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

4. SIGNAL-ONTOLOGY - ontology for cell signaling - 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. Cell Signaling in Biology Many signaling processes were shown to be conserved throughout the eukaryotic kingdom, from yeast to vertebrates. 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) present | first mono-cellular organism 100 million years old | 350 million years old | first multicellular organism | formation of the earth

6. SIGNAL-ONTOLOGY 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 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 SIGNAL-ONTOLOGY

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

9. Signal Modules in eukaryotes SIGNAL-ONTOLOGY

10. 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 SIGNAL-ONTOLOGY

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

12. 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 SIGNAL-ONTOLOGY

13. Cellular Function

14. 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) Cellular Function Data are collected from original articles by hand. We refer review articles of Cell.

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

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

17. 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. 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. GiGi K+K+ DAG IP 3 PLC P etc. e.g.

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 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. ligand -> G protein-coupled receptor -> G- protein switching ligand -> transmembran e signaling -> phosphorylatio n -> clustering kinase cascade G-protein switching -> kinase second messenger -> kinase phospholipid -> second messenger conformation change and release of signal peptide -> nuclear localization target gene expression 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. In our final goal, signaling networks will be deducted from the genome information …