Transcriptional enhancer factor (TEAD) autopalmitoylation site (TEAD autopalmitoylation site)

The TEAD transcription factors (TEAD1-4) are the primary nuclear effectors of the Hippo signaling pathway, which regulates organ size and tissue homeostasis (UniProt P28347). A unique feature of TEAD proteins is a deep hydrophobic pocket that undergoes autopalmitoylation at a conserved cysteine residue, a process essential for the structural stability and transcriptional activity of the TEAD-YAP/TAZ complex (Noland et al., 2016, PMID: 26742041). In many cancers, the Hippo pathway is dysregulated, leading to hyperactivation of YAP/TAZ and subsequent TEAD-mediated transcription of genes promoting cell proliferation and survival (Harvey et al., 2013, PMID: 23846671). Targeting the TEAD autopalmitoylation site with small-molecule inhibitors has emerged as a promising therapeutic strategy to disrupt the Hippo-YAP/TAZ axis (Pobbati et al., 2015, PMID: 26151217). These inhibitors occupy the palmitate-binding pocket, preventing palmitoylation and effectively silencing the oncogenic transcriptional program (Tang et al., 2021, PMID: 34108461). This approach is particularly relevant for tumors harboring mutations in upstream Hippo components, such as NF2, which render the cells dependent on TEAD activity for growth.

Other names

TEAD palmitoylation pocketTEAD hydrophobic pocketTEAD lipid-binding pocketTEAD palmitate-binding siteTEAD P-pocketTEAD palmitoylation site

Small molecule inhibitors bind to the TEAD autopalmitoylation pocket, preventing the covalent attachment of palmitate. This destabilizes the TEAD protein or prevents its interaction with YAP/TAZ co-activators, thereby inhibiting the expression of pro-proliferative and anti-apoptotic genes (Tang et al., 2021, PMID: 34108461).