| In the classical view of the Hippo Pathway, an upstream signal can cause Mammalian STE20-like protein kinase 1 or 2 to phosphorylate and thereby activate Large tumor suppressor 1 or 2 resulting in the phosphorylation and inhibition of transcriptional co-activators yes-associated-protein (YAP) and transcriptional co-activator with PDZ-binding domain (TAZ). Phosphorylated YAP/TAZ is either sequestered in the cytoplasm or degraded and can no longer enter the nucleus bind to TEAD transcription factor to induce the expression of target genes. Aberrant YAP-TEAD mediated transcription in tumors promotes cell cycle re-entry of non-dividing cells, increased cellular migration, proliferation and resistance to apoptosis thus contributing to tumor maintenance and progression. To date, there are no specific inhibitors targeting this deregulated pathway used in the clinic despite the increasing body of literature surrounding the relevance of YAP/TAZ hyperactivition in cancers. Here, I show that Tankyrase inhibitors provide a means of impeding YAP-TEAD transcriptional activity via the stabilization of Angiomotin, a component of the pathway capable of sequestering YAP in the cytoplasm regardless of YAP phosphorylation state. These findings illustrate the importance of the relationship between Tankyrase and Angiomotin in regulating deregulated YAP-TEAD target gene transcription and highlight Tankyrase inhibitors as a class of potential new therapeutic agents for dysregulated Hippo signaling. |
