Role of glutamine synthetase in angiogenesis beyond glutamine synthesis

Guy Eelen (), Charlotte Dubois, Anna Rita Cantelmo, Jermaine Goveia, Ulrike Brüning, Michael DeRan, Gopala Jarugumilli, Jos Rijssel, Giorgio Saladino, Federico Comitani, Annalisa Zecchin, Susana Rocha, Rongyuan Chen, Hongling Huang, Saar Vandekeere, Joanna Kalucka, Christian Lange, Francisco Morales-Rodriguez, Bert Cruys, Lucas Treps, Leanne Ramer, Stefan Vinckier, Katleen Brepoels, Sabine Wyns, Joris Souffreau, Luc Schoonjans, Wouter H. Lamers, Yi Wu, Jurgen Haustraete, Johan Hofkens, Sandra Liekens, Richard Cubbon, Bart Ghesquière, Mieke Dewerchin, Francesco L. Gervasio, Xuri Li (), Jaap D. Buul, Xu Wu and Peter Carmeliet ()
Additional contact information
Guy Eelen: Center for Cancer Biology, University of Leuven
Charlotte Dubois: Center for Cancer Biology, University of Leuven
Anna Rita Cantelmo: Center for Cancer Biology, University of Leuven
Jermaine Goveia: Center for Cancer Biology, University of Leuven
Ulrike Brüning: Center for Cancer Biology, University of Leuven
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
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
Saar Vandekeere: Center for Cancer Biology, University of Leuven
Joanna Kalucka: Center for Cancer Biology, University of Leuven
Christian Lange: Center for Cancer Biology, University of Leuven
Francisco Morales-Rodriguez: Center for Cancer Biology, University of Leuven
Bert Cruys: Center for Cancer Biology, University of Leuven
Lucas Treps: Center for Cancer Biology, University of Leuven
Leanne Ramer: Center for Cancer Biology, University of Leuven
Stefan Vinckier: Center for Cancer Biology, University of Leuven
Katleen Brepoels: Center for Cancer Biology, University of Leuven
Sabine Wyns: Center for Cancer Biology, University of Leuven
Joris Souffreau: Center for Cancer Biology, University of Leuven
Luc Schoonjans: Center for Cancer Biology, University of Leuven
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
Johan Hofkens: Molecular Imaging and Photonics, University of Leuven
Sandra Liekens: University of Leuven
Richard Cubbon: Center for Cancer Biology, University of Leuven
Bart Ghesquière: Center for Cancer Biology, VIB
Mieke Dewerchin: Center for Cancer Biology, University of Leuven
Francesco L. Gervasio: 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

Nature, 2018, vol. 561, issue 7721, 63-69

Abstract: 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.

Keywords: Glutamate-ammonia Ligase (GLUL); Glutamine Synthetase (GS); Rhosis; Human Umbilical Vein ECs (HUVECs); Bimolecular Fluorescence Complementation (BiFC) (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41586-018-0466-7

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