Processing of Integrin αv Subunit by Membrane Type 1 Matrix Metalloproteinase Stimulates Migration of Breast Carcinoma Cells on Vitronectin and Enhances Tyrosine Phosphorylation of Focal Adhesion Kinase

• Published in: The Journal of biological chemistry 2002-03, Vol.277 (12), p.9749-9756
• Main Authors: Deryugina, Elena I., Ratnikov, Boris I., Postnova, Tanya I., Rozanov, Dmitri V., Strongin, Alex Y.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110269200

Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of αvintegrin subunit (pro-αv) into the heavy and light α-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing αvβ3 integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-αv maturation. We present evidence that MT1-MMP cleavage of pro-αv in the cells did not affect RGD-ligand binding of the resulting αvβ3 integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and αvβ3integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of αvβ3integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and αvβ3 integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells.