Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP
Open accessAbstract
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.
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A number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU, and small molecules such as verteporfin and MGH-CP1.
“Over the years, a number of inhibitors targeting YAP/TAZ-TEAD have been reported, including peptides such as super-TDU (173),437 and small molecules such as verteporfin (174) and MGH-CP1 (175).438–440”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [437]
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References 24 · Cited by 1,452
- Authors
- Liu-Chittenden, Y., Huang, B., Shim, J. S., Chen, Q., Lee, S.-J., Anders, R. A., Liu, J. O., & Pan, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-06-07
- Volume
- 26
- Issue
- 12
- Pages
- 1300-1305
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3387657
- OpenAlex
- W2100641053
- Cited by
- 1,452
- References
- 24
- Citations by year
- 2026: 69 · 2025: 106 · 2024: 113 · 2023: 128 · 2022: 141 · 2021: 135 · 2020: 137 · 2019: 130 · 2018: 116 · 2017: 86 · 2016: 97 · 2015: 90 · 2014: 66 · 2013: 29 · 2012: 7
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Eye Institute (R01EY015708)
- National Cancer Institute (R01CA122814)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081417)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060636)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- YAP, Scalloped, Yki, hepatomegaly, hepatocarcinogenesis, Merlin, verteporfin, small molecule inhibitors, tissue overgrowth, Drosophila
- MeSH terms
- Verteporfin, YAP-Signaling Proteins, TEA Domain Transcription Factors, Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Genes, Dominant, Hepatomegaly, Humans, Liver, Mice, Transgenic, Phenotype, Phosphoproteins, Porphyrins, Protein Binding, Transcription Factors, Cell Cycle Proteins, Neurofibromin 2, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Mice, HEK293 Cells
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