unraveling cellular phosphorylation networks using computational biology
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Unraveling cellular phosphorylation networks using computational biology
Lars Juhl Jensen
EMBL Heidelberg
the problem
Oda & Kitano, Molecular Systems Biology, 2006
a good start
long way to go
the toolbox
mass spectrometry
Linding, Jensen, Ostheimer et al., Cell, 2007
phosphorylation sites
in vivo
kinases are unknown
peptide assays
Miller, Jensen et al., Science Signaling, 2008
sequence specificity
kinase-specific
in vitro
no context
what a kinase could do
not what it actually does
computational methods
sequence specificity
Miller, Jensen et al., Science Signaling, 2008
kinase-specific
no context
what a kinase could do
not what it actually does
in vitro
in vivo
context
localization
expression
co-activators
scaffolders
association networks
Linding, Jensen, Ostheimer et al., Cell, 2007
the idea
mass spectrometry
phosphorylation sites
sequence motifs
sequence specificity
association network
context
in vitro
in vivo
Linding, Jensen, Ostheimer et al., Cell, 2007
the sequence motifs
NetPhorest
Miller, Jensen et al., Science Signaling, 2008
pipeline
data organization
Miller, Jensen et al., Science Signaling, 2008
compilation of datasets
Miller, Jensen et al., Science Signaling, 2008
redundancy reduction
Miller, Jensen et al., Science Signaling, 2008
cross-validation partitioning
Miller, Jensen et al., Science Signaling, 2008
training and evaluation
classifier selection
Miller, Jensen et al., Science Signaling, 2008
motif atlas
179 kinases
93 SH2 domains
8 PTB domains
BRCT domains
WW domains
14-3-3 proteins
benchmarking
Miller, Jensen et al., Science Signaling, 2008
low-specificity kinases
disease-related kinases
Miller, Jensen et al., Science Signaling, 2008
docking domains
Miller, Jensen et al., Science Signaling, 2008
the context network
STRING
functional associations
373 genomes
Jensen et al., Nucleic Acids Research, 2008
genomic context methods
gene fusion
Korbel et al., Nature Biotechnology, 2004
conserved neighborhood
Korbel et al., Nature Biotechnology, 2004
phylogenetic profiles
Korbel et al., Nature Biotechnology, 2004
primary experimental data
protein interactions
Jensen & Bork, Science, 2008
gene coexpression
literature mining
curated knowledge
Letunic & Bork, Trends in Biochemical Sciences, 2008
different formats
parsers
different gene identifiers
thesaurus
redundancy
bookkeeping
variable reliability
benchmarking
von Mering et al., Nucleic Acids Research, 2005
spread over many species
transfer by orthology
von Mering et al., Nucleic Acids Research, 2005
combine all evidence
Linding, Jensen, Ostheimer et al., Cell, 2007
the results
NetworKIN
123 kinases
5515 substrates
21,702 sites
benchmarking
Phospho.ELM
Linding, Jensen, Ostheimer et al., Cell, 2007
2.5-fold better accuracy
context is crucial
localization
Linding, Jensen, Ostheimer et al., Cell, 2007
ATM signaling
Linding, Jensen, Ostheimer et al., Cell, 2007
Linding, Jensen, Ostheimer et al., Cell, 2007
small-scale validation
ATM phosphorylates Rad50
Linding, Jensen, Ostheimer et al., Cell, 2007
Cdk1 phosphorylates 53BP1
Linding, Jensen, Ostheimer et al., Cell, 2007
high-throughput validation
multiple reaction monitoring
Linding, Jensen, Ostheimer et al., Cell, 2007
systematic validation
design optimal experiments
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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