Functional activation of integrin alpha V beta 3 in tumor cells expressing membrane-type 1 matrix metalloproteinase.
Matrix metalloproteinases (MMPs) and integrins have been implicated in a variety of processes involved in tumor progression. To evaluate the individual roles of integrin alphavbeta3 and membrane-type 1 matrix metalloproteinase (MT1-MMP), as well as the effects of their joint expression on tumor cell functions, MCF7 breast carcinoma cells were transfected stably with either the MT1-MMP, the beta3 integrin subunit or both MT1-MMP and beta3 cDNAs. MT1-MMP expression is accompanied by the functional activation of integrin alphaVbeta3, thereby increasing vitronectin-mediated adhesion and migration of MCF7 cells transfected with MT1-MMP and integrin alphaVbeta3. MT1-MMP-dependent functional activation of alphaVbeta3 correlates with modification(s) of the beta3 subunit, including its higher electrophoretic mobility and affected the LM609-binding site. MCF7 cells jointly expressing MT1-MMP and alphaVbeta3 were the most efficient in adhesion to the recombinant C-terminal domain of MMP-2 as well as in generating soluble and cell surface associated mature MMP-2 enzyme. These findings suggest a mechanism of selective docking of MMP-2 at tumor cell surfaces, specifically at the sites that include MT1-MMP and activated integrin alphaVbeta3. These mechanisms may provide a link between spatial regulation of focal proteolysis by the cell surface associated MMPs and the regulation of integrin-mediated motility of tumor cells.
Deryugina
E I
EI
La Jolla Institute for Experimental Medicine, CA, USA.
Bourdon
M A
MA
Jungwirth
K
K
Smith
J W
JW
Strongin
A Y
AY
D015703:Antigens, CD / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011233:Precipitin Tests; D019030:Receptors, Vitronectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D015703:Antigens, CD; D004792:Enzyme Precursors; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D019030:Receptors, Vitronectin; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase; D020778:Matrix Metalloproteinase 2