PMID- 9668053
OWN - NLM
STAT- MEDLINE
DCOM- 19980820
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 30
DP  - 1998 Jul 24
TI  - Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial 
      cells through a novel pathway.
PG  - 18793-801
AB  - 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.
FAU - Khwaja, A
AU  - Khwaja A
AD  - Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United 
      Kingdom.
FAU - Lehmann, K
AU  - Lehmann K
FAU - Marte, B M
AU  - Marte BM
FAU - Downward, J
AU  - Downward J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - Animals
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors/metabolism
MH  - Cell Line
MH  - Chromones/pharmacology
MH  - Dogs
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/*metabolism
MH  - Flavonoids/pharmacology
MH  - GTP Phosphohydrolases/metabolism
MH  - Hepatocyte Growth Factor/*metabolism
MH  - Kidney Tubules/*growth & development
MH  - Mitogen-Activated Protein Kinase 1
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Signal Transduction
MH  - ras Proteins/metabolism
EDAT- 1998/07/21 00:00
MHDA- 1998/07/21 00:01
CRDT- 1998/07/21 00:00
PHST- 1998/07/21 00:00 [pubmed]
PHST- 1998/07/21 00:01 [medline]
PHST- 1998/07/21 00:00 [entrez]
AID - S0021-9258(18)80203-4 [pii]
AID - 10.1074/jbc.273.30.18793 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Jul 24;273(30):18793-801. doi: 10.1074/jbc.273.30.18793.