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Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway
Open accessAbstract
TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.
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“YAP/TAZ primarily pairs with the TEAD family of TFs to induce gene expression signatures that play an important role in cancer development, progression, and metastasis.435,436”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [436]
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Metadata
- Authors
- Chan, P., Han, X., Zheng, B., DeRan, M., Yu, J., Jarugumilli, G. K., Deng, H., Pan, D., Luo, X., & Wu, X.
- Affiliations
- Harvard University (US)
- Jilin University (CN)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Luo, Xuelian
- Wu, Xu
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-02-22
- Volume
- 12
- Issue
- 4
- Pages
- 282-289
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4798901
- OpenAlex
- W2274646531
- Cited by
- 313
- References
- 49
- Citations by year
- 2026: 40 · 2025: 38 · 2024: 54 · 2023: 37 · 2022: 39 · 2021: 21 · 2020: 26 · 2019: 19 · 2018: 21 · 2017: 13 · 2016: 4
- FWCI
- 13.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (DE-AC02-06CH11357, R01CA181537, W81XWH, R01DK107651, W81XWH-13)
- Howard Hughes Medical Institute
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
- Melanoma Research Alliance (R01CA181537, R01DK107651)
- University of Texas Southwestern Medical Center
- National Institutes of Health (DE-AC02–06CH11357, W81XWH)
- National Eye Institute (R01EY015708)
- National Cancer Institute (R01CA181537, DE-AC02-06CH11357)
- National Institute of General Medical Sciences (DE-AC02-06CH11357, R01GM107415)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107651)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- TEAD transcription factors, S-palmitoylation, Hippo signaling pathway, YAP, TAZ, VGLL4, protein lipidation, transcriptional regulation, myogenesis, tissue overgrowth, Yorkie, organ size control
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, TEA Domain Transcription Factors, Amino Acid Sequence, Animals, Cell Differentiation, Cell Line, Cysteine, DNA-Binding Proteins, Fatty Acids, Unsaturated, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Palmitates, Protein Binding, Transcription Factors, Signal Transduction, Trans-Activators, Sequence Alignment, Conserved Sequence, Protein Serine-Threonine Kinases, Muscle Fibers, Skeletal, Protein Transport, Drosophila Proteins, Lipoylation
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