TIMP-2 mediates cell surface binding of MMP-2.
In order to understand the mechanism for neoplastic cell invasion, we utilized binding studies of TIMP-2, gelatinase A and the TIMP-2/gelatinase A complex to neoplastic cells and correlated these results with their capacity to invade a matrix substrate in a modified Boyden chamber assay. Binding studies were performed on malignant human breast cancer cells and fibrosarcoma cells with rTIMP-2, rGelatinase A, and TIMP-2/gelatinase A complex. Competition studies of the binding characteristics of these proteins indicated that gelatinase A and gelatinase A/TIMP-2 complex bound to the surface of cells via TIMP-2. Furthermore, the localization of either latent or active protease to the surface of MDA-MB-435 breast cancer cells facilitated the invasion of these neoplastic cells through a matrigel barrier. This suggests that in addition to binding this complex, these cells can activate this pro-enzyme-inhibitor complex and use this activity to facilitate cellular invasion. Moreover, their enhanced invasion was suppressed by exogenous additions of rTIMP-2. A working hypothesis and model for the role of gelatinase A/TIMP-2 complex in cellular invasion is presented.
Corcoran
M L
ML
Extracellular Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Emmert-Buck
M R
MR
McClanahan
J L
JL
Pelina-Parker
M
M
Stetler-Stevenson
W G
WG
D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology*; D011485:Protein Binding; D011506:Proteins / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011506:Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2