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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\u2010induced cell migration. The model contributes to the system\u2010level 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.<\/jats:p>","DOI":"10.15252\/msb.20198828","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T09:44:01Z","timestamp":1565084641000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9988-1957","authenticated-orcid":false,"given":"Alexander","family":"Sch\u00e4fer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-0395","authenticated-orcid":false,"given":"Enio","family":"Gjerga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard WD","family":"Welford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Renz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Lehembre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter MA","family":"Groenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8552-8976","authenticated-orcid":false,"given":"Julio","family":"Saez\u2010Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9576-3267","authenticated-orcid":false,"given":"Ruedi","family":"Aebersold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Gstaiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,6]]},"reference":[{"key":"BFMSB198828_CR1","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1158\/1078-0432.CCR-10-2340","volume":"17","author":"J Asundi","year":"2011","unstructured":"Asundi J, Reed C, Arca J, McCutcheon K, Ferrando R, Clark S, Luis E, Tien J, Firestein R, Polakis P (2011) An antibody\u2010drug conjugate targeting the endothelin B receptor for the treatment of melanoma. 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