Abstract
Hepatocyte growth factor/scatter factor (HGF/SF) controls a genetic program known as 'invasive growth', which involves as critical steps cell adhesion, migration, and trespassing of basement membranes. We show here that in MDA-MB-231 carcinoma cells, these steps are elicited by HGF/SF but not by epidermal growth factor (EGF). Neither factor substantially alters the production or activity of extracellular matrix proteases. HGF/SF, but not EGF, selectively promotes cell adhesion on laminins 1 and 5, fibronectin, and vitronectin through a PI3-K-dependent mechanism. Increased adhesion is followed by enhanced invasiveness through isolated matrix proteins as well as through reconstituted basement membranes. Inhibition assays using function-blocking antibodies show that this phenomenon is mediated by multiple integrins including beta1, beta3, beta4, and beta5. HGF/SF triggers clustering of all these integrins at actin-rich adhesive sites and lamellipodia but does not quantitatively modify their membrane expression. These data suggest that HGF/SF promotes cell adhesion and invasiveness by increasing the avidity of integrins for their specific ligands.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / drug effects
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Actins / metabolism
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Antibodies / immunology
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Antibodies / pharmacology
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Basement Membrane / chemistry
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Basement Membrane / metabolism
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology*
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Cadherins / metabolism
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Cell Adhesion / drug effects
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Cell Division / drug effects
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Cell Movement / drug effects*
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Collagen / metabolism
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Cytoskeleton / drug effects
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Cytoskeleton / metabolism
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Dose-Response Relationship, Drug
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Drug Combinations
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Epidermal Growth Factor / pharmacology
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Extracellular Matrix Proteins / metabolism
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Gene Expression / drug effects
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Hepatocyte Growth Factor / pharmacology*
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Humans
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Integrins / antagonists & inhibitors
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Integrins / immunology
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Integrins / metabolism*
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Laminin / metabolism
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Ligands
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Matrix Metalloproteinase 9 / metabolism
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Neoplasm Invasiveness / pathology
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Phenotype
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans / metabolism
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Tumor Cells, Cultured
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Urokinase-Type Plasminogen Activator / metabolism
Substances
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Actins
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Antibodies
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Cadherins
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Drug Combinations
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Extracellular Matrix Proteins
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Integrins
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Laminin
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Ligands
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans
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matrigel
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Epidermal Growth Factor
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Hepatocyte Growth Factor
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Collagen
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Urokinase-Type Plasminogen Activator
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Matrix Metalloproteinase 9