Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase.
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 alpha(v) integrin subunit (pro-alpha(v)) into the heavy and light alpha-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing alpha(v)beta(3) 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-alpha(v) maturation. We present evidence that MT1-MMP cleavage of pro-alpha(v) in the cells did not affect RGD-ligand binding of the resulting alpha(v)beta(3) 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 alpha(v)beta(3) integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of alpha(v)beta(3) integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and alpha(v)beta(3) 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.
Deryugina
Elena I
EI
Burnham Institute, La Jolla, California 92037, USA.
Ratnikov
Boris I
BI
Postnova
Tanya I
TI
Rozanov
Dmitri V
DV
Strongin
Alex Y
AY
D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry; D009930:Organic Chemicals; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism*
D000970:Antineoplastic Agents; D004220:Disulfides; D008024:Ligands; D009842:Oligopeptides; D009930:Organic Chemicals; D019030:Receptors, Vitronectin; D019096:Vitronectin; C113282:prinomastat; D014443:Tyrosine; C047981:arginyl-glycyl-aspartic acid; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020781:Matrix Metalloproteinase 1