Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data.
Mol Syst Biol
; 15(8): e8828, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31464372
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
/
Transdução de Sinais
/
Regulação Neoplásica da Expressão Gênica
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Processamento de Proteína Pós-Traducional
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Endotelinas
/
Melanócitos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Mol Syst Biol
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOTECNOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Suíça
País de publicação:
Reino Unido