An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase.
Membrane type-1 matrix metalloproteinase (MT1-MMP) and alpha(v)beta(3) integrin are both essential to cell invasion. Maturation of integrin pro-alpha(v)chain (pro-alpha(v)) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light alpha chains. Our report presents evidence of an alternative pathway of pro-alpha(v) processing involving MT1-MMP. In breast carcinoma MCF7 cells deficient in MT1-MMP, pro-alpha(v) is processed by a conventional furin-like PC, and the mature alpha(v) integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp(891). In contrast, in cells co-expressing alpha(v)beta(3) and MT1-MMP, MT1-MMP functions as an integrin convertase. MT1-MMP specifically cleaves pro-alpha(v), generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu(892). PC-cleavable alpha(3) and alpha(5) but not the PC-resistant alpha(2) integrin subunit are also susceptible to MT1-MMP cleavage. These novel mechanisms involved in the processing of integrin alpha subunits underscore the significance and complexity of interactions between MT1-MMP and adhesion receptors and suggest that regulation of integrin functionality may be an important role of MT1-MMP in migrating tumor cells.
Ratnikov
Boris I
BI
Burnham Institute, 10901 N Torrey Pines Road, La Jolla, California 92037, USA.
Rozanov
Dmitri V
DV
Postnova
Tanya I
TI
Baciu
Peter G
PG
Zhang
Heying
H
DiScipio
Richard G
RG
Chestukhina
Galina G
GG
Smith
Jeffrey W
JW
Deryugina
Elena I
EI
Strongin
Alex Y
AY
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006801:Humans; D039564:Integrin alphaV; D016023:Integrins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019030:Receptors, Vitronectin / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D004220:Disulfides; D039564:Integrin alphaV; D016023:Integrins; C507096:Mmp14 protein, mouse; D019030:Receptors, Vitronectin; D001224:Aspartic Acid; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14