RalB directly triggers invasion downstream Ras by mobilizing the Wave complex

Author:

Zago Giulia12ORCID,Veith Irina12,Singh Manish Kumar12,Fuhrmann Laetitia13,De Beco Simon14,Remorino Amanda14,Takaoka Saori12,Palmeri Marjorie12,Berger Frédérique15,Brandon Nathalie12,El Marjou Ahmed16,Vincent-Salomon Anne13,Camonis Jacques12,Coppey Mathieu14,Parrini Maria Carla12ORCID

Affiliation:

1. Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France

2. ART Group, Inserm U830, Paris, France

3. Department of Pathology, Institut Curie, Paris, France

4. LOCCO Group, UMR168, Paris, France

5. Department of Biostatistics, Institut Curie, Paris, France

6. Protein Expression and Purification Core Facility, Paris, France

Abstract

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.

Funder

Fondation ARC pour la Recherche sur le Cancer

Institut National de la Santé et de la Recherche Médicale

Agence Nationale de la Recherche

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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