β-Catenin is a prominent example of multifunctional protein. On the one hand, it has a structural function binding N-Cadherin to form the adherens junctions (AJs) at the apical pole of the neuroblasts, and on the other it is a key element in Wnt signalling pathway acting as a necessary cofactor for TCF/LEF dependent transcription activation. Work from our laboratory has shown that β-Catenin regulates the polarity of neuroblasts by inducing both the transcription and the recruitment of molecules such as aPKC to the apical complex (AC), altering not only the cellular adhesiveness, but also the ability of neuroblasts to remain as progenitors. Stabilizing mutations of β-Catenin (sβ-Catenin) cause Wnt type Meduloblastoma, a posterior fossa brain tumour occurring mainly during childhood. Among the four molecular subgroups so far described, Wnt type Meduloblastoma holds the best prognosis, even more, the presence of sβ-Catenin improves the prognosis in other Meduloblastoma groups. Using chicken embryo neural tube as a model, we demonstrated that sβ-Catenin induces pre-neoplastic lesions of the neuroepithelium, where neuroblasts remain as progenitors in spite that proliferation is significantly reduced due to increased adhesiveness, acting sβ-Catenin simultaneously as an oncogene and a tumour suppressor. β-Catenin binds to N-Cadherin early in the Endoplasmic Reticulum supporting its maturation and transport to the AJs. Combining affinity purification to liquid mass spectroscopy we have described a group of proteins that bind to N-Cadherin/β-Catenin complex, among them, the small GTPase Cdc42 contributes to the correct processing of N-Cadherin at the RE/Golgi. Notably, a defective N-Cadherin delivery to the AJs increases the amount of free β-Catenin that is translocated to the nucleus causing a major activation of TCF-dependent transcription. Therefore, a bidirectional regulation exists between AJs/AC and β-Catenin, in one way, β-Catenin transcriptional and structural activities are crucial to form functional AJs/AC, and on the other, AJs/AC control the amount of free β-Catenin that can be translocated to the nucleolus and therefore its transcriptional activity. Like so, loos of N- Cadherin/β-Catenin complex components would decrease cell adhesiveness and simultaneously stimulate TCF-dependent transcription and may constitute one of the main factors that eventually lead to tumour progression of Wnt type Meduloblastoma.
Cell and Developmental Biology Programme Seminar
Fecha y hora de inicio: 13/09/2017, 15.00h
Fecha y hora de fin: 13/09/2017, 17.00h
Organizador: IRB - Institut de Recerca Biomèdica
Sitio: Edifici Clúster Laboratoris, Aula Félix Serratosa
Host: Marco Milán, IRB Barcelona