Detalle Publicación


C3G knock-down enhances migration and invasion by increasing Rap1-mediated p38a activation, while it impairs tumor growth through p38a-independent mechanisms

Autores: Priego, N.; Arechederra Calderon, Maria; Sequera, C.; Bragado, P. ; Vázquez-Carballo, A.; Gutiérrez-Uzquiza, A. ; Martín-Granado, V. ; Ventura, J.J. ; Kazanietz, M. G. ; Guerrero, C.; Porras, A.
Título de la revista: ONCOTARGET
ISSN: 1949-2553
Volumen: 7
Número: 29
Páginas: 45060 - 45078
Fecha de publicación: 2016
C3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38¿ MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38¿ hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38¿ collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38¿ individually or together promoted cell death in vitro, although only the double C3G-p38¿ silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38¿ or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis.