Towards the systematic discovery of signal transduction networks using phosphorylation dynamics data

Haruna Imamura, Nozomu Yachie, Rintaro Saito, Yasushi Ishihama, Masaru Tomita

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Phosphorylation is a ubiquitous and fundamental regulatory mechanism that controls signal transduction in living cells. The number of identified phosphoproteins and their phosphosites is rapidly increasing as a result of recent mass spectrometry-based approaches.Results: We analyzed time-course phosphoproteome data obtained previously by liquid chromatography mass spectrometry with the stable isotope labeling using amino acids in cell culture (SILAC) method. This provides the relative phosphorylation activities of digested peptides at each of five time points after stimulating HeLa cells with epidermal growth factor (EGF). We initially calculated the correlations between the phosphorylation dynamics patterns of every pair of peptides and connected the strongly correlated pairs to construct a network. We found that peptides extracted from the same intracellular fraction (nucleus vs. cytoplasm) tended to be close together within this phosphorylation dynamics-based network. The network was then analyzed using graph theory and compared with five known signal-transduction pathways. The dynamics-based network was correlated with known signaling pathways in the NetPath and Phospho.ELM databases, and especially with the EGF receptor (EGFR) signaling pathway. Although the phosphorylation patterns of many proteins were drastically changed by the EGF stimulation, our results suggest that only EGFR signaling transduction was both strongly activated and precisely controlled.Conclusions: The construction of a phosphorylation dynamics-based network provides a useful overview of condition-specific intracellular signal transduction using quantitative time-course phosphoproteome data under specific experimental conditions. Detailed prediction of signal transduction based on phosphoproteome dynamics remains challenging. However, since the phosphorylation profiles of kinase-substrate pairs on the specific pathway were localized in the dynamics-based network, our method will be a complementary strategy to explore new components of protein signaling pathways in combination with previous methods (including software) of predicting direct kinase-substrate relationships.

Original languageEnglish
Article number232
JournalBMC Bioinformatics
Volume11
DOIs
Publication statusPublished - 2010 May 7

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Signal transduction
Phosphorylation
Signal Transduction
Signaling Pathways
Growth Factors
Peptides
Mass Spectrometry
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Receptor
Mass spectrometry
Pathway
Phosphotransferases
Substrate
Isotope Labeling
Proteins
Protein
Cell Culture
Phosphoproteins
Graph theory

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Structural Biology
  • Applied Mathematics

Cite this

Towards the systematic discovery of signal transduction networks using phosphorylation dynamics data. / Imamura, Haruna; Yachie, Nozomu; Saito, Rintaro; Ishihama, Yasushi; Tomita, Masaru.

In: BMC Bioinformatics, Vol. 11, 232, 07.05.2010.

Research output: Contribution to journalArticle

Imamura, Haruna ; Yachie, Nozomu ; Saito, Rintaro ; Ishihama, Yasushi ; Tomita, Masaru. / Towards the systematic discovery of signal transduction networks using phosphorylation dynamics data. In: BMC Bioinformatics. 2010 ; Vol. 11.
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