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Unraveling signaling networks by large-scale data integration
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Unraveling signaling networksby large-scale data integration
Lars Juhl Jensen
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the problem
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phosphoproteomics
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Linding, Jensen, Ostheimer et al., Cell, 2007
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in vivo phosphosites
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kinases are unknown
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peptide assays
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Miller, Jensen et al., Science Signaling, 2008
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machine-learning methods
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sequence motifs
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Miller, Jensen et al., Science Signaling, 2008
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kinase-specific
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sequence specificity
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no context
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what a kinase could do
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not what it actually does
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context
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co-activators
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scaffolders
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localization
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expression
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association networks
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Linding, Jensen, Ostheimer et al., Cell, 2007
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the good idea
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Linding, Jensen, Ostheimer et al., Cell, 2007
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a lot of work
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the sequence motifs
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NetPhorest
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Miller, Jensen et al., Science Signaling, 2008
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data organization
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Miller, Jensen et al., Science Signaling, 2008
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automated pipeline
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compilation of datasets
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redundancy reduction
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training and evaluation
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classifier selection
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motif atlas
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179 kinases
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93 SH2 domains
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8 PTB domains
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BRCT domains
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WW domains
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14-3-3 proteins
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phosphatases
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model organisms
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biological insights
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docking domains
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Miller, Jensen et al., Science Signaling, 2008
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disease-related kinases
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Miller, Jensen et al., Science Signaling, 2008
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the context network
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STRING
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Jensen, Kuhn et al., Nucleic Acids Research, 2009
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functional associations
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data integration
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primary experimental data
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protein interactions
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Jensen & Bork, Science, 2008
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gene coexpression
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genomic context methods
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gene fusion
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Korbel et al., Nature Biotechnology, 2004
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conserved neighborhood
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Korbel et al., Nature Biotechnology, 2004
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literature mining
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curated knowledge
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Letunic & Bork, Trends in Biochemical Sciences, 2008
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too easy …
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… to be true
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different formats
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different identifiers
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variable quality
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spread over 630 genomes
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parsers
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thesaurus
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raw quality scores
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benchmarking
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von Mering et al., Nucleic Acids Research, 2005
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transfer by orthology
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von Mering et al., Nucleic Acids Research, 2005
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combine all evidence
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visualize
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Frishman et al., Modern Genome Annotation, 2009
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the results
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NetworKIN
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benchmarking
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Linding, Jensen, Ostheimer et al., Cell, 2007
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DNA damage response
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Linding, Jensen, Ostheimer et al., Cell, 2007
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small-scale validation
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ATM phosphorylates Rad50
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Linding, Jensen, Ostheimer et al., Cell, 2007
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high-throughput validation
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multiple reaction monitoring
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Linding, Jensen, Ostheimer et al., Cell, 2007
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Acknowledgments
NetworKIN.info– Rune Linding– Gerard Ostheimer– Francesca Diella– Karen Colwill– Jing Jin– Pavel Metalnikov– Vivian Nguyen– Adrian Pasculescu– Jin Gyoon Park– Leona D. Samson– Rob Russell– Peer Bork– Michael Yaffe– Tony Pawson
NetPhorest.info– Martin Lee Miller– Francesca Diella– Claus Jørgensen– Michele Tinti– Lei Li– Marilyn Hsiung– Sirlester A. Parker– Jennifer Bordeaux– Thomas Sicheritz-Pontén– Marina Olhovsky– Adrian Pasculescu– Jes Alexander– Stefan Knapp– Nikolaj Blom– Peer Bork– Shawn Li– Gianni Cesareni– Tony Pawson– Benjamin E. Turk– Michael B. Yaffe– Søren Brunak
STRING.embl.de– Christian von Mering– Michael Kuhn– Manuel Stark– Samuel Chaffron– Philippe Julien– Tobias Doerks– Jan Korbel– Berend Snel– Martijn Huynen– Peer Bork
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