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Vol. 11, Issue 11, 3751-3763, November 2000
Centre National de la Recherche Scientifique EP 560, Institut de
Biologie de Lille, Institut Pasteur de Lille, 59021 Lille, France
The scattering of Madin-Darby canine kidney (MDCK) epithelial cells
by scatter factor/hepatocyte growth factor (SF/HGF) is associated with
transcriptional induction of the urokinase gene, which occurs
essentially through activation of an EBS/AP1 response element. We have
investigated the signal transduction pathways leading to this
transcriptional response. We found that SF/HGF induces rapid and
sustained phosphorylation of the extracellular signal-regulated kinase
(ERK) MAPK while stimulating weakly and then repressing phosphorylation
of the JUN N-terminal kinase (JNK) MAPK for several hours. This delayed
repression of JNK was preceded by phosphorylation of the MKP2
phosphatase, and both MKP2 induction and JNK dephosphorylation were
under the control of MEK, the upstream kinase of ERK. ERK and MKP2
stimulate the EBS/AP1-dependent transcriptional response to SF/HGF, but
not JNK, which inhibits this response. We further demonstrated that
depending on cell density, the RAS-ERK-MKP2 pathway controls this
transrepressing effect of JNK. Together, these data demonstrate that in
a sequential manner SF/HGF activates ERK and MKP2, which in turn
dephosphorylates JNK. This sequence of events provides a model for
efficient cell scattering by SF/HGF at low cell density.
Centre
National de la Recherche Scientifique, Unité Mixte de Recherche
8527, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P.
447, 59021 Lille, France.
Corresponding author. E-mail address:
veronique.fafeur{at}ibl.fr.
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