Transcriptional enhancer factor TEAD–Yes-associated protein 1 complex (TEAD–YAP1)

The Transcriptional enhancer factor TEAD–Yes-associated protein 1 (TEAD–YAP1) complex is the terminal transcriptional effector of the Hippo signaling pathway, which is essential for regulating organ size, tissue homeostasis, and regeneration (PMID: 30104373). YAP1 (Yes-associated protein 1) and its paralog TAZ function as transcriptional co-activators that do not bind DNA directly but must interact with TEA domain (TEAD1–4) transcription factors to drive the expression of genes associated with cell proliferation and survival (UniProt P46527). In many human cancers, the Hippo pathway is inactivated through mutations in upstream regulators like NF2 or LATS1/2, leading to the constitutive nuclear localization of YAP1 and its persistent interaction with TEAD (PMID: 34634258). This interaction promotes oncogenic transformation, epithelial-to-mesenchymal transition, and resistance to conventional therapies. Therapeutic strategies focus on disrupting this protein-protein interaction using small molecules that target the conserved hydrophobic palmitoylation pocket of TEAD, which is required for its structural stability and co-activator binding (PMID: 33005034). Clinical-stage inhibitors such as IK-930 and IAG933 are currently being investigated for the treatment of YAP-driven malignancies, including malignant mesothelioma and other solid tumors with Hippo pathway alterations (ClinicalTrials.gov NCT05228015).

Other names

YAP1–TEAD complexHippo pathway effector complexYAP–TEAD interactionTEAD–YAP complexYAP1–TEAD1/2/3/4 interactionTEAD–YAP1 protein-protein interaction

Small molecule inhibition of the protein-protein interaction between TEAD and YAP1, often via covalent or non-covalent binding to the TEAD palmitoylation pocket to prevent YAP1/TAZ recruitment (PMID: 33005034).