An atlas of the human kinome reveals the mutational landscape underlying dysregulated phosphorylation cascades in cancer
| Autor: | Aleksandra Olow, Aleksandr Pankov, Laura J. van't Veer, Christina Yau, Zhongzhong Chen, Jean-Philippe Coppe, Denise M. Wolf, R. Hannes Niedner, Evelyn Lee, Lamorna Brown-Swigart |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Nonsynonymous substitution Cancer Research In silico Oncology and Carcinogenesis Computational biology Biology medicine.disease_cause Article 03 medical and health sciences Neoplasms Genetics medicine 2.1 Biological and endogenous factors Humans Kinome Protein phosphorylation Oncology & Carcinogenesis Aetiology Phosphorylation Cancer Kinase 3. Good health 030104 developmental biology Oncology Mutation Signal transduction Carcinogenesis Reprogramming Signal Transduction |
| Zdroj: | Cancer research, vol 76, iss 7 |
| Popis: | Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR. |
| Databáze: | OpenAIRE |
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