Activation of the extracellular signal-regulated protein kinase (ERK) cascade by membrane-type-1 matrix metalloproteinase (MT1-MMP).
The mechanisms underlying membrane-type-1 matrix metalloproteinase (MT1-MMP)-dependent induction of cell migration were investigated. Overexpression of MT1-MMP induced a marked increase in cell migration, this increase being dependent on the presence of the cytoplasmic domain of the protein. MT1-MMP-dependent migration was inhibited by a mitogen-activated protein kinase kinase 1 inhibitor, suggesting the involvement of the extracellular signal-regulated protein kinase (ERK) cascade in the induction of migration. Accordingly, MT1-MMP overexpression induced the activation of ERK, this process being also dependent on the presence of its cytoplasmic domain. MT1-MMP-induced activation of both migration and ERK required the catalytic activity of the enzyme as well as attachment of the cells to matrix proteins. The MT1-MMP-dependent activation of ERK was correlated with the activation of transcription through the serum response element, whereas other promoters were unaffected. Taken together, these results indicate that MT1-MMP trigger important changes in cellular signal transduction events, leading to cell migration and to gene transcription, and that these signals possibly originate from the cytoplasmic domain of the protein.
Gingras
D
D
Laboratoire de Médecine Moléculaire Ste-Justine-UQAM, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine et Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC, Canada H3C 3P8.
Bousquet-Gagnon
N
N
Langlois
S
S
Lachambre
M P
MP
Annabi
B
B
Béliveau
R
R
D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020928:Mitogen-Activated Protein Kinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases