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J Biol Chem, Vol. 273, Issue 30, 18793-18801, July 24, 1998
From the Imperial Cancer Research Fund, 44 Lincoln's Inn Fields,
London WC2A 3PX, United Kingdom
Hepatocyte growth factor/scatter factor (HGF/SF)
treatment of the Madin-Darby canine kidney epithelial cell line causes
scattering of cells grown in monolayer culture and the formation of
branching tubules by cells grown in collagen gels.
HGF/SF causes prolonged activation of both the mitogen-activated
protein (MAP) kinase extracellular signal-regulated kinase 2 (ERK2) and
the phosphoinositide 3-OH kinase (PI 3-kinase) target protein kinase B
(PKB)/Akt; inhibition of either the MAP kinase pathway by the MAP
kinase/ERK kinase inhibitor PD98059 or the PI 3-kinase pathway by
LY294002 blocks HGF/SF induction of scattering, although in
morphologically distinct ways. Expression of constitutively activated
PI 3-kinase, Ras, or R-Ras will cause scattering, but activated Raf
will not, indicating that activation of the MAP kinase pathway is not
sufficient for this response. Downstream of PI 3-kinase, activated
PKB/Akt and Rac are both unable to induce scattering, implicating a
novel pathway. Scattering induced by Ras or PI 3-kinase is sensitive to
PD98059, as well as to LY294002, suggesting that basal MAP kinase
activity is required, but not sufficient, for the scattering response.
Induction of MDCK cell tubulogenesis in collagen gels by HGF/SF is
inhibited by PD98059; expression of activated Ras and Raf causes
disorganized growth in this system, but activated PI 3-kinase or R-Ras
causes branching tubule formation similar to that seen with HGF/SF
treatment. These data indicate that multiple signaling pathways acting
downstream of Met and Ras are needed for these morphological effects;
scattering is induced primarily by the PI 3-kinase pathway, which acts
through effectors other than PKB/Akt or Rac and requires at least basal MAP kinase function. Elevated PI 3-kinase activity induces
tubulogenesis, but total inhibition and excess activation of the MAP
kinase pathway both oppose this effect.
Phosphoinositide 3-Kinase Induces Scattering and Tubulogenesis in
Epithelial Cells through a Novel Pathway
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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