Regulation of Ras and Rho small G proteins by SHP-2.
BACKGROUND
Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through the tyrosine kinase-type HGF/SF receptor, c-Met. We have previously shown that SHP-2, a protein tyrosine phosphatase, positively regulates the HGF/SF-induced cell scattering through modulating the activity of Rho to form stress fibres and focal adhesions. To further investigate the role of SHP-2 in HGF/SF-induced cell scattering, we have now examined the effect of a dominant active mutant of SHP-2 (SHP-2-DA).


RESULTS
Expression of SHP-2-DA markedly increased the formation of lamellipodia with ruffles, while it decreased the accumulation of E-cadherin and beta-catenin at cell-cell adhesion sites in MDCK cells. In addition, expression of SHP-2-DA markedly enhanced cell scattering of MDCK cells in response to HGF/SF. Expression of SHP-2-DA induced the activation of MAP kinase without HGF/SF stimulation, whereas an inhibitor of MEK partly reversed the SHP-2-DA-induced morphological phenotypes. Furthermore, expression of either a dominant-active mutant of Rho or Vav2 also reversed the SHP-2-DA-induced morphological phenotypes.


CONCLUSIONS
These results indicate that SHP-2 plays a crucial role in the HGF/SF-induced cell scattering through the regulation of two distinct small G proteins, Ras and Rho.
Kodama
A
A
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan.
Matozaki
T
T
Shinohara
M
M
Fukuhara
A
A
Tachibana
K
K
Ichihashi
M
M
Nakanishi
H
H
Takai
Y
Y
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D051176:beta Catenin; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D051176:beta Catenin; D017228:Hepatocyte Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one