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Sci Rep. 2015 Jul 8;5:11759. doi: 10.1038/srep11759.

RalB regulates contractility-driven cancer dissemination upon TGFβ stimulation via the RhoGEF GEF-H1.

Author information

1
1] Institut Curie, Centre de Recherche, Paris Sciences et Lettres University, 75248 Paris, France [2] ART group, Inserm U830.
2
1] Institut Curie, Centre de Recherche, Paris Sciences et Lettres University, 75248 Paris, France [2] UMR168, CNRS, UPMC Equipe labellisée Ligue contre le Cancer.
3
Department of Biomedicine, University of Basel, Switzerland.

Abstract

RalA and RalB proteins are key mediators of oncogenic Ras signaling in human oncogenesis. Herein we investigated the mechanistic contribution of Ral proteins to invasion of lung cancer A549 cells after induction of epithelial-mesenchymal transition (EMT) with TGFβ. We show that TGFβ-induced EMT promotes dissemination of A549 cells in a 2/3D assay, independently of proteolysis, by activating the Rho/ROCK pathway which generates actomyosin-dependent contractility forces that actively remodel the extracellular matrix, as assessed by Traction Force microscopy. RalB, but not RalA, is required for matrix deformation and cell dissemination acting via the RhoGEF GEF-H1, which associates with the Exocyst complex, a major Ral effector. Indeed, uncoupling of the Exocyst subunit Sec5 from GEF-H1 impairs RhoA activation, generation of traction forces and cell dissemination. These results provide a novel molecular mechanism underlying the control of cell invasion by RalB via a cross-talk with the Rho pathway.

PMID:
26152517
PMCID:
PMC4495419
DOI:
10.1038/srep11759
[Indexed for MEDLINE]
Free PMC Article

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