Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep11759
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Funding
- Ligue National contre le Cancer
- Fondation ARC pour la Recherche sur le Cancer
- MHV grant from the Swiss National Science Foundation
- Fondation ARC pour la Recherche sur le Cancer [MCP SFI20121205710, JC SFI20111203931, SFI20121205686]
- Ligue National contre le Cancer [MCP RS14/75-54]
- Agence Nationale de la Recherche [ANR-11 BSV2 012 01]
- European Research Council (ERC ZEBRATECTUM) [311159]
- Fondation Pierre-Gillles de Gennes pour la recherche
- Association Christelle Bouillot
- European Research Council (ERC) [311159] Funding Source: European Research Council (ERC)
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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 TGF beta. We show that TGF beta-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.
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