DOCK5 couples CDC42-GSK3β activation with focal adhesion morphogenesis to reinforce the establishment of polarity and promote YAP/TAZ activation during migration

Abstract YAP and TAZ are transcriptional co-activators that are often constitutively active in triple negative breast cancer (TNBC) cells. However the mechanisms responsible for YAP/TAZ dysregulation in TNBC remain unclear. We hypothesised that RhoGEF activity in TNBC cells underpins YAP/TAZ activation in TNBC cells. Through systematic RNAi screening we found that the Focal Adhesion (FA) associated RhoGEF DOCK5 promotes YAP/TAZ nuclear translocation in proliferating TNBC cells. DOCK5 is required for 2D migration and 3D invasion, acting as a coincident detector that maintains cell polarity by stabilising GSK3β activation downstream of CDC42 at polarised leading edges only where FAs are being assembled. DOCK5 and CDC42 are required for cell survival and drug resistance in TNBC cells. Based on these studies we propose that cancer cell phenotypes such as drug resistance can be driven by cells adopting polarised, migratory shapes.