D. Gingras et al., Rapid activation of matrix metalloproteinase-2 by glioma cells occurs through a posttranslational MT1-MMP-dependent mechanism, BBA-MOL CEL, 1497(3), 2000, pp. 341-350
Citations number
27
Categorie Soggetti
Cell & Developmental Biology
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Matrix metalloproteinase-2 (MMP-2) has been suggested to play a crucial rol
e in tumor invasion and angiogenesis. In order to understand the mechanisms
underlying proMMP-2 activation, we compared the biochemical and cellular e
vents triggered by two potent MMP-2 activators, the lectin concanavalin A (
ConA) and the cytoskeleton disrupting agent cytochalasin D (CytoD). Incubat
ion of U87 human glioma cells for 24 h in the presence of ConA or CytoD ind
uced a marked activation of proMMP-2 and this activation was correlated in
both cases with an increase in the mRNA levels of MT1-MMP. At the protein l
evel, proMMP-2 activation induced by CytoD or ConA strongly correlated with
the appearance of a 43-kDa MT1-MMP proteolytic breakdown product in cell l
ysates. Interestingly, CytoD also induced a very rapid (2 h) activation of
proMMP-2 that was independent of protein synthesis. Under these conditions,
CytoD also promoted the rapid proteolytic breakdown of the 63 kDa pro form
of MT1-MMP, resulting in the appearance of the 43 kDa MT1-MMP processed fo
rm. Overexpression of a recombinant full-length MT1-MMP protein in glioma c
ells resulted in the activation of proMMP-2 that was correlated with the ge
neration of the 43 kDa fragment of the protein. By contrast, overexpression
of the protein in COS-7 cells promoted proMMP-2 activation without inducin
g the production of the 43 kDa fragment. These results thus suggest that ac
tivation of proMMP-2 occurs through both translational and post-translation
al mechanisms, both involving proteolytic processing of membrane-associated
MT1-MMP. This processing of MT1-MMP is, however, not essential to proMMP-2
activation but may represent a regulatory mechanism to control the activit
y of MT1-MMP. (C) 2000 Elsevier Science B.V. All rights reserved.