PMID- 9038378
OWN - NLM
STAT- MEDLINE
DCOM- 19970317
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 14
IP  - 6
DP  - 1997 Feb 13
TI  - Regulation of the urokinase-type plasminogen activator gene by the oncogene 
      Tpr-Met involves GRB2.
PG  - 705-11
AB  - The oncogene Tpr-Met is a constitutively active form of the hepatocyte growth 
      factor/scatter factor (HGF/SF) receptor Met. It comprises the intracellular 
      moiety of Met linked to the dimerization domain of the nuclear envelope protein 
      Tpr, thus functioning as a constitutively activated Met. HGF/SF is responsible 
      for various biological processes including angiogenesis and wound healing, in 
      which secreted serine protease urokinase-type plasminogen activator (uPA) is 
      implicated. The action of HGF/SF on cells is mediated by the autophosphorylation 
      of Met on two carboxyterminal tyrosine residues, Y1349VHVNATVY1356VNV. The two 
      tyrosine residues provide docking sites for various effector molecules, 
      suggesting that multiple signaling pathways are activated to exert biological 
      effects of HGF/SF [Ponzetto et al., Cell (1994) 77: 261]. We found that Tpr-Met 
      efficiently activates the uPA gene via a SOS/Ras/extracellular signal regulated 
      kinase (ERK)-dependent signaling pathway. Mutation of Y1356, which abrogates GRB2 
      binding, reduced the induction to half of the control level, while mutation of 
      Y1349 showed little effect on uPA induction, suggesting an important but partly 
      replaceable role for GRB2 in Met-dependent uPA gene induction. Mutation of both 
      Y1349VHV and Y1356VNV into optimal PI 3-kinase sites resulted in a residual 
      induction of about one quarter of the control level, suggesting a potential role 
      for PI 3-kinase. Dose-response analysis of the Tpr-Met showed a biphasic curve. 
      These results suggest that the interplay among different signaling molecules on 
      the receptor is important for full induction of the pathway leading to the 
      activation of the uPA gene.
FAU - Besser, D
AU  - Besser D
AD  - Friedrich Miescher Institute, Basel, Switzerland.
FAU - Bardelli, A
AU  - Bardelli A
FAU - Didichenko, S
AU  - Didichenko S
FAU - Thelen, M
AU  - Thelen M
FAU - Comoglio, P M
AU  - Comoglio PM
FAU - Ponzetto, C
AU  - Ponzetto C
FAU - Nagamine, Y
AU  - Nagamine Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (GRB2 Adaptor Protein)
RN  - 0 (Grb2 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Son of Sevenless Proteins)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - 3T3 Cells/enzymology/metabolism/physiology
MH  - *Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Cells, Cultured
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Induction
MH  - GRB2 Adaptor Protein
MH  - Gene Expression Regulation, Enzymologic/*physiology
MH  - Kidney/cytology/physiology
MH  - Membrane Proteins/physiology
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/genetics/*physiology
MH  - Mutation
MH  - Nerve Tissue Proteins/physiology
MH  - Phosphatidylinositol 3-Kinases
MH  - Phosphotransferases (Alcohol Group Acceptor)/physiology
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/physiology
MH  - Proteins/*physiology
MH  - Proto-Oncogene Proteins/physiology
MH  - Proto-Oncogene Proteins c-met
MH  - Proto-Oncogene Proteins c-raf
MH  - Signal Transduction/physiology
MH  - Son of Sevenless Proteins
MH  - Transcriptional Activation
MH  - Urokinase-Type Plasminogen Activator/biosynthesis/*genetics
MH  - ras Proteins/physiology
EDAT- 1997/02/13 00:00
MHDA- 1997/02/13 00:01
CRDT- 1997/02/13 00:00
PHST- 1997/02/13 00:00 [pubmed]
PHST- 1997/02/13 00:01 [medline]
PHST- 1997/02/13 00:00 [entrez]
AID - 10.1038/sj.onc.1200879 [doi]
PST - ppublish
SO  - Oncogene. 1997 Feb 13;14(6):705-11. doi: 10.1038/sj.onc.1200879.