title: PTEN mediates Notch-dependent stalk cell arrest in angiogenesis.
abstract: Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch-PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Serra
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Chivite
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo-Urarte
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Soler
authors.affiliation: CIC-bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: James D
authors.initials: JD
authors.lastname: Sutherland
authors.affiliation: CIC-bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Arruabarrena-Aristorena
authors.affiliation: Vascular Biology Laboratory, London Research Institute-Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Anan
authors.initials: A
authors.lastname: Ragab
authors.affiliation: Max Planck Institute for Heart and Lung Research, D61231 Bad Nauheim, Germany.
authors.forename: Radiance
authors.initials: R
authors.lastname: Lim
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Marcos
authors.identifier: 0000000208296315
authors.initials: M
authors.lastname: Malumbres
authors.affiliation: UCL Institute of Ophthalmology, University Collage of London, London EC1V9EL, UK.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fruttiger
authors.affiliation: Max Planck Institute for Heart and Lung Research, D61231 Bad Nauheim, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Potente
authors.affiliation: Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Centre d'Oncologia Molecular, IDIBELL, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona.
authors.forename: Àngels
authors.initials: À
authors.lastname: Fabra
authors.affiliation: 1] Translation Research Laboratory, Catalan Institute of Oncology, IDIBELL, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain [2] Departament de Ciències Fisiològiques II, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Viñals
authors.affiliation: Translation Research Laboratory, Catalan Institute of Oncology, IDIBELL, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Casanovas
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Program in Cancer Research, Hospital del Mar Medical Research Institute (IMIM), Barcelona Biomedical Research Park, 08003 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: 1] CIC-bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain [2] IKERBASQUE, Basque Foundation of Science, 48011 Bilbao, Bizkaia, Spain [3] Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao 48940, Spain.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: 1] Vascular Biology Laboratory, London Research Institute-Cancer Research UK, London WC2A 3LY, UK [2] Max-Delbrueck Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, Berlin 13125, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D064200:Cdh1 Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D012333:RNA, Messenger; D051880:Receptors, Notch; D064173:Anaphase-Promoting Complex-Cyclosome; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse