Distinct roles for the catalytic and hemopexin domains of membrane type 1-matrix metalloproteinase in substrate degradation and cell migration.
Substrate degradation and cell migration are key steps in cancer metastasis. Membrane-type 1-matrix metalloproteinase (MT1-MMP) has been linked with these processes. Using the fluorescein isothiocyanate (FITC)-labeled fibronectin degradation assay combined with the phagokinetic cell migration assay, structure-function relationships of MT1-MMP were studied. Our data indicate that MT1-MMP initiates substrate degradation and enhances cell migration; cell migration occurs as a concurrent but independent event. Using recombinant DNA approaches, we demonstrated that the hemopexin-like domain and a nonenzymatic component of the catalytic domain of MT1-MMP are essential for MT1-MMP-mediated cell migration. Because the cytoplasmic domain of MT1-MMP was not required for MT1-MMP-mediated fibronectin degradation and cell migration, it is proposed that cross-talk between the hemopexin domain of MT1-MMP and adjacent cell surface molecules is responsible for outside-in signaling. Employing cDNAs encoding dominant negative mutations, we demonstrated that Rac1 participates in the MT1-MMP signal transduction pathway. These data demonstrated that each domain of MT1-MMP plays a distinct role in substrate degradation and cell migration.
Cao
Jian
J
Department of Medicine, School of Medicine, State University of New York, Stony Brook, New York 11794, USA.
Kozarekar
Pallavi
P
Pavlaki
Maria
M
Chiarelli
Christian
C
Bahou
Wadie F
WF
Zucker
Stanley
S
D000818:Animals; D001943:Breast Neoplasms; D019556:COS Cells; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D006466:Hemopexin / Q000737:chemistry*; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D011471:Prostatic Neoplasms; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
C507096:Mmp14 protein, mouse; D011994:Recombinant Proteins; D006466:Hemopexin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein