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

The Yes-associated protein 1–TEA domain transcription factor (YAP–TEAD) complex is the terminal transcriptional effector of the Hippo signaling pathway, playing a central role in regulating organ size, cell proliferation, and tissue regeneration [1, 3]. Under physiological conditions, the Hippo kinase cascade (MST1/2 and LATS1/2) phosphorylates YAP1, leading to its cytoplasmic retention and degradation; however, when the pathway is inactivated, unphosphorylated YAP1 translocates to the nucleus to form a complex with TEAD transcription factors [3, 17]. This complex binds to specific DNA motifs to drive the expression of genes that promote cell survival and inhibit apoptosis, such as CTGF and CYR61 [2, 9]. In many cancers, particularly those with NF2 mutations or Hippo pathway dysregulation, the YAP–TEAD complex is constitutively active, driving tumor growth, metastasis, and drug resistance [4, 16]. Therapeutic strategies targeting this complex include small molecules that disrupt the YAP–TEAD protein-protein interaction or inhibit TEAD autopalmitoylation, which is essential for its stability and activity [6, 7]. Clinical development of these inhibitors is ongoing, with a focus on treating mesothelioma and other YAP-driven solid tumors, though potential side effects like renal toxicity remain a significant concern [11, 17].

Other names

YAP1-TEAD complexYAP/TEAD complexYAP-TEAD1-4 complexHippo pathway effector complexYes-associated protein 1–Transcriptional enhancer associate domain complex

Inhibition of protein-protein interaction (PPI) between YAP and TEAD, inhibition of TEAD autopalmitoylation, and induction of a cofactor switch (molecular glue) to enhance interaction with repressive cofactors like VGLL4.