title: The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling.
abstract: Vascular endothelial (VE)-cadherin transfers intracellular signals contributing to vascular hemostasis. Signaling through VE-cadherin requires association and activity of different intracellular partners. Yes-associated protein (YAP)/TAZ transcriptional cofactors are important regulators of cell growth and organ size. We show that EPS8, a signaling adapter regulating actin dynamics, is a novel partner of VE-cadherin and is able to modulate YAP activity. By biochemical and imaging approaches, we demonstrate that EPS8 associates with the VE-cadherin complex of remodeling junctions promoting YAP translocation to the nucleus and transcriptional activation. Conversely, in stabilized junctions, 14-3-3-YAP associates with the VE-cadherin complex, whereas Eps8 is excluded. Junctional association of YAP inhibits nuclear translocation and inactivates its transcriptional activity both in vitro and in vivo in Eps8-null mice. The absence of Eps8 also increases vascular permeability in vivo, but did not induce other major vascular defects. Collectively, we identified novel components of the adherens junction complex, and we introduce a novel molecular mechanism through which the VE-cadherin complex controls YAP transcriptional activity.
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy Dipartimento di Bioscienze, Università degli Studi di Milano, 20122 Milan, Italy costanza.giampietro@unimi.it elisabetta.dejana@ifom.eu giorgio.scita@ifom.eu.
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Disanza
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bravi
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Barrios-Rodiles
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frittoli
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Savorani
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.affiliation: Department of Dermatology, Cologne Excellence Cluster for Stress Responses in Ageing-Associated Diseases, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Boggetti
authors.affiliation: Department of Dermatology, Cologne Excellence Cluster for Stress Responses in Ageing-Associated Diseases, Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
authors.forename: Carien
authors.initials: C
authors.lastname: Niessen
authors.affiliation: Center for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20122 Milan, Italy costanza.giampietro@unimi.it elisabetta.dejana@ifom.eu giorgio.scita@ifom.eu.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy Dipartimento di Bioscienze, Università degli Studi di Milano, 20122 Milan, Italy Department of Immunology, Genetics and Pathology, Uppsala University, 751 05 Uppsala, Sweden costanza.giampietro@unimi.it elisabetta.dejana@ifom.eu giorgio.scita@ifom.eu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins; D000099152:Cadherin 5
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; D000099152:Cadherin 5; C083430:Eps8 protein, mouse; C486223:Yap1 protein, mouse