Unraveling cellular phosphorylation networks using computational biology
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Unraveling cellular phosphorylation networks using computational biology

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BRIC/LEO Minisymposium on Protein Kinases in Health and Disease, Copenhagen Biocenter, Copenhagen, September 26, 2008

BRIC/LEO Minisymposium on Protein Kinases in Health and Disease, Copenhagen Biocenter, Copenhagen, September 26, 2008

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Unraveling cellular phosphorylation networks using computational biology Presentation Transcript

  • 1. Unraveling cellular phosphorylation networks using computational biology Lars Juhl Jensen EMBL Heidelberg
  • 2. the problem
  • 3. Oda & Kitano, Molecular Systems Biology , 2006
  • 4. a good start
  • 5. long way to go
  • 6. the toolbox
  • 7. mass spectrometry
  • 8. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 9. phosphorylation sites
  • 10. in vivo
  • 11. kinases are unknown
  • 12. peptide assays
  • 13. Miller, Jensen et al., Science Signaling , 2008
  • 14. sequence specificity
  • 15. kinase-specific
  • 16. in vitro
  • 17. no context
  • 18. what a kinase could do
  • 19. not what it actually does
  • 20. computational methods
  • 21. sequence specificity
  • 22. Miller, Jensen et al., Science Signaling , 2008
  • 23. kinase-specific
  • 24. no context
  • 25. what a kinase could do
  • 26. not what it actually does
  • 27. in vitro
  • 28. in vivo
  • 29. context
  • 30. localization
  • 31. expression
  • 32. co-activators
  • 33. scaffolders
  • 34. association networks
  • 35. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 36. the idea
  • 37. mass spectrometry
  • 38. phosphorylation sites
  • 39. sequence motifs
  • 40. sequence specificity
  • 41. association network
  • 42. context
  • 43. in vitro
  • 44. in vivo
  • 45. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 46. the sequence motifs
  • 47. NetPhorest
  • 48. Miller, Jensen et al., Science Signaling , 2008
  • 49. pipeline
  • 50. data organization
  • 51. Miller, Jensen et al., Science Signaling , 2008
  • 52. compilation of datasets
  • 53. Miller, Jensen et al., Science Signaling , 2008
  • 54. redundancy reduction
  • 55. Miller, Jensen et al., Science Signaling , 2008
  • 56. cross-validation partitioning
  • 57. Miller, Jensen et al., Science Signaling , 2008
  • 58. training and evaluation
  • 59. classifier selection
  • 60. Miller, Jensen et al., Science Signaling , 2008
  • 61. motif atlas
  • 62.  
  • 63. 179 kinases
  • 64. 93 SH2 domains
  • 65. 8 PTB domains
  • 66. BRCT domains
  • 67. WW domains
  • 68. 14-3-3 proteins
  • 69. benchmarking
  • 70. Miller, Jensen et al., Science Signaling , 2008
  • 71. low-specificity kinases
  • 72. disease-related kinases
  • 73. Miller, Jensen et al., Science Signaling , 2008
  • 74. docking domains
  • 75. Miller, Jensen et al., Science Signaling , 2008
  • 76. the context network
  • 77. STRING
  • 78. functional associations
  • 79. 373 genomes
  • 80. Jensen et al., Nucleic Acids Research , 2008
  • 81. genomic context methods
  • 82. gene fusion
  • 83. Korbel et al., Nature Biotechnology , 2004
  • 84. conserved neighborhood
  • 85. Korbel et al., Nature Biotechnology , 2004
  • 86. phylogenetic profiles
  • 87. Korbel et al., Nature Biotechnology , 2004
  • 88. primary experimental data
  • 89. protein interactions
  • 90. Jensen & Bork, Science , 2008
  • 91. gene coexpression
  • 92.  
  • 93. literature mining
  • 94.  
  • 95. curated knowledge
  • 96. Letunic & Bork, Trends in Biochemical Sciences , 2008
  • 97. different formats
  • 98. parsers
  • 99. different gene identifiers
  • 100. thesaurus
  • 101. redundancy
  • 102. bookkeeping
  • 103. variable reliability
  • 104. benchmarking
  • 105. von Mering et al., Nucleic Acids Research , 2005
  • 106. spread over many species
  • 107. transfer by orthology
  • 108. von Mering et al., Nucleic Acids Research , 2005
  • 109. combine all evidence
  • 110. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 111. the results
  • 112. NetworKIN
  • 113. 123 kinases
  • 114. 5515 substrates
  • 115. 21,702 sites
  • 116. benchmarking
  • 117. Phospho.ELM
  • 118. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 119. 2.5-fold better accuracy
  • 120. context is crucial
  • 121. localization
  • 122. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 123. ATM signaling
  • 124. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 125. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 126. small-scale validation
  • 127. ATM phosphorylates Rad50
  • 128. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 129. Cdk1 phosphorylates 53BP1
  • 130. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 131. high-throughput validation
  • 132. multiple reaction monitoring
  • 133. Linding, Jensen, Ostheimer et al., Cell , 2007
  • 134. systematic validation
  • 135. design optimal experiments
  • 136. 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
  • 137. Want to work on this project?