A Workbench for Systematic Constructionof Signal Transduction Pathways:
Ontologies and Architectures

Kenichiro Fukuda

ichiro@ims.u-tokyo.ac.jp

Mikio Yoshidamikio@ims.u-tokyo.ac.jp

Toshihisa Takagi

takagi@ims.u-tokyo.ac.jp

Human Genome Center, Institute of Medical Science, University of Tokyo
4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

1 Introduction
To understand the phenomena of life, we need to grasp all events that occur in the life of a living cell,and then describe and comprehend the cell as a system. To that end, all proteins expressed by thecell and their functional relationships should be recorded so that researchers can build models.
Meanwhile, as a result of the recent complete sequencing of microbial genomes, DBs of complete
proteomes and DBs for comparative genomics studies have been developed[1, 6, 5]. With this detailed
information of all ORFs and known proteins stored in databases, researchers can now conduct systematic screening for functional analysis and acquire a large quantity of mutual interaction data[2, 4].
These data will be essential to understand the behavior of a cell as a whole system.
However conventional modeling methodology does not provide the ability to verify if the model iscoherent as a biological system. Currently, researchers build their models step by step from genetic or
physical binary relation data, which are mostly obtained from coimmunoprecipitation or two-hybrid
screenings and synthetic lethal screenings [3].
To understand the mechanisms of a cell system, we need to verify if the stored knowledge on signaltransduction pathway is correct and complement the missing links with the above mentioned data.
Thus, a model construction environment with which users can conduct the following steps needs tobe developed : 1. design a model interactively by accessing various kinds of resources, 2. simulate
biological systems with this model, 3. debug this model or determine what it lacks, 4. verify andre ne the model, 5. iterate step 1 to 4.

2 Ontology & Knowledge Expression
In this work we de ne signal transduction as the following; A \signaling event" is a phenomenon where an object's change of state cause another object'schange of state1 . Here, change of state means phosphorylation, dephosphorylation, degradation,
compound formation, binding of adapter proteins (for example, proteins with an SH2 domain).

 Signal transduction is a cascade of \signaling events", where the occurrence of one signaling

event depends on other signaling events.

In this work, our cell system is represented as an event-driven system.
1

Currently \objects" mean proteins or DNA

290

3 System architecture
The model construction system is GUI compatible and has the following features;
 pathway edit function
 truth maintenance links to protein DBs, transcription factor DBs and other DBs
 change view function
A \view" is a representation of a network. Users can change their view from a genetic interaction viewto a physical interaction view and vise versa. Or they can switch from a signal transduction pathway
view to a gene regulation network view.

Figure 1: A snap-shot of the environment.

References[1] MBGD : Microbial Genome Database for Comparative Analysis,
http://mbgd.genome.ad.jp/[2] DeRisi, J.L., Iyer, V.R., and Brown, P.O., Exploring the Metabolic and Genetic Control of Gene
Expression on a Genomic Scale, Science, 278:680{686, 1997.
[3] Doye, V. and Hurt, E.C., Genetic approaches to nuclear pore structure and function, Trends inGenetics, 11(6):235{241, 1995.
[4] Fromont-Racine, M., Rain, J., and Legrain, P., Toward a functional analysis of the yeast genome
through exhaustive two-hybrid screens, nature genetics, 16:277{282, 1997.
[5] Hodges, P.E., Payne, W.E., and Garrels, J.I., Yeast Protein Database (YPD): a database forthe complete proteome of Saccharomyces cerevisiae, Nucleic Acids Research, 26:68{72.(1998),
http://www.oup.co.uk/nar.
[6] Mewes, H.W., Hani, J., Pfei er, F., Frishman, D., MIPS: a database for protein sequences andcomplete genomes, Nucleic Acids Research, 26:33{37, 1998.
291