ProKinO: a unified resource for mining the cancer kinome.
Protein kinases represent a large and diverse family of evolutionarily related proteins that are abnormally regulated in human cancers. Although genome sequencing studies have revealed thousands of variants in protein kinases, translating "big" genomic data into biological knowledge remains a challenge. Here, we describe an ontological framework for integrating and conceptualizing diverse forms of information related to kinase activation and regulatory mechanisms in a machine readable, human understandable form. We demonstrate the utility of this framework in analyzing the cancer kinome, and in generating testable hypotheses for experimental studies. Through the iterative process of aggregate ontology querying, hypothesis generation and experimental validation, we identify a novel mutational hotspot in the αC-β4 loop of the kinase domain and demonstrate the functional impact of the identified variants in epidermal growth factor receptor (EGFR) constitutive activity and inhibitor sensitivity. We provide a unified resource for the kinase and cancer community, ProKinO, housed at http://vulcan.cs.uga.edu/prokino.
Institute of Bioinformatics, University of Georgia, Athens, Georgia.
Daniel Ian
DI
McSkimming
Shima
S
Dastgheib
Eric
E
Talevich
Anish
A
Narayanan
Samiksha
S
Katiyar
Susan S
SS
Taylor
Krys
K
Kochut
Natarajan
N
Kannan
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016466:CHO Cells; D020134:Catalytic Domain; D006224:Cricetinae; D003412:Cricetulus; D057225:Data Mining; D000077156:Gefitinib; D063990:Gene Ontology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051188:Knowledge Bases; D008958:Models, Molecular; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology; D016415:Sequence Alignment; D012984:Software
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011494:Protein Kinases; D000077156:Gefitinib
big data; cancer therapy; conformation; database; disease; drug discovery; kinase; mutation; personalized medicine; regulation; resistance