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PTEN mediates Notch-dependent stalk cell arrest in angiogenesis

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  • 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
    Departament de Ciències Fisiològiques II, Universitat de Barcelona)

  • 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
    IKERBASQUE, Basque Foundation of Science
    University of the Basque Country (UPV/EHU))

  • Holger Gerhardt

    (Vascular Biology Laboratory, London Research Institute-Cancer Research UK
    Max-Delbrueck Center for Molecular Medicine (MDC))

  • 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)

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.

Suggested Citation

  • Helena Serra & Iñigo Chivite & Ana Angulo-Urarte & Adriana Soler & James D. Sutherland & Amaia Arruabarrena-Aristorena & Anan Ragab & Radiance Lim & Marcos Malumbres & Marcus Fruttiger & Michael Poten, 2015. "PTEN mediates Notch-dependent stalk cell arrest in angiogenesis," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8935
    DOI: 10.1038/ncomms8935
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