title: Discoidin domain receptor 1 controls linear invadosome formation via a Cdc42-Tuba pathway.
abstract: Accumulation of type I collagen fibrils in tumors is associated with an increased risk of metastasis. Invadosomes are F-actin structures able to degrade the extracellular matrix. We previously found that collagen I fibrils induced the formation of peculiar linear invadosomes in an unexpected integrin-independent manner. Here, we show that Discoidin Domain Receptor 1 (DDR1), a collagen receptor overexpressed in cancer, colocalizes with linear invadosomes in tumor cells and is required for their formation and matrix degradation ability. Unexpectedly, DDR1 kinase activity is not required for invadosome formation or activity, nor is Src tyrosine kinase. We show that the RhoGTPase Cdc42 is activated on collagen in a DDR1-dependent manner. Cdc42 and its specific guanine nucleotide-exchange factor (GEF), Tuba, localize to linear invadosomes, and both are required for linear invadosome formation. Finally, DDR1 depletion blocked cell invasion in a collagen gel. Altogether, our data uncover an important role for DDR1, acting through Tuba and Cdc42, in proteolysis-based cell invasion in a collagen-rich environment.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Juin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Di Martino
authors.affiliation: National Heart and Lung Institute, Imperial College London, London SW7 2AZ, England, UK.
authors.forename: Birgit
authors.initials: B
authors.lastname: Leitinger
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Henriet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Gary
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Paysan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1085, Institut de Recherche sur la Santé l'Environnement et le Travail (IRSET), Université de Rennes 1, 35043 Rennes, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bomo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1085, Institut de Recherche sur la Santé l'Environnement et le Travail (IRSET), Université de Rennes 1, 35043 Rennes, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Baffet
authors.affiliation: Universités Montpellier 2 et 1, Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, UMR 5237, 34293 Montpellier, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gauthier-Rouvière
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France violaine.moreau@inserm.fr frederic.saltel@inserm.fr.
authors.forename: Violaine
authors.initials: V
authors.lastname: Moreau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1053, F-33076 Bordeaux, France Université de Bordeaux, F-33076 Bordeaux, France violaine.moreau@inserm.fr frederic.saltel@inserm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Saltel
mesh_terms: D008841:Actin Cytoskeleton; D000199:Actins / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D000070819:Discoidin Domain Receptor 1; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D033942:Adaptor Proteins, Vesicular Transport; D024042:Collagen Type I; D003598:Cytoskeletal Proteins; C482331:DNMBP protein, human; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D034741:RNA, Small Interfering; C478582:SH3PXD2A protein, human; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D017364:Collagenases; D020764:cdc42 GTP-Binding Protein