Regulation of Wnt signal transduction pathways

We are interested in regulation of the Wnt/Frizzled-mediated signaling pathways. Wnt signal transduction pathways (canonical and non-canonical) play critical roles in animal development and maintaining cellular homeostasis through regulation of cell proliferation, differentiation, migration, and apoptosis. The canonical Wnt signaling (the Wnt/β-Catenin signal transduction) has been well investigated since it is deregulated in a wide range of human cancers. According to the current model, in the absence of the Wnt ligands, β-Catenin protein levels decrease via binding of β-Catenin to the components of a destruction protein complex including APC, Axin, and GSK-3β. GSK-3β and Casein kinase1 phosphorylate β-Catenin and this phosphorylation is facilitated in the presence of Axin and APC. Phosphorylated β-Catenin is ubiquitinated and degraded by the proteasome degradation system. When the Wnt ligands bind to the Frizzled receptors and the LRP6 co-receptor, CK1 and GSK-3β phosphorylate LRP6 and then Axin is recruited to the cell membrane. Therefore β-Catenin degradation will be blocked in the destruction complex lacking Axin. Accumulated β-Catenin is translocated into the nucleus and binds TCF/LEF transcription factors to regulate expression of the Wnt/β-Catenin target genes which some of them are involved in initiation and promotion of carcinogenesis. All cancers, especially carcinomas are molecularly very complex. This complexity makes treatment of these diseases very difficult, especially at late stages. Therefore targeting pathways involved in initiation or early stages of carcinogenesis could produce better results for translational clinical studies. Investigation of colon carcinogenesis has clearly shown that deregulation of the Wnt/β-Catenin signaling is an early event. A proof of this comes from studies of FAP (familial adenomatous polyposis) patients. Although Wnt/β-Catenin signaling pathway has been studied extensively, there are still some unanswered questions especially at the upstream levels. G protein-coupled receptors (GPCRs) and the Frizzled receptors are structurally similar in having seven putative hydrophobic transmembrane domains. In 1997, we proposed an interaction between G-protein signaling and the Wnt/β-Catenin pathway. Since then, we and others have got evidence suggesting a positive role for the Gq class of hetero-trimeric G proteins in the regulation of Wnt/β-Catenin signaling. Our main research program addresses this interaction in more detail. We are investigating this interaction in colon cancer cells in the hope to find the mechanism(s) of regulation of Wnt/β-Catenin pathway by Gq signaling (and other hetero-trimeric G-proteins). The results can be further investigated using animal studies. The final goal is to find better targets (perhaps G-proteins and their receptors) to control β-Catenin signaling in human colon cancer and other cancers in which the Wnt/β-Catenin signaling is deregulated.