RalB directly triggers invasion downstream Ras by mobilizing the Wave complex

Nom de la revue
Giulia Zago, Irina Veith, Manish Kumar Singh, Laetitia Fuhrmann, Simon De Beco, Amanda Remorino, Saori Takaoka, Marjorie Palmeri, Frédérique Berger, Nathalie Brandon, Ahmed El Marjou, Anne Vincent-Salomon, Jacques Camonis, Mathieu Coppey, Maria Carla Parrini

The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appears to be more important than that of MAPK and PI3K pathways. Moreover, on the clinical side, we uncovered a potential role of RalB in human breast cancers by determining that RalB expression at protein level increases in a manner consistent with progression toward metastasis. This work highlights the Ras-RGL1/2-RalB-exocyst-WRC axis as appealing target for novel anticancer strategies.