Investigating βPix as a Novel Upstream Regulator of the Hippo Pathway

The Hippo pathway regulates cell growth and organ size and dysregulation of the pathway leads to cancer. In mammals, the core Hippo pathway consists of Mst/Lats kinases, which phosphorylate and inhibit transcriptional co-activators, Yap and Taz, by promoting cytoplasmic sequestration. Here, we identify the guanine nucleotide exchange factor (GEF), Arhgef7, or βPix, as a positive Hippo pathway regulator. Upon upstream Hippo signals emanating from cell-cell contact and actin cytoskeletal rearrangements, βPix functions to regulate Yap/Taz localization and activity in a GEF-independent manner. βPix interacts with Yap via the C-terminal KER domain and this physical interaction plays a key role in βPix-mediated Yap/Taz regulation. In normal mammary epithelial cells, Lats kinases are required for βPix function while Mst kinases are not required for Hippo signalling. In breast cancer cells, ectopic expression of βPIX is sufficient to re-couple the Hippo kinase cassette to Yap/Taz, suggesting a possible role as a tumour suppressor.M.Sc