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Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data

Endothelins (EDN) are peptide hormones that activate a GPCR signalling system and contribute to several diseases, including hypertension and cancer. Current knowledge about EDN signalling is fragmentary, and no systems level understanding is available. We investigated phosphoproteomic changes caused...

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Bibliographic Details
Main Authors: Schäfer, Alexander (Author) , Sáez Rodríguez, Julio (Author)
Format: Article (Journal)
Language:English
Published: 6 August 2019
In: Molecular systems biology
Year: 2019, Volume: 15, Issue: 8
ISSN:1744-4292
DOI:10.15252/msb.20198828
Online Access:Verlag, Volltext: https://doi.org/10.15252/msb.20198828
Verlag: https://www.embopress.org/doi/full/10.15252/msb.20198828
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Author Notes:Alexander Schäfer, Enio Gjerga, Richard WD Welford, Imke Renz, Francois Lehembre, Peter MA Groenen, Julio Saez-Rodriguez, Ruedi Aebersold, Matthias Gstaiger

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520 |a Endothelins (EDN) are peptide hormones that activate a GPCR signalling system and contribute to several diseases, including hypertension and cancer. Current knowledge about EDN signalling is fragmentary, and no systems level understanding is available. We investigated phosphoproteomic changes caused by endothelin B receptor (ENDRB) activation in the melanoma cell lines UACC257 and A2058 and built an integrated model of EDNRB signalling from the phosphoproteomics data. More than 5,000 unique phosphopeptides were quantified. EDN induced quantitative changes in more than 800 phosphopeptides, which were all strictly dependent on EDNRB. Activated kinases were identified based on high confidence EDN target sites and validated by Western blot. The data were combined with prior knowledge to construct the first comprehensive logic model of EDN signalling. Among the kinases predicted by the signalling model, AKT, JNK, PKC and AMP could be functionally linked to EDN-induced cell migration. The model contributes to the system-level understanding of the mechanisms underlying the pleiotropic effects of EDN signalling and supports the rational selection of kinase inhibitors for combination treatments with EDN receptor antagonists. 
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