From individual Wnt pathways towards a Wnt signalling network - PubMed (original) (raw)

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From individual Wnt pathways towards a Wnt signalling network

Hans A Kestler et al. Philos Trans R Soc Lond B Biol Sci. 2008.

Abstract

Wnt proteins play important roles during vertebrate and invertebrate development. They obviously have the ability to activate different intracellular signalling pathways. Based on the characteristic intracellular mediators used, these are commonly described as the Wnt/beta-catenin, the Wnt/calcium and the Wnt/Jun N-terminal kinase pathways (also called planar cell polarity pathway). In the past, these different signalling events were mainly described as individual and independent signalling branches. Here, we discuss the possibility that Wnt proteins activate a complex intracellular signalling network rather than individual pathways and suggest a graph representation of this network. Furthermore, we discuss different ways of how to predict the specific outcome of an activation of this network in a particular cell type, which will require the use of mathematical models. We point out that the use of deterministic approaches via the application of differential equations is suitable to model only small aspects of the whole network and that more qualitative approaches are possibly a suitable starting point for the prediction of the global behaviour of such large protein interaction networks.

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Figures

Figure 1

Figure 1

The classical view of three independent Wnt signalling pathways. Graph representations are given, including the core components of the (a) canonical Wnt/β-catenin pathway (yellow), (b) the Wnt/calcium pathway (orange) and (c) the Wnt/JNK pathway (white, also called planar cell polarity pathway). Edges indicate direct protein–protein interactions or may relate to an epistatic relationship between two components within a signalling pathway.

Figure 2

Figure 2

The integrative approach of analysing Wnt signalling results in a Wnt signalling network. Several components have been linked to all signalling branches such as Wnt, Fz, heterotrimeric G-proteins, dsh or PKC (indicated in light blue); others were linked to at least two branches such as CKIϵ, diversin, dkk, cdc 42 or CKIα (indicated in green). Please note that this network does not represent all interactions identified in Wnt signalling so far for reasons of clarity. Most of the edges represent direct interactions of entities indicated and some of them however represent the epistatic relationship of these components within the network as discussed in the main text. Dashed lines for the upstream molecules of yes indicate that the upstream receptor for yes activation through Wnts is unknown so far.

Figure 3

Figure 3

Modelling aspects of Wnt signalling by the use of ordinary differential equations. Part of the canonical Wnt signalling branch has been modelled in the Lee–Heinrich model (Lee et al. 2003). (a) Components of the network as indicated in figure 1_a_, which were included in the Lee–Heinrich model. In addition, dephosphorylation events, de novo synthesis and degradation of some components are included. (b) Reaction scheme included in the Lee–Heinrich model. Note that just a very small aspect of the Wnt signalling network has been implemented in the Lee–Heinrich model.

Figure 4

Figure 4

Network motifs of direct protein–protein interactions found within the Wnt signalling network. Examples for (a) triads and (b) tetrads of interactions identified. (c) Major components of the network, i.e. dishevelled represent hubs. Not all known interactions of dsh are shown. Additional interaction partners include Frodo/Dapper, Iday, Naked, MuSK, Eps8, Par-1, PAK and PP2C. Other hubs are LEF/TCF, β-catenin, axin or Frizzled.

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