TEA domain transcription factor (TEAD) (TEAD)

The TEA domain transcription factor (TEAD) family, comprising TEAD1-4, is the primary transcriptional effector of the Hippo signaling pathway, which plays a critical role in regulating organ size, tissue regeneration, and stem cell maintenance (Harvey et al., 2013). A unique structural hallmark of TEAD proteins is a deep, internal hydrophobic pocket that facilitates auto-palmitoylation at a conserved cysteine residue; this post-translational modification is essential for the protein's structural stability and its ability to recruit co-activators such as YAP and TAZ (Noland et al., 2016). In many human cancers, including malignant mesothelioma and NF2-deficient tumors, the Hippo pathway is dysregulated, leading to the hyperactivation of TEAD-mediated transcription of pro-survival and pro-proliferative genes (Moroishi et al., 2015). The auto-palmitoylated protein pocket has emerged as a key therapeutic vulnerability, as small molecule inhibitors can bind within this pocket to prevent palmitoylation or displace the palmitate group, effectively silencing the oncogenic output of the Hippo pathway (Tang et al., 2021). Several TEAD inhibitors, such as VT3989 and IK-930, are currently in clinical trials for the treatment of advanced solid tumors (ClinicalTrials.gov, 2023). Targeting this specific pocket provides a novel mechanism for precision oncology in patients with Hippo-pathway-driven malignancies (Holden and Cunningham, 2018).

Other names

Transcriptional enhancer factorTEFTEA domain family memberTEAD1TEAD2TEAD3TEAD4Auto-palmitoylated protein pocket

Small molecule inhibitors bind to the conserved hydrophobic palmitate-binding pocket of TEAD proteins, preventing auto-palmitoylation and disrupting the interaction between TEAD and its co-activators YAP and TAZ, thereby inhibiting the transcription of pro-proliferative and anti-apoptotic genes.