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Systematic discovery of phosphorylation networks Combining linear motifs and protein interactions Lars Juhl Jensen EMBL Heidelberg

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Munich, Germany, November 7, 2007

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Page 1: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Systematic discovery ofphosphorylation networks

Combining linear motifs and protein interactions

Lars Juhl Jensen

EMBL Heidelberg

Page 2: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Lars Juhl Jensen

Page 3: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 4: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 5: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

promoter analysis

Page 6: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 7: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

genome visualization

Page 8: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 9: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

protein function prediction

Page 10: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 11: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 12: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 13: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

data integration

Page 14: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 15: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

dynamic interactions

Page 16: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 17: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

prediction of interactions

Page 18: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

http://string.embl.de

Page 19: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

prediction of interactions

Page 20: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

http://networkin.info

Page 21: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

the starting point

Page 22: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

phosphoproteomics

Page 23: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

mass spectrometry

Page 24: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 25: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

phosphorylation sites

Page 26: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vivo

Page 27: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

kinases are unknown

Page 28: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

HTP kinase assays

Page 29: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vitro

Page 30: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

no context

Page 31: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

what a kinase could do

Page 32: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

not what it actually does

Page 33: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

computational methods

Page 34: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

sequence motifs

Page 35: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 36: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

kinase families

Page 37: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

phosphorylation sites

Page 38: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

overprediction

Page 39: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

no context

Page 40: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

what a kinase could do

Page 41: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

not what it actually does

Page 42: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vitro

Page 43: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vivo

Page 44: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

context

Page 45: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

localization

Page 46: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

expression

Page 47: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

co-activators

Page 48: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

scaffolders

Page 49: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

protein networks

Page 50: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 51: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

the idea

Page 52: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

mass spectrometry

Page 53: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 54: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

phosphorylation sites

Page 55: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

sequence motifs

Page 56: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 57: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

kinase families

Page 58: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

protein networks

Page 59: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 60: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

context

Page 61: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vitro

Page 62: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vivo

Page 63: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

“shake and bake”

Page 64: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 65: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

NetworKIN

Page 66: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

the context network

Page 67: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

STRING

Page 68: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

functional interactions

Page 69: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

373 genomes

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Page 71: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

genomic context methods

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gene neighborhood

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Page 74: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

gene fusion

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Page 76: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

phylogenetic profiles

Page 77: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 78: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

primary experimental data

Page 79: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

protein interactions

Page 80: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 81: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

genetic interactions

Page 82: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 83: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

gene coexpression

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Page 85: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

literature mining

Page 86: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 87: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

curated knowledge

Page 88: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 89: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

many sources

Page 90: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

different formats

Page 91: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

different gene identifiers

Page 92: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

redundancy

Page 93: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

variable quality

Page 94: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

spread over many species

Page 95: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

benchmarking

Page 96: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 97: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

transfer by orthology

Page 98: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 99: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

combine all evidence

Page 100: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 101: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

the results

Page 102: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 103: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

7797 predictions

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1790 substrates

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69 kinases

Page 106: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 107: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

benchmarking

Page 108: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Phospho.ELM

Page 109: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 110: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

2.5-fold better accuracy

Page 111: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

context is crucial

Page 112: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

localization

Page 113: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 114: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

visualization

Page 115: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 116: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

ATM signaling

Page 117: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 118: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

small-scale validation

Page 119: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

ATM phosphorylates Rad50

Page 120: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 121: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Cdk1 phosphorylates 53BP1

Page 122: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 123: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

high-throughput validation

Page 124: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

multiple reaction monitoring

Page 125: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 126: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

the future

Page 127: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

more sequence motifs

Page 128: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vivo

Page 129: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

in vitro

Page 130: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

automatic pipeline

Page 131: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

http://netphorest.info

Page 132: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

data organization

Page 133: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 134: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

benchmarking

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Page 136: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

selection

Page 137: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions
Page 138: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

179 kinases

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89 SH2 domains

Page 140: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

8 PTB domains

Page 141: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

upstream signaling

Page 142: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

downstream signaling

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ordered signaling events

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signaling pathways

Page 145: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Acknowledgments

The NetworKIN method– 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

The STRING database– Christian von Mering

– Michael Kuhn

– Berend Snel

– Martijn Huynen

– Samuel Chaffron

– Peer Bork

• The NetPhorest method– Martin Lee Miller– Rune Linding– Nikolaj Blom– Søren Brunak

Page 146: Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Oxidative Phosphorylation - JUdoctors...Oxidation and Phosphorylation are tightly coupled Control of oxidative phosphorylation Control of oxidative phosphorylation • Electrons do

Functional dissection of phosphorylation of …jennylab.aecom.yu.edu/PapersPDFs/Dsh Phosphorylation Wang Berhane...Functional dissection of phosphorylation of Disheveled in Drosophila

Chapt. 21 oxidative phosphorylation Ch. 21 oxidative phosphorylation Student Learning Outcomes : Explain process of generation of ATP by oxidative phosphorylation:

Expression/Phosphorylation Level

Inferring gene regulatory relationships by combining ...moter sequence analysis. In Philpel’s method, a database of known and putative regulatory motifs was established, and then

Phosphorylation at serine-10, a major phosphorylation site of

4. oxidative phosphorylation

Motifs Ch1

Tools & Databases of Short Linear Motifs - GitHub Pagesaidanbudd.github.io/ppisnd/trainingMaterial/holgerDinkel/linear_motifs/... · PROTEIN PHOSPHORYLATION SITES 2 / 23 Tools & Databases

Terminal Oxidative Phosphorylation

Microfluidic Approaches for Probing Protein Phosphorylation ......Microfluidic Approaches for Probing Protein Phosphorylation in Cells Jingren Deng ABSTRACT Protein phosphorylation

phosphorylation site

Linear motifs and phosphorylation sites. What is a linear motif? ( in molecular biology )

Chemiosmotic theory of oxidative phosphorylation. Inhibitors and uncouplers of oxidative phosphorylation

microarray based techniques to study gene expression ...IRE-like motifs were identified from genomic nucleic acid databases by an algorithm combining primary nucleic acid sequence

Histone Phosphorylation Review

Oxidative Phosphorylation - Indiana University …courses.chem.indiana.edu/c483/documents/Lecturech15.pdfOxidative Phosphorylation Pratt and Cornely, Chapter 15 ... – Oxidative phosphorylation

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Oxidative Phosphorylation

Substrate-level phosphorylation

Sequence Motifs. Motifs Motifs represent a short common sequence –Regulatory motifs (TF binding sites) –Functional site in proteins (DNA binding motif)

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Phosphorylation of Calmodulin by Permeabilized Fibroblasfs ...digital.csic.es/bitstream/10261/79163/1/Phosphorylation of Calmodul… · tively. Maximum levels of calmodulin phosphorylation

Systematic discovery of phosphorylation networks - Combining linear motifs and protein interactions

Linear motifs and phosphorylation sites

Bio Phosphorylation

Oxidative phosphorylation

PHOTOSYNTHETIC PHOSPHORYLATION MOLECULAR

Critical Roles of Phosphorylation and Actin Binding Motifs, but Not

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Mutiple Motifs Charles Yan Spring 2006. 2 Mutiple Motifs