title: Gelatinase A activity directly modulates melanoma cell adhesion and spreading.
abstract: Interaction of cells with the extracellular matrix (ECM) plays an important role in the regulation of cell behavior. Formation of adhesive contacts leads to transduction of signals into the cell and results in altered gene expression and modulation of the cellular phenotype. Specific adhesive interactions of the fibronectin and vitronectin receptors with their ligands in the matrix modulates expression of ECM-degrading metalloproteases. These proteases are involved in the acquisition of the invasive phenotype by a number of cell types. The activity of matrix metalloproteases (MMPs) is reduced by endogenous inhibitors referred to as tissue inhibitors of metalloproteases (TIMPs). Alterations in the balance between the activity of MMPs and TIMPs alters cellular invasion through effects on matrix degradation. In this study we demonstrate that inhibition of endogenous gelatinase A activity in A2058 human melanoma cells results in enhanced cellular adhesion. To further explore this phenomenon, we have used retroviral infection vectors to control the amount of the MMP inhibitor TIMP-2 in human melanoma A2058 cells. Altering the production of TIMP-2 modulates not only proteolysis of the extracellular matrix, but also the adhesive and spreading properties of the cells and results in altered cell morphology. These effects of TIMP-2 appear to be mediated by inhibition of gelatinase A activity. We conclude that gelatinase A, in addition to contributing to proteolysis of ECM components, also functions to proteolyse cell surface components that mediate attachment of A2058 cells to the ECM. Thus, gelatinase A may function to modulate cell attachment and facilitate cell migration and invasion.
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: J M
authors.initials: JM
authors.lastname: Ray
authors.forename: W G
authors.initials: WG
authors.lastname: Stetler-Stevenson
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005780:Gelatin / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics; D020778:Matrix Metalloproteinase 2; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2; D014407:Tumor Cells, Cultured; D019096:Vitronectin
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D006023:Glycoproteins; D011506:Proteins; D019096:Vitronectin; D019716:Tissue Inhibitor of Metalloproteinase-2; D005780:Gelatin; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2