Met-driven invasive growth involves transcriptional regulation of Arhgap12.
Invasive growth is a complex biological program triggered by hepatocyte growth factor (HGF) through its tyrosine kinase receptor encoded by the Met proto-oncogene. The program involves-besides proliferation-cell dissociation, motility and invasiveness, controlled by intracellular signals impinging on PI3K and on the small G-proteins of the Rac/Rho family. The mechanism(s) unbalancing Rac/Rho activation are still not completely clarified. Here, we describe a functional link between HGF and Arhgap12, a gene encoding a previously uncharacterized protein of the RhoGAP family. We identified Arhgap12 as a transcriptional target of HGF, through a novel gene trapping strategy. We found that Arhgap12 mRNA and protein are robustly suppressed by HGF treatment, but not by serum. Arhgap12 displayed GTPase activating protein (GAP) activity towards Rac1 and, upon overexpression, impaired cell scattering, invasion and adhesion to fibronectin in response to HGF. Consistently, Arhgap12 silencing by RNA interference selectively increased the scatter and adhesion responses. These data show that HGF-driven invasive growth involves transcriptional regulation of a Rac1-specific GAP.
Gentile
A
A
Laboratory of Functional Genomics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Turin Medical School, Turin, Italy.
D'Alessandro
L
L
Lazzari
L
L
Martinoglio
B
B
Bertotti
A
A
Mira
A
A
Lanzetti
L
L
Comoglio
P M
PM
Medico
E
E
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D009361:Neoplasm Invasiveness; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000235:genetics
C454999:ARHGAP12 protein, human; D020690:GTPase-Activating Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C107953:RAC1 protein, human; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020830:rac1 GTP-Binding Protein