Unraveling signal transduction networks through data integration

Lars Juhl Jensen

the problem

phosphoproteomics

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

in vivo phosphosites

kinases are unknown

functions are unknown

sequence specificity

peptide assays

Miller, Jensen et al., Science Signaling, 2008

domain-specific

in vitro

no context

what could happen

not what does happen

machine-learning methods

sequence motifs

Miller, Jensen et al., Science Signaling, 2008

domain-specific

group-specific

no context

what could happen

not what does happen

in vitro

in vivo

context

co-activators

protein scaffolds

subcellular localization

spatial expression

temporal expression

association networks

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

the idea

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

the sequence motifs

NetPhorest

automated pipeline

Miller, Jensen et al., Science Signaling, 2008

data organization

Miller, Jensen et al., Science Signaling, 2008

compilation of datasets

redundancy reduction

training and evaluation

classifier selection

motif atlas

179 kinases

89 SH2 domains

8 PTB domains

BRCT domains

WW domains

14-3-3 proteins

use cases

Miller, Jensen et al., Science Signaling, 2008

the context network

guilt by association

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

Korbel et al., Nature Biotechnology, 2004

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

context network

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

the results

NetworKIN

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

benchmarking

Phospho.ELM

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

context is crucial

much context still missing

subcellular localization

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

ATM signaling

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

the future

new scoring scheme

two separate scores

one combined score

path length penalty

model organisms

S. cerevisiae

D. melanogaster

C. elegans

(S. pombe)

other modifications

phosphatases

ubiquitylation

acetylation

glycosylation

AcknowledgmentsNetPhorest.info

– Rune Linding– 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-DB.org– Christian von Mering– Michael Kuhn– Manuel Stark– Samuel Chaffron– Chris Creevey– Jean Muller– Tobias Doerks– Philippe Julien– Alexander Roth– Milan Simonovic– Jan Korbel– Berend Snel– Martijn Huynen– Peer Bork

NetworKIN.info– Rune Linding– Gerard Ostheimer– Heiko Horn– Martin Lee Miller– Francesca Diella– Karen Colwill– Jing Jin– Pavel Metalnikov– Vivian Nguyen– Adrian Pasculescu– Jin Gyoon Park– Leona D. Samson– Rob Russell– Peer Bork– Michael B. Yaffe– Tony Pawson

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