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Role of glutamine synthetase in angiogenesis beyond glutamine synthesis

Author

Listed:
  • Guy Eelen

    (Center for Cancer Biology, University of Leuven
    Zhongshan Ophthalmic Center, Sun Yat-Sen University
    Center for Cancer Biology, VIB)

  • Charlotte Dubois

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Anna Rita Cantelmo

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    Université de Lille, INSERM U1003, Physiologie Cellulaire)

  • Jermaine Goveia

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Ulrike Brüning

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    Max-Delbrück-Center for Molecular Medicine)

  • Michael DeRan

    (Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School)

  • Gopala Jarugumilli

    (Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School)

  • Jos Rijssel

    (Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam)

  • Giorgio Saladino

    (University College London)

  • Federico Comitani

    (University College London)

  • Annalisa Zecchin

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Susana Rocha

    (Molecular Imaging and Photonics, University of Leuven)

  • Rongyuan Chen

    (Zhongshan Ophthalmic Center, Sun Yat-Sen University)

  • Hongling Huang

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    St. Jude Children’s Research Hospital)

  • Saar Vandekeere

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Joanna Kalucka

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Christian Lange

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    DFG-Research Center for Regenerative Therapies, Technical University Dresden)

  • Francisco Morales-Rodriguez

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Bert Cruys

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Lucas Treps

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Leanne Ramer

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    Simon Fraser University)

  • Stefan Vinckier

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Katleen Brepoels

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Sabine Wyns

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Joris Souffreau

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Luc Schoonjans

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Wouter H. Lamers

    (Tytgat Institute for Liver and Gastrointestinal Research, Academic Medical Center, University of Amsterdam)

  • Yi Wu

    (Center for Cell Analyses and Modelling, University of Connecticut Health Centre)

  • Jurgen Haustraete

    (Inflammation Research Center, VIB
    Ghent University)

  • Johan Hofkens

    (Molecular Imaging and Photonics, University of Leuven)

  • Sandra Liekens

    (University of Leuven)

  • Richard Cubbon

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB
    Multidisciplinary Cardiovascular Research Centre, University of Leeds)

  • Bart Ghesquière

    (Center for Cancer Biology, VIB)

  • Mieke Dewerchin

    (Center for Cancer Biology, University of Leuven
    Center for Cancer Biology, VIB)

  • Francesco L. Gervasio

    (University College London
    Institute of Structural Molecular Biology, University College London)

  • Xuri Li

    (Zhongshan Ophthalmic Center, Sun Yat-Sen University)

  • Jaap D. Buul

    (Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam)

  • Xu Wu

    (Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School)

  • Peter Carmeliet

    (Center for Cancer Biology, University of Leuven
    Zhongshan Ophthalmic Center, Sun Yat-Sen University
    Center for Cancer Biology, VIB)

Abstract

Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation.

Suggested Citation

  • Guy Eelen & Charlotte Dubois & Anna Rita Cantelmo & Jermaine Goveia & Ulrike Brüning & Michael DeRan & Gopala Jarugumilli & Jos Rijssel & Giorgio Saladino & Federico Comitani & Annalisa Zecchin & Susa, 2018. "Role of glutamine synthetase in angiogenesis beyond glutamine synthesis," Nature, Nature, vol. 561(7721), pages 63-69, September.
  • Handle: RePEc:nat:nature:v:561:y:2018:i:7721:d:10.1038_s41586-018-0466-7
    DOI: 10.1038/s41586-018-0466-7
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    Citations

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    Cited by:

    1. Nieves Montenegro-Navarro & Claudia García-Báez & Melissa García-Caballero, 2023. "Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jing Wang & Xinyang Zhao & Yucheng Tao & Xiuxiu Wang & Li Yan & Kuang Yu & Yi Hsu & Yuncong Chen & Jing Zhao & Yong Huang & Wei Wei, 2024. "Biocompatible aggregation-induced emission active polyphosphate-manganese nanosheets with glutamine synthetase-like activity in excitotoxic nerve cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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