Magnitude of Ubiquitination Determines the Fate of Epidermal Growth Factor Receptor Upon Ligand Stimulation

Vyacheslav Akimov, Mirjam Fehling-Kaschek, Inigo Barrio-Hernandez, Michele Puglia, Jakob Bunkenborg, Mogens M. Nielsen, Jens Timmer, Jörn Dengjel*, Blagoy Blagoev

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Abstrakt

Receptor tyrosine kinases (RTK) bind growth factors and are critical for cell proliferation and differentiation. Their dysregulation leads to a loss of growth control, often resulting in cancer. Epidermal growth factor receptor (EGFR) is the prototypic RTK and can bind several ligands exhibiting distinct mitogenic potentials. Whereas the phosphorylation on individual EGFR sites and their roles for downstream signaling have been extensively studied, less is known about ligand-specific ubiquitination events on EGFR, which are crucial for signal attenuation and termination. We used a proteomics-based workflow for absolute quantitation combined with mathematical modeling to unveil potentially decisive ubiquitination events on EGFR from the first 30 seconds to 15 minutes of stimulation. Four ligands were used for stimulation: epidermal growth factor (EGF), heparin-binding-EGF like growth factor, transforming growth factor-α and epiregulin. Whereas only little differences in the order of individual ubiquitination sites were observed, the overall amount of modified receptor differed depending on the used ligand, indicating that absolute magnitude of EGFR ubiquitination, and not distinctly regulated ubiquitination sites, is a major determinant for signal attenuation and the subsequent cellular outcomes.

OriginalsprogEngelsk
Artikelnummer167240
TidsskriftJournal of Molecular Biology
Vol/bind433
Udgave nummer21
Antal sider13
ISSN0022-2836
DOI
StatusUdgivet - 15. okt. 2021

Bibliografisk note

Funding Information:
This work was supported by the canton of Fribourg, the Swiss National Science Foundation, and the Novartis Foundation for Medical-biological Research (all to JD), the Lundbeck Foundation, the Danish National Research Foundation (DNRF grant No. 141 to ATLAS), the Danish Council for Technology and Production Sciences (DFF – 8022-00051) and the Novo Nordisk Foundation (NNF18OC0052768) (all to BB). The work was also supported in part by the Villum Foundation through the Villum Center for Bioanalytical Sciences. We would like to thank the PRO-MS Danish National Mass Spectrometry Platform for Functional Proteomics for instrument support and assistance. This work was further supported by the Ministry of Science, Research and the Arts Baden-Wuerttemberg within the Brigitte-Schlieben-Lange program and by the Joachim Herz Stiftung (all to MFK).

Funding Information:
This work was supported by the canton of Fribourg, the Swiss National Science Foundation, and the Novartis Foundation for Medical-biological Research (all to JD), the Lundbeck Foundation, the Danish National Research Foundation (DNRF grant No. 141 to ATLAS), the Danish Council for Technology and Production Sciences (DFF ? 8022-00051) and the Novo Nordisk Foundation (NNF18OC0052768) (all to BB). The work was also supported in part by the Villum Foundation through the Villum Center for Bioanalytical Sciences. We would like to thank the PRO-MS Danish National Mass Spectrometry Platform for Functional Proteomics for instrument support and assistance. This work was further supported by the Ministry of Science, Research and the Arts Baden-Wuerttemberg within the Brigitte-Schlieben-Lange program and by the Joachim Herz Stiftung (all to MFK). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Publisher Copyright:
© 2021 The Author(s)

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