Fbxw7 controls angiogenesis by regulating endothelial notch activity

Izumi N, Helker C, Ehling M, Behrens A, Herzog W, Adams RH (2012)

Publication Type: Journal article

Publication year: 2012

Journal

PLoS ONE Public Library of Science

Book Volume: 7

Article Number: e41116

Journal Issue: 7

DOI: 10.1371/journal.pone.0041116

Abstract

Notch signaling controls fundamental aspects of angiogenic blood vessel growth including the selection of sprouting tip cells, endothelial proliferation and arterial differentiation. The E3 ubiquitin ligase Fbxw7 is part of the SCF protein complex responsible for the polyubiquitination and thereby proteasomal degradation of substrates such as Notch, c-Myc and c-Jun. Here, we show that Fbxw7 is a critical regulator of angiogenesis in the mouse retina and the zebrafish embryonic trunk, which we attribute to its role in the degradation of active Notch. Growth of retinal blood vessel was impaired and the Notch ligand Dll4, which is also a Notch target, upregulated in inducible and endothelial cell-specific Fbxw7^iECKO mutant mice. The stability of the cleaved and active Notch intracellular domain was increased after siRNA knockdown of the E3 ligase in cultured human endothelial cells. Injection of fbxw7 morpholinos interfered with the sprouting of zebrafish intersegmental vessels (ISVs). Arguing strongly that Notch and not other Fbxw7 substrates are primarily responsible for these phenotypes, the genetic inactivation of Notch pathway components reversed the impaired ISV growth in the zebrafish embryo as well as sprouting and proliferation in the mouse retina. Our findings establish that Fbxw7 is a potent positive regulator of angiogenesis that limits the activity of Notch in the endothelium of the growing vasculature. © 2012 Izumi et al.

Authors with CRIS profile

Wiebke Herzog

Involved external institutions

Max-Planck-Institut für molekulare Biomedizin / Max Planck Institute for Molecular Biomedicine

Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster

Germany (DE) Cancer Research UK

United Kingdom (GB)

How to cite

APA:

Izumi, N., Helker, C., Ehling, M., Behrens, A., Herzog, W., & Adams, R.H. (2012). Fbxw7 controls angiogenesis by regulating endothelial notch activity. PLoS ONE, 7(7). https://doi.org/10.1371/journal.pone.0041116

MLA:

Izumi, Nanae, et al. "Fbxw7 controls angiogenesis by regulating endothelial notch activity." PLoS ONE 7.7 (2012).

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