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Mechanisms of tumorigenesis and tumor progression Antonio García de Herreros

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The analysis of signal transduction activated by Wnt factors

Directed by Dr. García de Herreros and Dr. Duñach

This project is carried out in close collaboration with Dr. Mireia Duñach (Autonomous University of Barcelona). Our group is devoted to the study of proteins associated with E-cadherin, such as β-catenin and p120-catenin, and their function in signalling pathways. In recent years, our work has focused on p120-catenin, which, as well as binding to and stabilising E-cadherin, has additional functions as it controls the activity of the Rho family of GTPases and the Kaiso transcription factor.

Our results have also shown that p120-catenin plays a crucial role in the Wnt signalling pathway that induces the transcriptional activity of β-catenin. In this way, the p120-catenin/E-cadherin complex is bound to the Wnt LRP5/6 co-receptor and is necessary for the very early responses to Wnt, such as the activation of CK1e. Additionally, the separation of p120-catenin from the complex, which takes place later on, is required for a full β-catenin stabilization and transcriptional activation. A current model of our view of this pathway is shown in Figure 1.

 

Figure 1: Fast and late regulation of the activity of GSK3 on β-catenin and the stability of this protein. For more information, Vinyoles et al (2014).

Once released from E-cadherin, p120-catenin participates in other processes necessary for the complete transcriptional activity of the β-catenin/Tcf-4 complex. On the one hand, it facilitates the activation of Rac1, necessary for the stimulation of the JNK and the transport of β-catenin to the nucleus; on the other, it eliminates the repression caused by the Kaiso transcriptional factor, binding directly with that factor.

The CK1activation mechanism has also been determined which depends on the dephosphorylation of this protein kinase by the phosphatase PP2A. The formation of the complex between the Fz receptor and the LRP5/6 co-receptor, induced by the Wnt3a ligand, enables CK1e,linked indirectly to LRP5/6, to approach PP2A phosphatase, which is associated with Fz through the regulatory subunit PR61e. This facilitates the dephosphorylation and activation of CK1e and the action of this kinase on Dvl-2 and/or Fz, increasing the interaction between these proteins. This association is necessary for subsequent reactions such as the inhibition of the kinases that act on β- catenin (see Figure 1 and also Duñach et al., 2017).

Currently the group works on the signal transmission pathway activated by Wnt factors that do not induce the stabilisation of β-catenin, the so-called non-canonical Wnt pathway. Although the final effects are very different in the canonical pathway, both Wnt pathways use common elements, such as the same Fz receptors (although the co-receptors are different) and they also promote the interaction of Dvl-2 with the complex. The initial results indicate that Wnt non-canonical also requires the action of CK1e and p120-catenin.

The four most recent publications on this topic are:

  • Valls G, Codina M, Miller RK, Del Valle-Pérez B, Vinyoles M, Caelles C, McCrea P, García de Herreros A*, Duñach M*. Rac1 activation upon Wnt stimulation requires Rac1 and Vav2 binding to p120-catenin. J Cell Sci 2012.125, 5288-5301.
  • Vinyoles M, Del Valle-Pérez B, Curto J, Viñas-Castells R, Alba-Castellón L, García de Herreros A*, Duñach M*. Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6. Mol Cell 2014, 53, 444-457.
  • Vinyoles M, Del Valle-Pérez B, Curto J, Padilla M, Villarroel A, Yang J, García de Herreros A*, Duñach M*. Activation of CK1e by PP2A/PR61? is required for the initiation of Wnt signaling. Oncogene 2017, 36, 429-438.
  • Duñach M*, Del Valle-Pérez B, García de Herreros A*.p120-catenin in canonical Wnt signalling. Crit Rev Biochem Mol Biol 2017, 52, 327-339. (*Corresponding authors)

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