A comprehensive modular map of molecular interactions in RB/E2F pathway

Abstract

We present, here, a detailed and curated map of molecular interactions taking place in the regulation of the cell cycle by the retinoblastoma protein (RB/RB1). Deregulations and/or mutations in this pathway are observed in most human cancers. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner 3.5 software and converted into BioPAX 2.0 pathway description format. In the current state the map contains 78 proteins, 176 genes, 99 protein complexes, 208 distinct chemical species and 165 chemical reactions. Overall, the map recapitulates biological facts from approximately 350 publications annotated in the diagram. The network contains more details about RB/E2F interaction network than existing large-scale pathway databases. Structural analysis of the interaction network revealed a modular organization of the network, which was used to elaborate a more summarized, higher-level representation of RB/E2F network. The simplification of complex networks opens the road for creating realistic computational models of this regulatory pathway.

Figure 1

Textbook view of the RB/E2F pathway. When CycD1/CDK4,6 is activated, it phosphorylates RB, which in turn is inactivated and releases E2F transcription factors leading to cell proliferation.

Figure 2

The textbook pathway of RB has been expanded by integrating data from the literature. The E2F transcription factors (represented here by single proteins in the nuclear compartment) are connected by activation and inhibition arrows to their gene targets. (A) Map of target genes of E2F transcription factors. Each E2F associates with different cofactors to activate or inhibit the transcription of many genes; pointed arrows mean activation and flat arrows mean inhibitions (B) Map of protein–protein interaction network. Each icon on the diagram represents distinct chemical species. See Kitano and co-workers' description of CellDesigner's standard notation (Kitano et al, 2005) for a detailed meaning of shapes. When the information is available (from Atlas Oncology web-page: http://www.atlasgeneticsoncology.org/), tumour suppressor genes and the corresponding proteins are coloured in blue and oncogenes in red, the other proteins are in green. To read and navigate through the map, visit our webpage: http://bioinfo-out.curie.fr/projects/rbpathway/. The map is clickable and allows easy access to all included information (such as literature references or standard protein ids) and hyperlinked to other databases.

Figure 3

Modular view of the comprehensive map presented in Figure 2. The comprehensive map has been simplified using curated structural analysis techniques to divide the graph in modules. The links between the nodes represent the influence that a module has on the others. There are 16 protein modules (green rounded rectangles) and 8 E2F target gene modules (yellow rectangles).

Figure 4

Cytoscape view of (A) E2F1-3 module and (B) RB module.

Figure 5

Examples of textual representation of species structure. In CellDesigner, information about sites of phosphorylation or acetylation, and so on can be showed on the protein itself. A complex is represented as a black box surrounding the proteins composing the complex.

Figure 6

Example of a simple network converted from CellDesigner to Cytoscape. In Cytoscape, single proteins are represented by white squares and complexes by grey squares.