Yes-associated protein 1 - TEA domain transcription factor complex (YAP-TEAD)

The Yes-associated protein 1 - TEA domain transcription factor (YAP-TEAD) complex is the central transcriptional effector of the Hippo signaling pathway, a conserved mechanism that governs organ size, tissue homeostasis, and cell proliferation (PMID: 30305713). Under normal physiological conditions, the Hippo kinase cascade (MST1/2 and LATS1/2) phosphorylates YAP1, leading to its sequestration in the cytoplasm or proteasomal degradation. However, when the Hippo pathway is inactivated or dysregulated, YAP1 translocates into the nucleus where it lacks its own DNA-binding domain and must bind to TEA domain (TEAD1-4) transcription factors to initiate the expression of pro-survival and proliferative genes (PMID: 29123255). This complex is a major driver in various cancers, particularly those characterized by loss-of-function mutations in Neurofibromin 2 (NF2) or other Hippo pathway components, making it a high-priority therapeutic target (PMID: 34635837). Pharmacological intervention strategies primarily focus on small molecules that bind to a deep hydrophobic pocket in the TEAD protein, which is normally occupied by palmitate; targeting this site inhibits TEAD auto-palmitoylation and subsequently disrupts its interaction with YAP1 (PMID: 33144463). Clinical-stage inhibitors like IK-930 and VT-104 are currently being evaluated for their ability to suppress tumor growth in YAP-dependent malignancies such as mesothelioma and NF2-deficient schwannomas (ClinicalTrials.gov: NCT05228015).

Other names

YAP-TEAD complexYAP1-TEAD complexHippo pathway effector complexYAP/TAZ-TEAD complex

Inhibition of TEAD auto-palmitoylation and disruption of the YAP-TEAD protein-protein interaction