Introduction

Investigations in the molecular mechanisms which lead to diseases, malfunctions of organs and developmental defects are of great pharmaceutical interest. As research on cellular signaling is rapidly growing, a database is required for compiling all information available and producing a simplified, coherent picture of complex cellular signaling. TRANSPATH approaches this notion. It is a database on gene-regulatory signal transduction networks.
Here we give an insight  in general cellular signaling and in one specific pathway û the IL-1 signal transduction û and its implementation in TRANSPATH.

In general signaling many hormones, cytokines, growth factors or neurotransmitters bind to specific receptors on the cell-membrane. The signal is transmitted through the receptor to other signaling mediators in the cell, like

• enzymes
• adapter proteins
• effector proteins

The ligand-activated state is gene-regulation through specific effector proteins which activate transcription factors.

Figure 1: General signaling

Interleukin-1

IL-1 (interleukin-1) is a pivotal pro-inflammatory cytokine centrally involved in local and systemic responses in the immune system leading to typical effects of inflammation. Dysregulated, prolonged synthesis and release of IL-1 in chronic inflammatory situations contributes to many diseases, e.g. rheumatoid arthritis. Because of its importance in these diseases more research has to be done on IL-1 signaling.

Figure 2 shows a likely and possible network of pathways associated with IL-1 signal transduction and its interconnection with the related TNF (tumor necrosis factor) signal transduction. TNF also represents an pro-inflammatory cytokine that leads to many inflammatory diseases as known for IL-1.

IL-1 pathway

In IL-1 signaling the signal-mediating IL-1 receptor Type I (IL1-RI) forms a heterodimer with a second molecule (Figure 3), the IL-1 receptor accessory protein (IL-1RAcP). Binding of IL-1 to this receptor complex leads to activation of the transcription factor NFB through different signaling molecules.
DNA-binding motifs for NFB are found in the promotors and enhancers of many genes that are known to be activated upon inflammation.

TRANSPATH objectives and content

We are aiming to construct a comprising database for two reasons: primarily there is a demand for structuring the growing amount of signal transduction data. Secondly in order to predict cellular responses simulation models can be established on the comprehensive database. To give a clue about how data is implemented in TRANSPATH the IL-1 signaling as an example is given.
The main entries of TRANSPATH are signal molecules and reactions/ interactions that build up a coherent, detailed system. Further information can be obtained by other linked databases such as TRANSFAC, Cytomer, PathoDB, S/MARt DB, Swissprot or EMBL.
Visualization is a useful tool to summarize the information about the complex signaling network. Therefore schematic figures are integrated into TRANSPATH. Figure 3 represents the IL-1 signal transduction.

Figure 3: Aimed browsable map of IL-1 signaling pathway

Perspectives

Growing information on cellular signaling demands for compiling and structuring all relevant data. TRANSPATH meets this need. Currently we are working on the implementation of the data into TRANSPATH in a general manner visualizing the topics. After achieving a general overview on well known pathways we are going to extract precise data to evaluate the interactions between specific signaling molecules inside the cell.

Reference

Auron, P. E. (1998): The Interleukin-1 receptor: Ligand interaction and signal transduction. Cytokine Growth Factor Rev. 9, 221-237