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Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.

Authors :
Huang LC
Ross KE
Baffi TR
Drabkin H
Kochut KJ
Ruan Z
D'Eustachio P
McSkimming D
Arighi C
Chen C
Natale DA
Smith C
Gaudet P
Newton AC
Wu C
Kannan N
Source :
Scientific reports [Sci Rep] 2018 Apr 25; Vol. 8 (1), pp. 6518. Date of Electronic Publication: 2018 Apr 25.
Publication Year :
2018

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 PKCĪ²II (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.

Details

Language :
English
ISSN :
2045-2322
Volume :
8
Issue :
1
Database :
MEDLINE
Journal :
Scientific reports
Publication Type :
Academic Journal
Accession number :
29695735
Full Text :
https://doi.org/10.1038/s41598-018-24457-1