Cell Signaling Ontology

1. Cell Signaling Ontology Takako Takai-Igarashi and Toshihisa Takagi Human Genome Center, Institute of Medical Science, University of Tokyo

2. Bioinformatics in the post-genome sequencing era We have to learn more from the biological system; investigate the biological system thoroughly, and find underlying algorithms of information processing in common to all the species.

3. external signals integration adaptation response perception transduction amplification switch physiological responses Cell signaling is an algorithm of information processing

4. SIGNAL-ONTOLOGY - ontology for cell signaling - Abstract the common features from the cell signaling systems of model species of eukaryotes (yeast, fruit fly, nematode, rat, mouse, and human) and reconstruct them in computers. Based on the knowledge accumulated in the Cell Signaling Networks Database (CSNDB)

5. 350 million years old | 100 million years old | present | Why did the cell signaling evolve ? To enable cells to communicate with one another so as to coordinate their behaviors for the benefit of the organism as a whole. (Alberts, B., et al. (1994). Molecular Biology of The Cell) | formation of the earth first mono-cellular organism first multicellular organism Cell Signaling in Biology Many signaling processes were shown to be conserved throughout the eukaryotic kingdom, from yeast to vertebrates.

6. SIGNAL-ONTOLOGY • Conceptual classes of SIGNAL-ONTOLOGY • Signal Module: an unit of signal processing in common to the model species. • Molecular Function：biochemical properties of a molecule. • Cellular Function：a biological response performed by a series of Molecular Functions. • Gene and Protein：genes and gene products which link to entries of GeneOntology and NCBI UniGene.

7. SIGNAL-ONTOLOGY • Signal Module • Minimum units of signal processing in common to the model species. • Every signaling cascade can be reconstructed by a set of Signal Modules. • Signal Module • Input Signal (property, location) • Output Signal (property, location) • Pointer to ‘Molecular Function’ Concept • Pointer to ‘Cellular Function’ Concept

8. input output input output input output input output input output input output input output input output Signal Module ligand -> transmembrane signaling -> phosphorylation -> clustering ligand -> G protein-coupled receptor -> G-protein switching phospholipid -> second messenger second messenger -> kinase G-protein switching -> kinase kinase cascade conformation change and release of signal peptide -> nuclear localization target gene expression

9. SIGNAL-ONTOLOGY Signal Modules in eukaryotes

10. SIGNAL-ONTOLOGY • Molecular Function • Biochemical property of molecules • Refer to the GeneOntology • Molecular Function • Higher Concept • Lower Concept • Pointer to ‘Signal Module’ Concept • Pointer to ‘Gene and Protein’ Concept

11. SO:0006002 ligand of G protein linked receptor GO:0004930 G protein linked receptor Link Table GO:0004947 opioid receptor GO:0005065 heterotrimeric G protein GO:0004948 calcitonin receptor GO:0004949 cannabinoid receptors Link Table SP:P41145 H.sapiens SP:P33534 M. musculus PID: g325610 D. melanogaster PID:g3881639 C. elegans SIGNAL-ONTOLOGY ligand -> G protein-coupled receptor -> G-protein switching

12. SIGNAL-ONTOLOGY • Cellular Function • Biological response performed by a series of Molecular Functions. • Similar classification of biological processes in the metabolic system, such as ‘TCA cycle’, ‘chlorophyll synthesis’, and ‘fatty acid desaturation’. • Cellular Function • Higher Concept • Lower Concept • Pointer to ‘Signal Module’ Concept • Pointer to ‘Gene and Protein’ Concept

13. Cellular Function

14. Cellular Function Data are collected from original articles by hand. We refer review articles of Cell. Another group of signaling molecules likely to mediate axon guidance signals is the Rho family of small GTPases. Activation of the Rho GTPases Rac and Cdc42 promotes the formation of lamellipodia and filopodia, respectively, and induces the formation of adhesive complexes that stabilize these structures. In contrast, activation of the Rho family member RhoA leads increased actinomyosin contractility and growth cone collapse.(Cell, 101, 239-242, 2000)

15. SO:0006002 ligand of G protein linked receptor ligand -> G protein-coupled receptor -> G-protein switching GO:0004930 G protein linked receptor Link Table GO:0004947 opioid receptor GO:0005065 heterotrimeric G protein GO:0004948 calcitonin receptor GO:0004949 cannabinoid receptors Link Table SP:P41145 H.sapiens SP:P33534 M. musculus PID: g325610 D. melanogaster PID:g3881639 C. elegans System design • SIGNAL-ONTOLOGY is implemented on an object-oriented system. All the components of Signal Module, Molecular Function and Cellular Function concepts are implemented as objects in the system.

16. ligand -> transmembrane signaling -> phosphorylation -> clustering ligand -> G protein-coupled receptor -> G-protein switching input output input output input output input output input output input output input output input output phospholipid -> second messenger second messenger -> kinase G-protein switching -> kinase kinase cascade conformation change and release of signal peptide -> nuclear localization target gene expression System design • Input and output signals that represent connections between objects of the Signal Module concept are implemented as methods that can pass the messagesbetween objects. Methods are implemented as table lookup or by logic programming.

17. P Schematized descriptions of components of the cell signaling, which straightforwardly represent the biochemical properties and molecular functions of the components based on the knowledge of SIGNAL-ONTOLOGY. Gi e.g. PLC IP3 DAG etc. K+ System design • The system will have external linkages to dictionaries, text books, and the Internet resources. • Graphical user interface, with which we propose a standard representation of the cell signaling, will be implemented.

18. SIGNAL-ONTOLOGY • Applications • Comparative genome analysis • Genome annotation • Knowledge extraction from texts • Information retrieval (query relaxation) • Knowledge-based integration of existing databases in the Internet • Gene expression profile analysis • Cell signaling simulation

19. SIGNAL-ONTOLOGY SIGNAL-ONTOLOGY Application：Genome annotation It will be a reference of functional roles of individual molecules in the cell signaling system and provide a list of molecules belong to the same functional role in the cell signaling.

20. input output input output input output input output input output input output input output input output Every gene will be mapped to a node in the signaling ontology. ligand -> transmembrane signaling -> phosphorylation -> clustering ligand -> G protein-coupled receptor -> G-protein switching phospholipid -> second messenger second messenger -> kinase G-protein switching -> kinase kinase cascade conformation change and release of signal peptide -> nuclear localization target gene expression In our final goal, signaling networks will be deducted from the genome information …