TY - JOUR
T1 - Met-driven invasive growth involves transcriptional regulation of Arhgap12
AU - Gentile, A.
AU - D'Alessandro, L.
AU - Lazzari, L.
AU - Martinoglio, B.
AU - Bertotti, A.
AU - Mira, A.
AU - Lanzetti, L.
AU - Comoglio, P. M.
AU - Medico, E.
PY - 2008/9/18
Y1 - 2008/9/18
N2 - 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.
AB - 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.
KW - Gene trapping
KW - GTPase activating protein
KW - HGF
KW - Rac1
KW - Rho family
KW - Scatter
UR - http://www.scopus.com/inward/record.url?scp=52149083055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52149083055&partnerID=8YFLogxK
U2 - 10.1038/onc.2008.173
DO - 10.1038/onc.2008.173
M3 - Article
C2 - 18504429
AN - SCOPUS:52149083055
SN - 0950-9232
VL - 27
SP - 5590
EP - 5598
JO - Oncogene
JF - Oncogene
IS - 42
ER -