Thesis supervisor: Szabolcs Lányi
Location of studies (in Hungarian): Csíkszereda Abbreviation of location of studies: Csík
Description of the research topic:
Wnt signaling regulates not just a variety of developmental processes but various diseases including cancers. Wnt molecules trigger gene transcription via at least three signaling pathways: the canonical or beta-catenin dependent, and two non-canonical pathways. Once stabilized, non-degraded β-catenin, a 92 kDa protein, moves to the nucleus where it activates TCF-LEF-dependent gene transcription leading for example to proliferation. In the absence of Wnt signals, the cytoplasmic β-catenin is subjected to serine/threonine phosphorylation in the APC-Axin-GSK3beta-complex then to ubiquitination and subsequent proteasomal degradation.
β-catenin is involved in cell adhesion forming cadherin-catenin complexes. In particular, phosphor-ylation of β-catenin results in release of cadherins and increase in transcriptional activity. Down-regulation of cellular adhesion is part of the initiation of metastasis. Four tyrosine residues in β-catenin are reported previously to regulate the integrity of the cadherin core complex, 86, 142, 489 and 654. Both Fer and Fyn Kinases phosphorylate tyrosine 142 in vitro. Overexpression of these kinases in epithelial cells disrupts interactions between α- and β-catenins. By designing peptides to the surface of the beta catenin, we can inhibit the phosphorylation by kinases and thus the translocation of the β-catenin to the nucleus. The design of the peptides in the first phase will be on the base of molecular docking, followed by the biosynthesis of a few well proven peptide. The in-teractions between the kinases and the β-catenin and their inhibition will be measured by fluores-cence polarization