Our main goal is to investigate the molecular mechanisms of tumour development and progression by cell and molecular biological methods as well as mouse models, to find new ways for diagnosis, prognosis and therapy.
The Wnt signalling pathway regulates various processes during embryonic development and can lead to cancer. Wnts are secreted glycoproteins, which induce the accumulation of b-catenin in the cytoplasm and nucleus by binding to frizzled and LRP receptors. b-Catenin interacts with TCF transcription factors and activates target genes. The destruction of b-catenin is induced by phosphorylation in a multi-protein complex, which consists of the scaffold components axin and conductin/axin2, the serine/threonine kinase GSK3b and the tumour suppressor APC (Adenomatous Polyposis Coli). The Wnt signal inhibits phosphorylation of b-catenin and thereby leads to its stabilisation. In colorectal tumours, mutations of APC or conductin, or mutations of the serine/threonine phosphorylation sites in b-catenin lead to stabilization of b-catenin and trigger constitutive signalling to the nucleus. Such b-catenin mutations are also found in a multitude of other tumour types suggesting that aberrant activation of Wnt signalling is a key mechanism of oncogenic transformation. Our research has contributed to the field by identifying b-catenin as a transcription factor through binding to TCF/LEF and identification of conductin, which in turn aided in describing the mechanisms of b-catenin regulation by the multiprotein destruction complex.