Document Type
Article
Publication Date
4-25-2018
JAX Source
Sci Rep 2018 Apr 25; 8(1):6518.
Volume
8
Issue
1
First Page
6518
Last Page
6518
ISSN
2045-2322
PMID
29695735
DOI
https://doi.org/10.1038/s41598-018-24457-1
Grant
GM120953, GM080646
Abstract
Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the 'hydrophobic motif' of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes. Sci Rep 2018 Apr 25; 8(1):6518.
Recommended Citation
Huang L,
Ross K,
Baffi T,
Drabkin HJ,
Kochut K,
Ruan Z,
D'Eustachio P,
McSkimming D,
Arighi C,
Chen C,
Natale D,
Smith C,
Gaudet P,
Newton A,
Wu C,
Kannan N.
Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources. Sci Rep 2018 Apr 25; 8(1):6518.
Comments
This open access article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)