Topological Analysis and Visualisation of large Signalling Networks: The TGF-beta Signal Transduction in Eukaryotic Systems

Knut Behrendt, Andreas Politzer, Julio Saez-Rodriguez, Matthias Reuss and Klaus Mauch




Institut für Bioverfahrenstechnik,
Allmandring 31,
70569 Stuttgart, Germany






Signalling pathways play a major role in proliferation and differentiation processes in multicellular organisms. From there, the set-up and analysis of the usually complex signal transduction networks in silico contributes to an integrated understanding of biological systems [1]. From a medical point of view, the analysis of signalling networks are vitally important since malfunction of signalling networks most often lead to severe consequences of the whole organism.

In this contribution we present an object orientated framework that enables the user to design, analyse and visualise signalling networks and their various topological properties. Large integer computing in combination with a newly developed, efficient algorithm allows the fast and reliable detection of elementary tranducing modes within complex signalling networks. Those modes represent autonomous modules [2] by which the manifold functionality of signalling networks can be composed. For this topological analysis only structural information on the various reaction steps are used whereas kinetic details are neglected.

The usefulness of this approach is demonstrated by means of a TGF-beta signalling network. Among the great variety of different signalling pathways, the processes activated by TGF-beta and their receptors are examined in detail [3]. According to the crosstalk with other pathways, the TGF-beta signalling network contains junction points to other signalling systems like, for example, the EGF signalling network. Within the TGF-beta signalling network, a central role in downstream activation is undertaken by the Smad system leading to a variety of transcriptional responses. Elementary transducing modes of the TGF-beta network contain the steps from ligand binding over receptor dimerization and activation to degradation of the receptor/growth factor complex, the guanine nucleotide exchange factor family as well as the activation of different kinds of MAP kinases. The identified functional modules provide useful insight on the manifold of signal transduction networks and their crosstalk within cells.


REFERENCES

  1. Weng, G.; Bhalla, U. S. and Iyengar, R. (1999) Complexity in biological signaling systems. Science 284: 92-96.
  2. Schuster, S.; Fell, D. A. and Dandekar, T. (2000) A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nat. Biotechnol. 18: 326-332.
  3. ten Dijke, P.; Miyozono, K. and Heldin, C.-H. (2000) Signalling inputs converge on nuclear effectors in TGF-beta signalling. TIBS 25: 64-70.