Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control
Open accessAbstract
The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila . Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.
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Increased cell-cell contact reduces mechanical loading of cells, which explains deactivation of Yap and Taz at high cell density.
“Later, it was shown that increased cell-cell contact reduces the mechanical loading of cells, which explained the previously observed (163) deactivation of Yap and Taz in response to cell-cell contact at high cell density (8).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [163]
The section “YAP localization and phosphorylation are regulated by cell density” reports that YAP moves from the nucleus to the cytoplasm and becomes phosphorylated at high cell density. This supports the cited observation for YAP, but our copy does not establish the same response for TAZ. It explains YAP regulation through Hippo-pathway phosphorylation, not reduced mechanical loading; the sentence appears to attribute that later explanation to a different citation. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIN10018 treatment accumulated Phospho YAP S127 within 24 h and reduced CYR61 level in NCI-H358 cells.
“Phospho YAP S127 which is indicative of YAP signaling inhibition,[ 30 ] was accumulated within 24 h of IN10018 treatment. Consistently, the level of CYR61, a downstream marker of YAP signaling, was apparently reduced by IN10018 treatment (Figure 4E).”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [30]
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References 48 · Cited by 3,092
- Authors
- Zhao, B., Wei, X., Li, W., Udan, R. S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., Li, L., Zheng, P., Ye, K., Chinnaiyan, A., Halder, G., Lai, Z.-C., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Pennsylvania State University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Emory University (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-11-01
- Volume
- 21
- Issue
- 21
- Pages
- 2747-2761
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2045129
- OpenAlex
- W2099709490
- Cited by
- 3,092
- References
- 48
- Citations by year
- 2026: 120 · 2025: 181 · 2024: 227 · 2023: 193 · 2022: 272 · 2021: 278 · 2020: 246 · 2019: 226 · 2018: 228 · 2017: 186 · 2016: 180 · 2015: 176 · 2014: 140 · 2013: 121 · 2012: 97
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- BearWorks (Missouri State University) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- National Science Foundation (0641914)
- 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 › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- Hippo signaling pathway, YAP, Yorkie, contact inhibition, cell density, cytoplasmic translocation, tissue growth control, organ size control, cell proliferation, Salvador, Bahia, neurofibromatosis type 2, fats, tumor suppressor, liver cancer, prostate cancer, transcriptional regulation
- MeSH terms
- YAP-Signaling Proteins, Hippo Kinases, Amino Acid Sequence, Animals, Cell Communication, Cell Count, Cells, Cultured, Contact Inhibition, Drosophila, HeLa Cells, Humans, Models, Biological, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Kinases, Signal Transduction, Trans-Activators, Protein Serine-Threonine Kinases, Amino Acid Motifs, Protein Transport, Drosophila Proteins, NIH 3T3 Cells, Intracellular Signaling Peptides and Proteins, 14-3-3 Proteins, Cell Proliferation, Mice
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