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

Liang-Chin Huang, Karen E. Ross, Timothy R. Baffi, Harold Drabkin, Krzysztof J. Kochut, Zheng Ruan, Peter D'Eustachio, Daniel McSkimming, Cecilia Arighi, Chuming Chen, Darren A. Natale, Cynthia Smith (+4 others)
2018 Scientific Reports  
Natarajan, "Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources." (2018). Faculty Research 2018. 96. https://mouseion.jax.org/stfb2018/96 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
more » ... dy, 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. Phosphorylation of serine, threonine and tyrosine residues by protein kinases is a major post-translational modification (PTM) that controls diverse regulatory and signalling mechanisms in cells. Aberrant phosphorylation is emerging as a common pathologic mechanism, and protein kinases are significantly overrepresented among mutant proteins in cancers 1 . It is even thought that in most tumours, at least one protein kinase or phosphatase gene is affected by mutation, copy number variation, or genetic rearrangements 2 . There is high interest in protein Published: xx xx xxxx OPEN www.nature.com/scientificreports/
doi:10.1038/s41598-018-24457-1 pmid:29695735 pmcid:PMC5916945 fatcat:bxzho6wisfckfhrza5vaabisya