title: P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces.
abstract: Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell-cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/β-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through β-PIX, which is specifically recruited at cell-cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through β-PIX-mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM.
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Plutoni
authors.affiliation: Institute for Bioengineering of Catalonia, Universitat de Barcelona, 08007 Barcelona, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Bazellieres
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Maïlys
authors.initials: M
authors.lastname: Le Borgne-Rochet
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Comunale
authors.affiliation: Institute for Bioengineering of Catalonia, Universitat de Barcelona, 08007 Barcelona, Spain.
authors.forename: Agusti
authors.initials: A
authors.lastname: Brugues
authors.affiliation: Functional Proteomics Platform, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale U1191, Universités Montpellier, 34094 Montpellier, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Séveno
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Planchon
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thuault
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Morin
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bodin
authors.affiliation: Institute for Bioengineering of Catalonia, Universitat de Barcelona, 08007 Barcelona, Spain Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina, 08010 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Trepat
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5237, Universités Montpellier, 34293 Montpellier, France cecile.gauthier@crbm.cnrs.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gauthier-Rouvière
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement; D016764:Cell Polarity; D002478:Cells, Cultured; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C576607:Arhgef7 protein, mouse; D015820:Cadherins; C581598:Cdc42 protein, mouse; D064067:Rho Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein