title: RPTPα controls epithelial adherens junctions, linking E-cadherin engagement to c-Src-mediated phosphorylation of cortactin.
abstract: Epithelial junctions are fundamental determinants of tissue organization, subject to regulation by tyrosine phosphorylation. Homophilic binding of E-cadherin activates tyrosine kinases, such as Src, that control junctional integrity. Protein tyrosine phosphatases (PTPs) also contribute to cadherin-based adhesion and signaling, but little is known about their specific identity or functions at epithelial junctions. Here, we report that the receptor PTP RPTPα (human gene name PTPRA) is recruited to epithelial adherens junctions at the time of cell-cell contact, where it is in molecular proximity to E-cadherin. RPTPα is required for appropriate cadherin-dependent adhesion and for cyst architecture in three-dimensional culture. Loss of RPTPα impairs adherens junction integrity, as manifested by defective E-cadherin accumulation and peri-junctional F-actin density. These effects correlate with a role for RPTPα in cellular (c)-Src activation at sites of E-cadherin engagement. Mechanistically, RPTPα is required for appropriate tyrosine phosphorylation of cortactin, a major Src substrate and a cytoskeletal actin organizer. Expression of a phosphomimetic cortactin mutant in RPTPα-depleted cells partially rescues F-actin and E-cadherin accumulation at intercellular contacts. These findings indicate that RPTPα controls cadherin-mediated signaling by linking homophilic E-cadherin engagement to cortactin tyrosine phosphorylation through c-Src.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Bâtiment Lamarck, Case 7042, 35 Rue Hélène Brion, F-75205 Paris Cedex 13, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Truffi
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Bâtiment Lamarck, Case 7042, 35 Rue Hélène Brion, F-75205 Paris Cedex 13, France veronique.dubrueil@univ-paris-diderot.fr jansap@fastmail.fm.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dubreuil
authors.affiliation: Division of Molecular Cell Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liang
authors.affiliation: Biotech Research and Innovation Centre and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vacaresse
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Bâtiment Lamarck, Case 7042, 35 Rue Hélène Brion, F-75205 Paris Cedex 13, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Nigon
authors.affiliation: Division of Molecular Cell Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia.
authors.forename: Siew Ping
authors.initials: SP
authors.lastname: Han
authors.affiliation: Division of Molecular Cell Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia.
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.affiliation: Division of Molecular Cell Biology, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Brisbane 4072, Australia.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Gomez
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Bâtiment Lamarck, Case 7042, 35 Rue Hélène Brion, F-75205 Paris Cedex 13, France Biotech Research and Innovation Centre and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark veronique.dubrueil@univ-paris-diderot.fr jansap@fastmail.fm.
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
mesh_terms: D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D015820:Cadherins; D051356:Cortactin; D034741:RNA, Small Interfering; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516841:PTPRA protein, human; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4
keywords: Adherens junctions; Cortactin; E-cadherin; Tyrosine phosphatase; c-Src