Wnt signaling


The Wnt signaling pathway has been implicated in a wide range of biological processes from maintaining the pluripotentiality of stem cells to the induction of specific tissues and organs during development. Moreover, a majority of the components of the Wnt signaling pathway are found throughout the animal kingdom.

The Wnt signaling pathway

In the mouse there are 19 different Wnt genes encoding for secreted proteins that signal by binding to their receptors. The family of Wnt receptors is composed of 10 Frizzled genes. Moreover, the co-receptors LRP5 and LRP6 participate in the transmission of the Wnt signals. The Wnt signals can be blocked by a series of secreted antagonists grouped in two categories.

The first group of antagonists is composed of Frzb and its four homologs, which form the secreted Frizzled Related Protein (Sfrp) family, as well as Wif and binds directly to Wnt proteins, thereby blocking activation of the receptor (Leyns et al., 1997). Secreted antagonists of the second category bind to the LRP co-receptors thereby blocking the activation of the Wnt signaling pathway. These antagonists include Dkk1 and its three homologs as well as Wise.
At the intracellular level, the activation of the Wnt receptors is transduced by several pathways . The best characterized one, called the canonical pathway, is based on a series of phosphorylation steps that ultimately leads to the stabilization and nuclear import of beta-Catenin. In the nucleus, beta-Catenin associates with TCF factors and this complex activates target genes of the Wnt pathway. Several Wnts (Wnt1, -2, -2b, -3, -3a, -6, -7b, -8a and -8b) have been shown to activate specifically the canonical pathway.

The signaling by other Wnts (Wnt4, -5a and -11) is mediated by non-canonical pathways involving intracellular signaling by Ca2+ or the JNK cascade. The signaling pathways triggered by the remaining Wnts (Wnt5b, -7a, -9a, -9b, -10a, -10b and -16) have not yet been characterized.

Due to technical limitations including those related to the purification of Wnt proteins, the binding specificities of the nineteen Wnt proteins with their ten Frizzled receptors, and the eleven potential secreted antagonists, as well as the integration of the signals through the various pathways, have not yet been completely elucidated.

Current research

We are currently investigating the binding specificities of several Wnt proteins with secreted antagonists such as Frzb or with the Frizzled receptors.

Two complementary approaches are used. First, we measure the biological activity of canonical Wnts such as Wnt3a by detecting the stabilization of intra-cellular beta-catenin in cells treated with Wnt. We then treated the cells with the Wnt protein as well as with the secreted antoganist or a soluble version of the Frizzled receptor. The binding of these proteins will reduce the amount of free Wnt in the culture medium and therefore limit the extent of beta-catenin stabilization.
With this approach we can analyse the binding specificities in living cells.

The second approach is purely biochemical and involves measuring the binding efficiency between purified Wnt proteins and sFRPs or Frizzled using plasmon surface resonance (Biacore).

The combination of these two approaches with genes expression studies showing when and where the extracellular members of the Wnt cascade are expressed will allow us to refine our understanding of the Wnt signals.


© 2005• Laboratory of Cell Genetics • VUB • Brussels - Belgium • Tel.: +32 2 629.34.43 • lleyns@vub.ac.be