DESIGN OF TEAD LIGANDS AS MODULATORS OF THE HIPPO PATHWAYS
TEAD (Transcriptional enhancer factor TEF with TEA/ATTS domain) transcription factors are the final effectors of the Hippo signaling pathway. Their functions are mainly mediated by their interactions with the nuclear coactivators (Yes Associated Protein) and its paralog TAZ (Transcriptional coactivator with PDZ-binding motif) (also called WWTR1).
Hippo signaling pathway is a conserved regulator of organ size which is composed of a core kinase cascade. Phosphorylation of the downstream effectors YAP or TAZ changes their subcellular localization from the nucleus (unphosphorylated) to the cytoplasm (phosphorylated) (Figure 1). When phosphorylated YAP and TAZ are sequestered by 14-3-3 protein or degraded via the ubiquitin/proteasomal pathway, whereas unphosphorylated YAP/TAZ translocates to the nucleus and activates several nuclear transcriptional factors included TEADs. The activation of TEADs induces the expression of several Hippo pathway target genes including CTGF, Cyr61 and Axl.
Figure 1: TEAD ligands: its localization and its partners
Recent progress has highlighted the effects of Hippo signaling in cell proliferation, differentiation, apoptosis and tumorigenesis, including its crucial role in cancer stem cell (CSC) regulation.
Besides its increasingly recognized role in tumour development, the family of TEAD transcription factors has recently emerged as a key regulator of the pool of neural stem cells (NSC) during embryonic development, controlling their proliferation, self-renewal, survival and differentiation
Figure 2: Druggable cavities of the coactivator binding domain of TEAD. The structure used for this analysis was 3KYS. The cavities corresponding to the interface 3, interface 2 and palmitate pocket are in purple, blue and pink respectively.
The aim of our project is to design new drugs able to bind to the coactivator binding domain of TEAD (Figure 2) in order to inhibit YAP(TAZ)/TEAD complex (cancer) or to activate YAP(TAZ)/TEAD complex (regenerative medicine).