Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription
Open accessAbstract
Intestinal homeostasis is tightly regulated by complex yet poorly understood signaling networks. Here, we demonstrate that Lats1/2, the core Hippo kinases, are essential to maintain Wnt pathway activity and intestinal stem cells. Lats1/2 deletion leads to loss of intestinal stem cells but drives Wnt-uncoupled crypt expansion. To explore the function of downstream transcriptional enhanced associate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylation that directly occupies its lipid-binding site and inhibits TEAD-mediated transcription in vivo. Combining this chemical tool with genetic and proteomics approaches, we show that intestinal Wnt inhibition by Lats deletion is Yes-associated protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ interact with Groucho/Transducin-Like Enhancer of Split (TLE) to block Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a pharmacological approach to inhibit TEAD palmitoylation and have important implications for targeting Wnt and Hippo signaling in human malignancies.
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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 [438]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling
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- Authors
- Li, Q., Sun, Y., Jarugumilli, G. K., Liu, S., Dang, K., Cotton, J. L., Xiol, J., Chan, P. Y., DeRan, M., Ma, L., Li, R., Zhu, L. J., Li, J. H., Leiter, A. B., Ip, Y. T., Camargo, F. D., Luo, X., Johnson, R. L., Wu, X., & Mao, J.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Boston Children's Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Wu, Xu
- Mao, Junhao
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 26
- Issue
- 5
- Pages
- 675-692.e8
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC7310193
- OpenAlex
- W3014826571
- Cited by
- 180
- References
- 89
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 44 · 2023: 24 · 2022: 35 · 2021: 27 · 2020: 9
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- LATS1/2, Hippo signaling pathway, intestinal stem cells, Wnt signaling, TEAD transcription factors, small molecule inhibitors, YAP/TAZ, temporal lobe epilepsy, c-Myc, intestinal homeostasis, APC mutation, adenomatous polyposis coli, epithelial cell proliferation
- MeSH terms
- Humans, Intestines, Neoplasms, Phosphoproteins, Protein Binding, Stem Cells, Transcription Factors, Protein Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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