The small G-protein RalA stimulates metastasis of transformed cells

Abstract

RAS oncogenes play a critical role in oncogenic transformation and metastases formation. Here we show that Ha-ras greatly stimulates spontaneous metastatic activity of transformed cells through the Ras/RalGDS/ RalA intracellular signaling pathway. Introduction of RalA alone leads to a drastic increase of metastatic activity of transformed cells. We demonstrate that metastatic ability of cells could be dramatically enhanced by RalA stimulation or, conversely, hampered by RalA suppression. Furthermore, we found that during in vivo selection cells acquire high metastatic properties as a result of endogenous RalA activation. The ability of RalA to induce metastasis was demonstrated in spontaneously transformed as well as in virus transformed fibroblasts.

RalA regulates vascular endothelial growth factor-C (VEGF-C) synthesis in prostate cancer cells during androgen ablation

“…Specifically, Ral GTPases RalA and RalB have been shown to serve essential functions in vesicle trafficking, cell morphology, transcriptional activation and human oncogenesis (Feig, 2003). Studies also suggest a role for RalA in tumor metastasis (Tchevkina et al, 2005) and anchorage-independent proliferation (Chien and White, 2003). In contrast, activation of RalGEF and Ral Ras-effector proteins is not a potent inducer of transformation in rodent fibroblast or epithelial cells (Urano et al, 1996;McFall et al, 2001;Ulku et al, 2003;Collette et al, 2004).…”

Elucidation of the Molecular Mechanism Underlying Lymph Node Metastasis in Prostate Cancer

“…One of them, as we observed, is RalA activation leading to VEGF-C production. Activation of RalA has been shown to be important for human cancer progression (Feig, 2003;Tchevkina et al, 2005). In this light, activation of RalA under androgen-ablated conditions is in itself an important observation, suggesting RalA's possible involvement in the transition of prostate cancer towards the androgen refractory phenotype.…”

CEACAM1 functionally interacts with filamin A and exerts a dual role in the regulation of cell migration

“…The influence of CEACAM1-L on RalA signaling via FLNa-binding extends the possibilities how CEACAM1-L could be implicated in oncogenesis. There is increasing evidence that the Ras effector RalA plays a substantial role in Ras-induced oncogenesis (Gonzalez-Garcia et al, 2005;Tchevkina et al, 2005). Further investigation of how CEACAM1 interferes with the RalA signaling pathway also could reveal an explanation for the contradictory potential of CEACAM1 to either suppress tumorigenic characteristics, e.g.…”