Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

By Y. Liu-Chittenden, Bo Huang, J. Shim, Qian Chen, Se-Jin Lee, R. Anders, Jun O. Liu, Duojia Pan. Genes & Development, 2012

1,386 citations recorded by the source corpus.

The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

Subfields: Biochemistry, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/655130899ea5e250d04b1a772c240c2dfe46b4f6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. M. Cordenonsi
5. Z. Meng
6. S. Dupont
7. H. Park
8. Jung-Soon Mo

In Molecular Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. M. Cordenonsi
5. Duojia Pan
6. Young Chul Kim
7. Z. Meng
8. Toshiro Moroishi

Citations in the corpus

• Metabolic control of YAP and TAZ by the mevalonate pathway (2014, background): “Luciferase reporters (300 ng cm−2) were transfected together with CMV–Renilla (100 ng cm−2) to normalize for transfection efficiency. pcDNA3 and pcDNA3–p53R280K plasmids were co-transfected at 100 ng cm−2.”
• The Hippo signaling pathway in stem cell biology and cancer (2014, neutral): “Studies of NF2 conditional knockout mice also support a role for YAP in liver tumorigenesis [93,98,99].”
• Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (2014, neutral): “Furthermore, overexpression of a previously characterized dominant-negative Tead2 mutant (Tead2; Liu-Chittenden et al., 2012), which harbors a deletion of the C-terminal Yap1-interacting domain while retaining the ability to bind DNA, strongly blocked tumor cell proliferation of Yap1-expressing cell”
• The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain (2012, background): “Although the TEAD-interaction domain of YAP is known to be important for several YAP-mediated processes (10, 11, 40, 59), the WW domains and the PDZbm also are important for certain YAP functions (24, 42, 43, 51).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “Moreover, a constitutive-repressive form of TEAD fused to the engrailed repressor domain blocked YAP-induced liver overgrowth (125).”
• Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model (2017, methodology): “To verify the role of the YAP-TEAD complex in the effects on chondrocyte function including ECM secretion, we used verteporfin, a chemical which can disrupt YAP-TEAD interaction [54], and further confirmed that the suppression of ECM secretion caused by SMSC-Exos was rescued by verteporfin (Figure 4”
• The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment (2013, neutral): “Since the co-crystal structure of the YAP/TEAD complex has been recently determined 216–218 , it is possible that this detailed structural information can be leveraged to rationally design small-molecule inhibitors of YAP/TEAD by targeting residues that line the YAP/TEAD polypeptide interaction inte”
• YAP/TAZ at the roots of cancer (2016, background): “…2015; Xia et al., 2014; Zanconato et al., 2015; Zhao et al., 2008), to the extent that inhibiting YAP/TAZ-TEAD interaction represents one of the most promising avenues for antiYAP/TAZ therapeutic intervention (Chen et al., 2010; Liu-Chittenden et al., 2012; Pobbati et al., 2015; Tian et al., 2010).”
• Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment (2013, background): “J Clin Endocrinol Metab 94(11):4540–4546.”
• Alternative Wnt Signaling Activates YAP/TAZ (2015, methodology): “To verify the role of the YAP/TAZ-TEAD complex in FZD/ROR-mediated transcriptional regulation, we utilized verteporphin (VP), a drug that disrupts YAP/TAZ-TEAD interaction (Liu-Chittenden et al., 2012).”
• The Hippo signalling pathway and its implications in human health and diseases (2022, neutral): “373 In subsequent studies, VP was widely used to treat various diseases, including cancers, 374 – 378 fi brotic diseases 379,380 and glaucoma.”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “While much of the efforts have focused on disrupting the YAP-TEAD complex (Liu-Chittenden et al., 2012), recent mechanistic insights into the transcriptional machinery of the Hippo pathway have suggested new approaches for targeting the YAP oncoprotein.”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, neutral): “By these mechanisms, YAP and TAZ antagonize each other and may provide a buffer for fluctuations in Hippo pathway activity to ensure tissue homeostasis.”
• Mechanisms of Hippo pathway regulation (2016, neutral): “…expansion of progenitor cells, and tissue overgrowth (Camargo et al. 2007; Dong et al. 2007; Zhou et al. 2009; Cai et al. 2010; Lee et al. 2010; Lu et al. 2010; Song et al. 2010; Zhang et al. 2010; Nishio et al. 2012; Chen et al. 2015b), supporting the functional roles of these genes in the…”