Yes-associated protein 1 - Transcriptional enhanced associate domain protein-protein interface (YAP-TEAD interface)

The YAP-TEAD protein-protein interface is the terminal effector complex of the Hippo signaling pathway, a critical regulator of organ size, cell proliferation, and tissue homeostasis [1, 7, 8]. In the 'Hippo-off' state, the transcriptional co-activator Yes-associated protein 1 (YAP) or its paralog TAZ translocates to the nucleus and binds to Transcriptional Enhanced Associate Domain (TEAD) transcription factors to drive the expression of genes that promote cell survival and growth [2, 14, 18]. Dysregulation of this interface, often caused by mutations in upstream tumor suppressors like NF2 or LATS1/2, leads to the constitutive activation of oncogenic gene programs across various cancers, including mesothelioma and glioblastoma [11, 13, 21]. Therapeutic strategies targeting this interface focus on small molecules that either orthosterically block the YAP-TEAD binding site or allosterically inhibit TEAD by binding to its conserved palmitoylation pocket [5, 15, 19]. While these inhibitors show significant promise in treating Hippo-driven malignancies and overcoming drug resistance, safety concerns regarding renal function and tissue repair remain a primary focus of clinical development [3, 9, 17]. Current research is also exploring the use of YAP-TEAD gene signatures as biomarkers to identify patients most likely to benefit from these targeted therapies [10, 18].

Other names

YAP1-TEAD complexYAP/TAZ-TEAD interfaceHippo pathway effector complexYAP-TEAD transcriptional complex

Direct disruption of the protein-protein interaction between YAP/TAZ and TEAD transcription factors, or allosteric inhibition via the blockade of TEAD auto-palmitoylation which is required for YAP binding and transcriptional activity.