Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data
Abstract 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 chang...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2019-08-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.20198828 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331540248494080 |
|---|---|
| author | Alexander Schäfer Enio Gjerga Richard WD Welford Imke Renz Francois Lehembre Peter MA Groenen Julio Saez‐Rodriguez Ruedi Aebersold Matthias Gstaiger |
| author_facet | Alexander Schäfer Enio Gjerga Richard WD Welford Imke Renz Francois Lehembre Peter MA Groenen Julio Saez‐Rodriguez Ruedi Aebersold Matthias Gstaiger |
| author_sort | Alexander Schäfer |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-59484df57a2745ddbf58fd5ea6952e69 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2019-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-59484df57a2745ddbf58fd5ea6952e692025-08-20T03:46:32ZengSpringer NatureMolecular Systems Biology1744-42922019-08-0115811910.15252/msb.20198828Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics dataAlexander Schäfer0Enio Gjerga1Richard WD Welford2Imke Renz3Francois Lehembre4Peter MA Groenen5Julio Saez‐Rodriguez6Ruedi Aebersold7Matthias Gstaiger8Department of Biology, Institute of Molecular Systems Biology, ETH ZurichFaculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC‐COMBINE), RWTH Aachen UniversityIdorsia PharmaceuticalsIdorsia PharmaceuticalsIdorsia PharmaceuticalsIdorsia PharmaceuticalsFaculty of Medicine, Joint Research Centre for Computational Biomedicine (JRC‐COMBINE), RWTH Aachen UniversityDepartment of Biology, Institute of Molecular Systems Biology, ETH ZurichDepartment of Biology, Institute of Molecular Systems Biology, ETH ZurichAbstract 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.https://doi.org/10.15252/msb.20198828endothelinGPCRmelanomamolecular modellingphosphoproteomics |
| spellingShingle | Alexander Schäfer Enio Gjerga Richard WD Welford Imke Renz Francois Lehembre Peter MA Groenen Julio Saez‐Rodriguez Ruedi Aebersold Matthias Gstaiger Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data Molecular Systems Biology endothelin GPCR melanoma molecular modelling phosphoproteomics |
| title | Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| title_full | Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| title_fullStr | Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| title_full_unstemmed | Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| title_short | Elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| title_sort | elucidating essential kinases of endothelin signalling by logic modelling of phosphoproteomics data |
| topic | endothelin GPCR melanoma molecular modelling phosphoproteomics |
| url | https://doi.org/10.15252/msb.20198828 |
| work_keys_str_mv | AT alexanderschafer elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT eniogjerga elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT richardwdwelford elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT imkerenz elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT francoislehembre elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT petermagroenen elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT juliosaezrodriguez elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT ruediaebersold elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata AT matthiasgstaiger elucidatingessentialkinasesofendothelinsignallingbylogicmodellingofphosphoproteomicsdata |