Funktionelle Charakterisierung des Frizzled-Dishevelled-Arrestin Komplexes in Frizzled abhängigen Wnt-Signalwegen
Year: 2012
Type: dissertation
Abstract: Summary: Wnt signaling is indispensable for early development and is good to explore on the model organism Xenopus laevis. Wnt signaling is subdivided in β-catenin dependent canonical) and independent (non canonical) pathways with PCP Ca2+ and Ror. It determines primary axis formation (β- catenin dependent) and plays an essential role in convergent extension movements at the gastrula stage (β- catenin independent). In canonical, PCP and Ca2+ pathways an external Wnt ligand binds to the G protein coupled receptor Frizzled (Fz) and Dishevelled (Dvl) is recruited to Fz. Additional β-Arrestin is also recruited to Fz in canonical and PCP pathway. In the Ca2+ pathway Gi/o plays a role in the pathway activation and is coupled to Fz. This topmost complex seems to be similar in almost all Wnt pathways. The specific activation of the different intracellular pathways is not known. In this work the complex consistend of Fz-Dvl and possible further binding proteins like Arrb and Gi/o should be specified. It could be shown by keller explants and PKCα recruitment analysis that Arrb is necessary for the activation of the Ca2+ pathway and Gi/o for the PCP activation. I could demonstrate by axis duplication assays and recruitment analysis of Dvl2 and PKCα that the third intrazellular loop of Fz7 has new binding motifs for Dvl2 and PKCα. Dvl isoforms are not redundant in function in the canonical and Ca2+ pathway. They prefer the activation of different pathways. Co-immunopräcipitation in HEK293T cells showed Arrb possibility to bind Dvl isoforms and Gβ1. Dvl2 has an inhibitory effect on the activation of PKCα. The signalling complex Fz-Dvl is apparently enhanced by the proetins Arrb and Gi/o. The specifity of the pathway activation seems to be generated by using different protein isoforms in different pathways and by autoregulatory control between the proteins.
Author: Seitz, Katharina
Language: German
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7019387359