title: An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Olow
authors.affiliation: The State Key Laboratory of Genetic Engineering, Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Zhongzhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: R Hannes
authors.initials: RH
authors.lastname: Niedner
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wolf
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Pankov
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Evelyn Pei Rong
authors.initials: EP
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Lamorna
authors.initials: L
authors.lastname: Brown-Swigart
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van 't Veer
authors.affiliation: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, California. Jean-Philippe.Coppe@ucsf.edu.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Coppé
mesh_terms: D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D010766:Phosphorylation; D015398:Signal Transduction