title: Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration.
abstract: Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges. Interestingly, the PLS is also required for the negative regulation of p190A RhoGAP activity. Further, we show that the F-actin binding protein cortactin binds the PLS and is required for p190A targeting to protrusions. Lastly, we demonstrate that cancer-associated mutations in PLS affect p190A localization and function, as well as tumor cell migration. Altogether, our data unveil a new mechanism of regulation of p190A in migrating tumor cells.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Binamé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Bidaud-Meynard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Laure
authors.identifier: 0000-0003-0880-7418
authors.initials: L
authors.lastname: Magnan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Léo
authors.identifier: 0000-0003-0228-0467
authors.initials: L
authors.lastname: Piquet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Bertille
authors.initials: B
authors.lastname: Montibus
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 441, F-33600 Pessac, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Chabadel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saltel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lagrée
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France Université de Bordeaux, Unité Mixte de Recherche 1053 Bordeaux Research In Translational Oncology, F-33000 Bordeaux, France violaine.moreau@inserm.fr.
authors.forename: Violaine
authors.identifier: 0000-0002-4513-7022
authors.initials: V
authors.lastname: Moreau
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D011485:Protein Binding; D000072417:Protein Domains; D011554:Pseudopodia / Q000378:metabolism; D012097:Repressor Proteins; D034421:Sus scrofa; D014162:Transfection
chemical_list: D000199:Actins; C513040:Arhgap35 protein, rat; D051356:Cortactin; D020662:Guanine Nucleotide Exchange Factors; D012097:Repressor Proteins