A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF β-TRCP
Open accessAbstract
The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14–3–3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1δ/ɛ in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF β-TRCP E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1δ/ɛ as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear–cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).
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YAP contains a phosphodegron, so decreased YAP phosphorylation leads to YAP accumulation and nuclear translocation.
“YAP bears a phosphodegron so decreased YAP phosphorylation leads to YAP accumulation and eventual translocation into the nucleus where it drives transcription of tumor-promoting genes (Figure 5) [106].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [106]
The Abstract (page unavailable) identifies a YAP phosphodegron and says its phosphorylation promotes YAP degradation; it separately links Ser127 phosphorylation to cytoplasmic retention. The Spatial and temporal regulation of YAP section (page unavailable) likewise treats degradation and nuclear–cytoplasmic localization as distinct mechanisms. The source therefore supports the broad effect of reduced phosphorylation on YAP accumulation and nuclear activity, but not the sentence’s implication that phosphodegron phosphorylation itself controls nuclear translocation or its specific claim about transcription of tumor-promoting genes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredNuclear YAP drives transcription of tumor-promoting genes.
“YAP bears a phosphodegron so decreased YAP phosphorylation leads to YAP accumulation and eventual translocation into the nucleus where it drives transcription of tumor-promoting genes (Figure 5) [106].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [106]
The paper describes YAP as a transcription coactivator and human oncogene, and the Spatial and temporal regulation of YAP section says phosphorylation keeps it apart from nuclear transcription factors such as TEAD (page not provided). This supports a role for nuclear YAP in transcription, but our copy does not establish that the genes it helps transcribe are tumor-promoting. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPhosphorylated Lats1 and Lats2 inhibit Yap and Taz by phosphorylating multiple serine residues.
“Phosphorylated Lats1 and Lats2 then inhibit the transcriptional co-factors Yap and Taz by phosphorylating multiple serine residues (86, 162).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [162]
The section “YAP is phosphorylated in vivo on multiple sites” identifies five YAP serines at Lats consensus sites, and the paper describes Lats-mediated inhibition of YAP. The passages do not establish the same phosphorylation-and-inhibition claim for TAZ. No page numbers were provided in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn AMG510 resistant cell line NCI-H1792, AMG510 caused dose-dependent decreases in Phospho YAP S127-total YAP ratio.
“Experiments with the AMG510 resistant cell line NCI‐H1792 revealed AMG510 dose‐dependent decreases in the Phospho YAP S127‐total YAP ratio, which is commonly used as a negative marker for YAP signaling[ 34 ] (Figure 5B,C; Figure S6C,D, Supporting Information).”
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 [34]
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Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis
He, X., Tolosa, M. F., Zhang, T., Goru, S. K., Ulloa Severino, L., Misra, P. S., McEvoy, C. M., Caldwell, L., Szeto, S. G., Gao, F., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.146243 · Cited by 106 · see citing works
A feed forward loop enforces YAP/TAZ signaling during tumorigenesis
Gill, M. K., Christova, T., Zhang, Y. Y., Gregorieff, A., Zhang, L., Narimatsu, M., Song, S., Xiong, S., Couzens, A. L., Tong, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05939-2 · Cited by 95 · see citing works
Zhang, B., Zhang, Y., Zhang, J., Liu, P., Jiao, B., Wang, Z., & Ren, R. (2021) · Advanced Science · doi:10.1002/advs.202100250 · Cited by 83 · see citing works
