Initial events in non-canonical wnt signaling
- Autores: Josué Curto Navarro
- Directores de la Tesis: Mireia Duñach i Masjuan (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Àngels Fabra Fres (presid.), Francesc Vinyals Canals (secret.), Isabel Puig Borrell (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular y Biomedicina
- Materias:
- Enlaces
- Resumen
Canonical and non-canonical Wnt pathway have shown to activate signaling pathways that trigger different cellular outputs. However, the initial signaling events upon ligand stimulation show some common elements. The two pathways require the receptor Frizzled (Fz) to promote Dishevelled phosphorylation and recruitment to the signaling complex. In canonical Wnt pathway, p120-catenin associated CK1ε must be activated to allow Dvl phosphorylation and recruitment to Fz. Here we demonstrate that these two proteins are also required to promote this step upon Wnt5a stimulation. Moreover, Fz associated PR61ε/PP2A is also necessary to activate CK1ε and induce receptor clustering. However, the dependence on these two factors is different, in non-canonical Wnt pathway p120 is not required for CK1ε association to the coreceptor since both proteins independently interact with Ror2. Moreover, p120-catenin associates to Ror2 in a tyrosine phosphorylation-dependent manner. P120-catenin stabilizes Ror2 at the membrane and avoids clathrin-mediated Ror2 internalization. On the other hand, CK1ε binding to the C-terminal part controls Ror2 total levels and prevents its lysosomal degradation. This central role of p120-catenin and CK1ε in the initial signaling events are required for later responses such as Siah2-dependent β-catenin downregulation, cell invasion and cortical actin polymerization. Therefore, our results demonstrate the requirement of these two key proteins in the non-canonical Wnt pathway and describe how this pathway is activated.
