Format

Send to

Choose Destination
Nat Commun. 2015 Jul 31;6:7935. doi: 10.1038/ncomms8935.

PTEN mediates Notch-dependent stalk cell arrest in angiogenesis.

Author information

1
Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de l'Hospitalet 199-203, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
2
CIC-bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
3
Vascular Biology Laboratory, London Research Institute-Cancer Research UK, London WC2A 3LY, UK.
4
Max Planck Institute for Heart and Lung Research, D61231 Bad Nauheim, Germany.
5
Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
6
UCL Institute of Ophthalmology, University Collage of London, London EC1V9EL, UK.
7
Centre d'Oncologia Molecular, IDIBELL, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona.
8
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.
9
Translation Research Laboratory, Catalan Institute of Oncology, IDIBELL, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
10
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
11
Program in Cancer Research, Hospital del Mar Medical Research Institute (IMIM), Barcelona Biomedical Research Park, 08003 Barcelona, Spain.
12
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.
13
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.

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.

PMID:
26228240
PMCID:
PMC5426521
DOI:
10.1038/ncomms8935
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center