title: KinasePA: Phosphoproteomics data annotation using hypothesis driven kinase perturbation analysis.
abstract: Mass spectrometry (MS)-based quantitative phosphoproteomics has become a key approach for proteome-wide profiling of phosphorylation in tissues and cells. Traditional experimental design often compares a single treatment with a control, whereas increasingly more experiments are designed to compare multiple treatments with respect to a control. To this end, the development of bioinformatic tools that can integrate multiple treatments and visualise kinases and substrates under combinatorial perturbations is vital for dissecting concordant and/or independent effects of each treatment. Here, we propose a hypothesis driven kinase perturbation analysis (KinasePA) to annotate and visualise kinases and their substrates that are perturbed by various combinatorial effects of treatments in phosphoproteomics experiments. We demonstrate the utility of KinasePA through its application to two large-scale phosphoproteomics datasets and show its effectiveness in dissecting kinases and substrates within signalling pathways driven by unique combinations of cellular stimuli and inhibitors. We implemented and incorporated KinasePA as part of the "directPA" R package available from the comprehensive R archive network (CRAN). Furthermore, KinasePA also has an interactive web interface that can be readily applied to annotate user provided phosphoproteomics data (http://kinasepa.pengyiyang.org).
authors.affiliation: School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.|Charles Perkins Centre, School of Molecular Biosciences, University of Sydney, Sydney, NSW, Australia.|Systems Biology Section, Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental, Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Pengyi
authors.initials: P
authors.lastname: Yang
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Broad Institute, Boston, MA, USA.
authors.forename: Ellis
authors.initials: E
authors.lastname: Patrick
authors.affiliation: Charles Perkins Centre, School of Molecular Biosciences, University of Sydney, Sydney, NSW, Australia.|Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Humphrey
authors.affiliation: School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.
authors.forename: Shila
authors.initials: S
authors.lastname: Ghazanfar
authors.affiliation: Charles Perkins Centre, School of Molecular Biosciences, University of Sydney, Sydney, NSW, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Systems Biology Section, Epigenetics & Stem Cell Biology Laboratory, National Institute of Environmental, Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Jothi
authors.affiliation: School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.
authors.forename: Jean Yee Hwa
authors.initials: JY
authors.lastname: Yang
mesh_terms: D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D030562:Databases, Protein; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D002867:Chromones; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; C548887:MK 2206; D009025:Morpholines; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Bioinformatics; Hypothesis testing; Kinase; Perturbation; Phosphoproteomics; Signalling