Intersection of Hippo/YAP and Wnt/&beta;-catenin signaling pathways
Konsavage, W. M., & Yochum, G. S. (2013) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gms084 · Cited by 94 · see citing works
The Hippo signal transduction network in skeletal and cardiac muscle
Wackerhage, H., Del Re, D. P., Judson, R. N., Sudol, M., & Sadoshima, J. (2014) · Science Signaling · doi:10.1126/scisignal.2005096 · Cited by 92 · see citing works
Wilson, K. E., Li, Y.-W., Yang, N., Shen, H., Orillion, A. R., & Zhang, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.534701 · Cited by 92 · see citing works
The Hippo Signaling Pathway in Drug Resistance in Cancer
Zeng, R., & Dong, J. (2021) · Cancers · doi:10.3390/cancers13020318 · Cited by 89 · see citing works
Nguyen, H. B., Babcock, J. T., Wells, C. D., & Quilliam, L. A. (2013) · Oncogene · doi:10.1038/onc.2012.431 · Cited by 84 · see citing works
Screening for YAP inhibitors identifies statins as modulators of fibrosis
Santos, D. M., Pantano, L., Pronzati, G., Grasberger, P., Probst, C. K., Black, K. E., Spinney, J. J., Hariri, L. P., Nichols, R., Lin, Y., et al. (2020) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0296oc · Cited by 72 · see citing works
Loss of DLG5 promotes breast cancer malignancy by inhibiting the Hippo signaling pathway
Liu, J., Li, J., Li, P., Wang, Y., Liang, Z., Jiang, Y., Li, J., Feng, C., Wang, R., Chen, H., et al. (2017) · Scientific Reports · doi:10.1038/srep42125 · Cited by 61 · see citing works
Label-free quantitative proteomic analysis of the YAP/TAZ interactome
Kohli, P., Bartram, M. P., Habbig, S., Pahmeyer, C., Lamkemeyer, T., Benzing, T., Schermer, B., & Rinschen, M. M. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00339.2013 · Cited by 61 · see citing works
The Hippo signal transduction network for exercise physiologists
Gabriel, B. M., Hamilton, D. L., Tremblay, A. M., & Wackerhage, H. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01076.2015 · Cited by 48 · see citing works
DEGRONOPEDIA: a web server for proteome-wide inspection of degrons
Szulc, N. A., Stefaniak, F., Piechota, M., Soszyńska, A., Piórkowska, G., Cappannini, A., Bujnicki, J. M., Maniaci, C., & Pokrzywa, W. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae238 · Cited by 35 · see citing works
Acetylation: a new target for protein degradation in cancer
Crawford, C. E. W., & Burslem, G. M. (2025) · Trends in Cancer · doi:10.1016/j.trecan.2025.01.013 · Cited by 20 · see citing works
Casein Kinase 1α—A Target for Prostate Cancer Therapy?
Lishman-Walker, E., & Coffey, K. (2024) · Cancers · doi:10.3390/cancers16132436 · Cited by 4 · see citing works
- Authors
- Zhao, B., Li, L., Tumaneng, K., Wang, C.-Y., & Guan, K.-L.
- Affiliations
- University of California San Diego (US)
- University of Michigan (US)
- University of California, Los Angeles (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-01-01
- Volume
- 24
- Issue
- 1
- Pages
- 72-85
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2802193
- OpenAlex
- W2134937820
- Cited by
- 1,418
- References
- 49
- Citations by year
- 2026: 63 · 2025: 105 · 2024: 148 · 2023: 102 · 2022: 130 · 2021: 119 · 2020: 118 · 2019: 120 · 2018: 95 · 2017: 63 · 2016: 62 · 2015: 74 · 2014: 58 · 2013: 66 · 2012: 48
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007752)
- 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 › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- YAP, Hippo signaling pathway, LATS kinase, phosphodegron, E3 ubiquitin ligase, ubiquitination, protein degradation, 14-3-3 binding, nucleocytoplasmic shuttling, oncogene regulation, organ size control
- MeSH terms
- YAP-Signaling Proteins, Cell Line, Gene Expression Regulation, HeLa Cells, Humans, Mutation, Phosphoproteins, Phosphorylation, Protein Binding, Serine, Transcription Factors, Protein Serine-Threonine Kinases, Amino Acid Motifs, SKP Cullin F-Box Protein Ligases, Casein Kinase I, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Ubiquitination, Protein Stability
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