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 o f 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 ki nase 1 inhibitor, suggesting the involvement of the extracellular signal-re gulated protein kinase (ERK) cascade in the induction of migration. Accordi ngly, MT1-MMP overexpression induced the activation of ERK, this process be ing also dependent on the presence of its cytoplasmic domain. MT1-MMP-induc ed 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-M MPdependent activation of ERK was correlated with the activation of transcr iption through the serum response element, whereas other promoters were una ffected. Taken together, these results indicate that MT1-MMP trigger import ant changes in cellular signal transduction events, leading to cell migrati on and to gene transcription, and that these signals possibly originate fro m the cytoplasmic domain of the protein. (C) 2001 Federation of European Bi ochemical Societies. Published by Elsevier Science B.V. All rights reserved .