP-3 and MMP-8, and to stimulation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Using a proteomic approach, we identified insulin-like growth factor binding protein-5 (IGFBP-5) as a previously unsuspected target of MMP-7 produced by colonic myofibroblasts. We present evidence that the MMP-7 cleavage of IGFBP-5 liberates IGF-II that functions as an autocrine myofibroblast growth factor. Thus, MMP-7 may act as a signal from epithelial cells for local recruitment of myofibroblasts and stimulation of their proliferation. Similar effects of MMP-7 produced in epithelial tumors might account for the expansion of stroma through activation of myofibroblasts.
Hemers
Elaine
E
Department of Physiology, University of Liverpool, Liverpool, United Kingdom.
Duval
Cedric
C
McCaig
Catherine
C
Handley
Mark
M
Dockray
Graham J
GJ
Varro
Andrea
A
D000595:Amino Acid Sequence; D048708:Cell Growth Processes / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003106:Colon / Q000166:cytology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism* / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism
D018975:Insulin-Like Growth Factor Binding Protein 5; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D020783:Matrix Metalloproteinase 7