Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites
| Autor: | Marie Kveiborg, Blanca Lopez Mendez, Kristina B. Emdal, Chiara Francavilla, Jan C. Refsgaard, Jesper V. Olsen, Svetlana Rajkumar Maurya, Anna Secher, Giulia Franciosa, Alicia Lundby, Lars Juhl Jensen, Indranil Paul, Sebastian Gnosa, Christian D. Kelstrup, Dorte B. Bekker-Jensen, Guillermo Montoya |
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| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Lung Neoplasms Carcinogenesis General Biochemistry Genetics and Molecular Biology Mass Spectrometry Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans Tyrosine Phosphorylation Phosphotyrosine Zebrafish 030304 developmental biology 0303 health sciences biology Phosphopeptide Phosphoproteomics Tyrosine phosphorylation biology.organism_classification Phosphoproteins Cell biology Rats ErbB Receptors chemistry A549 Cells Mutation Signal transduction 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | Lundby, A, Franciosa, G, Emdal, K B, Refsgaard, J C, Gnosa, S P, Bekker-Jensen, D B, Secher, A, Maurya, S R, Paul, I, Mendez, B L, Kelstrup, C D, Francavilla, C, Kveiborg, M, Montoya, G, Jensen, L J & Olsen, J V 2019, ' Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites ', Cell, vol. 179, no. 2, pp. 543-560 . https://doi.org/10.1016/j.cell.2019.09.008 Lundby, A, Franciosa, G, Emdal, K B, Refsgaard, J C, Gnosa, S P, Bekker-jensen, D B, Secher, A, Maurya, S R, Paul, I, Mendez, B L, Kelstrup, C D, Francavilla, C, Kveiborg, M, Montoya, G, Jensen, L J & Olsen, J V 2019, ' Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites ', Cell, vol. 179, no. 2, pp. 543-560.e26 . https://doi.org/10.1016/j.cell.2019.09.008 Cell |
| ISSN: | 1097-4172 |
| DOI: | 10.1016/j.cell.2019.09.008 |
| Popis: | Tyrosine phosphorylation regulates multi-layered signaling networks with broad implications in (patho)physiology, but high-throughput methods for functional annotation of phosphotyrosine sites are lacking. To decipher phosphotyrosine signaling directly in tissue samples, we developed a mass-spectrometry-based interaction proteomics approach. We measured the in vivo EGF-dependent signaling network in lung tissue quantifying >1,000 phosphotyrosine sites. To assign function to all EGF-regulated sites, we determined their recruited protein signaling complexes in lung tissue by interaction proteomics. We demonstrated how mutations near tyrosine residues introduce molecular switches that rewire cancer signaling networks, and we revealed oncogenic properties of such a lung cancer EGFR mutant. To demonstrate the scalability of the approach, we performed >1,000 phosphopeptide pulldowns and analyzed them by rapid mass spectrometric analysis, revealing tissue-specific differences in interactors. Our approach is a general strategy for functional annotation of phosphorylation sites in tissues, enabling in-depth mechanistic insights into oncogenic rewiring of signaling networks. |
| Databáze: | OpenAIRE |
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