Yes-associated protein 1–Transcriptional enhanced associate domain protein complex (YAP1–TEAD)

The Yes-associated protein 1–Transcriptional enhanced associate domain (YAP1–TEAD) protein–protein complex is the primary transcriptional effector of the Hippo signaling pathway, a conserved regulator of organ size and tissue homeostasis (UniProt P46937; PubMed: 29932355). YAP1 acts as a transcriptional co-activator that lacks its own DNA-binding domain, necessitating its interaction with TEAD family transcription factors (TEAD1–4) to facilitate DNA binding and promote the expression of genes associated with cell survival and proliferation. In many human cancers, the Hippo pathway is dysregulated through mutations in upstream regulators like NF2 or LATS1/2, leading to the constitutive nuclear accumulation of YAP1 and hyperactivation of the YAP1–TEAD complex (PubMed: 34634258). This aberrant activity drives oncogenic processes, including epithelial-mesenchymal transition, metastasis, and resistance to conventional therapies. Consequently, the YAP1–TEAD interaction has emerged as a high-priority therapeutic target, with drug development strategies focusing on direct protein-protein interaction inhibitors or small molecules that target the conserved palmitoylation pocket of TEAD proteins. Clinical candidates such as IK-930 and VT-104 are currently being evaluated in trials for patients with Hippo-pathway-deficient solid tumors, such as mesothelioma and NF2-mutated cancers (ClinicalTrials.gov: NCT05228015, NCT04665206).

Other names

YAP-TEAD complexYAP1/TEAD1-4 complexYAP/TAZ-TEAD complexYAP1-TEAD transcription factor complex

Inhibition of the protein-protein interaction between YAP1 and TEAD or inhibition of TEAD auto-palmitoylation to prevent transcriptional co-activation.