PTEN mediates Notch-dependent stalk cell arrest in angiogenesis

Helena Serra, Iñigo Chivite, Ana Angulo-Urarte, Adriana Soler, James D. Sutherland, Amaia Arruabarrena-Aristorena, Anan Ragab, Radiance Lim, Marcos Malumbres, Marcus Fruttiger, Michael Potente, Manuel Serrano, Àngels Fabra, Francesc Viñals, Oriol Casanovas, Pier Paolo Pandolfi, Anna Bigas, Arkaitz Carracedo, Holger Gerhardt and Mariona Graupera ()
Additional contact information
Helena Serra: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Iñigo Chivite: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Ana Angulo-Urarte: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Adriana Soler: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
James D. Sutherland: CIC-bioGUNE, Technology Park of Bizkaia
Amaia Arruabarrena-Aristorena: CIC-bioGUNE, Technology Park of Bizkaia
Anan Ragab: Vascular Biology Laboratory, London Research Institute-Cancer Research UK
Radiance Lim: Max Planck Institute for Heart and Lung Research
Marcos Malumbres: Spanish National Cancer Research Center (CNIO)
Marcus Fruttiger: UCL Institute of Ophthalmology, University Collage of London
Michael Potente: Max Planck Institute for Heart and Lung Research
Manuel Serrano: Spanish National Cancer Research Center (CNIO)
Àngels Fabra: Centre d’Oncologia Molecular, IDIBELL, Universitat de Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona,
Francesc Viñals: Translation Research Laboratory, Catalan Institute of Oncology, IDIBELL, Universitat de Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
Oriol Casanovas: Translation Research Laboratory, Catalan Institute of Oncology, IDIBELL, Universitat de Barcelona, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
Pier Paolo Pandolfi: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School
Anna Bigas: Program in Cancer Research, Hospital del Mar Medical Research Institute (IMIM)
Arkaitz Carracedo: CIC-bioGUNE, Technology Park of Bizkaia
Holger Gerhardt: Vascular Biology Laboratory, London Research Institute-Cancer Research UK
Mariona Graupera: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8935

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