TEAD-(YAP) structure, function and inhibition

The Hippo signalling is a metabolic control pathway of cells proliferation and apoptosis, thus represents an emerging topic in tumour suppression regulation and regenerative medicine. This pathway is activated by anti-proliferative signals which come from the extracellular environment received by membranes proteins. In the cytosol compartment, the pathway is regulated by a phosphorylation cascade of four main proteins with Serin-Treonin kinase activity. At the end-point of this cascade the phosphorylation of YAP/TAZ paralogues proteins, act as TEAD1-4 transcriptional coactivators. YAP-Ser127 phosphorylation activates YAP/TAZ proteasomal degradation, and this prevents its migration to the nucleus for YAP:TEAD interaction, thus preventing the transcription of genes activating cell proliferation. TEAD protein shows three binding surfaces, of which the lipid site is usually bound to palmitic/miristic acid. The functional roles of the interfaces is still unclear. The objectives of the project are the characterization of the protein-protein interaction, the function and inhibition.