UC San Diego

Wnt signaling is a key pathway in developing organisms for cell growth, embryonic patterning, and organogenesis. However, a dysregulation of the Wnt signaling pattern is associated with cancer progression in 90% of colon cancer and 50% of breast cancer patients. Since its initial discovery over 30 years ago, even today we are still uncovering the specifics on the mechanisms and processes that govern Wnt signaling. Based on our results currently undergoing publication, we know that that Daple, a non- receptor GEF protein, possesses a G-protein Binding and Activating (GBA) motif which can interact with and activate G-proteins during non-canonical Wnt stimulation to disassociate the heterotrimer into Ga and Gbg subunits, linking the Wnt pathway to G-protein signaling. This initiates downstream non-canonical Wnt responses, such as PI3k/Akt enhancement through Gbg subunit release. In this study, we examine Daple's GBA motif and its effect through the Wnt pathway on cell polarity and membrane stability using epithelial MDCK cells. We confirmed that Daple's GBA motif is a key regulator of PI3k/Akt signaling, [Beta]- catenin localization, and 3D cyst development to modulate adherens junction integrity and cell polarity. Future work in uncovering the mechanisms of Daple signaling would more clearly reveal its potential as a prime target in the Wnt pathway to thwart cancer progression and cell invasion