Unraveling signaling networksby large-scale data integration

Lars Juhl Jensen

the problem

phosphoproteomics

Linding, Jensen, Ostheimer et al., Cell, 2007

in vivo phosphosites

kinases are unknown

peptide assays

Miller, Jensen et al., Science Signaling, 2008

machine-learning methods

sequence motifs

Miller, Jensen et al., Science Signaling, 2008

kinase-specific

sequence specificity

no context

what a kinase could do

not what it actually does

context

co-activators

scaffolders

localization

expression

association networks

Linding, Jensen, Ostheimer et al., Cell, 2007

the good idea

Linding, Jensen, Ostheimer et al., Cell, 2007

a lot of work

the sequence motifs

NetPhorest

Miller, Jensen et al., Science Signaling, 2008

data organization

Miller, Jensen et al., Science Signaling, 2008

automated pipeline

compilation of datasets

redundancy reduction

training and evaluation

classifier selection

motif atlas

179 kinases

93 SH2 domains

8 PTB domains

BRCT domains

WW domains

14-3-3 proteins

phosphatases

model organisms

biological insights

docking domains

Miller, Jensen et al., Science Signaling, 2008

disease-related kinases

Miller, Jensen et al., Science Signaling, 2008

the context network

STRING

Jensen, Kuhn et al., Nucleic Acids Research, 2009

functional associations

data integration

primary experimental data

protein interactions

Jensen & Bork, Science, 2008

gene coexpression

genomic context methods

gene fusion

Korbel et al., Nature Biotechnology, 2004

conserved neighborhood

Korbel et al., Nature Biotechnology, 2004

literature mining

curated knowledge

Letunic & Bork, Trends in Biochemical Sciences, 2008

too easy …

… to be true

different formats

different identifiers

variable quality

spread over 630 genomes

parsers

thesaurus

raw quality scores

benchmarking

von Mering et al., Nucleic Acids Research, 2005

transfer by orthology

von Mering et al., Nucleic Acids Research, 2005

combine all evidence

visualize

Frishman et al., Modern Genome Annotation, 2009

the results

NetworKIN

benchmarking

Linding, Jensen, Ostheimer et al., Cell, 2007

DNA damage response

Linding, Jensen, Ostheimer et al., Cell, 2007

small-scale validation

ATM phosphorylates Rad50

Linding, Jensen, Ostheimer et al., Cell, 2007

high-throughput validation

multiple reaction monitoring

Linding, Jensen, Ostheimer et al., Cell, 2007

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