Yap1 acts downstream of α-catenin to control epidermal proliferation
Open accessAbstract
During development and regeneration, proliferation of tissue-specific stem cells is tightly controlled to produce organs of a predetermined size. The molecular determinants of this process remain poorly understood. Here, we investigate the function of Yap1, the transcriptional effector of the Hippo signaling pathway, in skin biology. Using gain- and loss-of-function studies, we show that Yap1 is a critical modulator of epidermal stem cell proliferation and tissue expansion. Yap1 mediates this effect through interaction with TEAD transcription factors. Additionally, our studies reveal that α-catenin, a molecule previously implicated in tumor suppression and cell density sensing in the skin, is an upstream negative regulator of Yap1. α-catenin controls Yap1 activity and phosphorylation by modulating its interaction with 14-3-3 and the PP2A phosphatase. Together, these data identify Yap1 as a determinant of the proliferative capacity of epidermal stem cells and as an important effector of a "crowd control" molecular circuitry in mammalian skin.
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In the absence of Hippo pathway activity (e.g., at low cell density), YAP1 is shuttled to the nucleus, which enhances the ability of TEAD2 to induce target gene expression.
“In the absence of Hippo pathway activity (e.g., at low cell density), YAP1 is shuttled to the nucleus, which enhances the ability of TEAD2 to induce target gene expression (Schlegelmilch et al., 2011).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Schlegelmilch et al., 2011
The Results section, “TEAD interaction is critical for the role of Yap1 in the epidermis” (page unavailable), reports that Yap1 increases TEAD-reporter activity and that the signal decreases at high cell density. The Discussion section, “14-3-3 and Yap1 phosphorylation in the skin” (page unavailable), describes Yap1 entering the nucleus, binding TEADs, and activating gene expression when its inhibitory regulation is lost. The paper discusses TEAD proteins collectively, however, and does not establish the claimed effect specifically for TEAD2. (LLM, conf=0.87)
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“Additionally, the number of cells expressing p63, a SC marker and essential regulator of stemness in stratified epithelia (Senoo et al., 2007), was amplified in Tg skin (Figure 1F).”
Wu, S., Liu, Y., Zheng, Y., Dong, J., & Pan, D. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.01.007 · Cited by 640 · see citing works
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- Authors
- Schlegelmilch, K., Mohseni, M., Kirak, O., Pruszak, J., Rodriguez, J. R., Zhou, D., Kreger, B. T., Vasioukhin, V., Avruch, J., Brummelkamp, T. R., & Camargo, F. D.
- Affiliations
- Boston Children's Hospital (US)
- Whitehead Institute for Biomedical Research (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Camargo, Fernando D.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 144
- Issue
- 5
- Pages
- 782-795
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3237196
- OpenAlex
- W2139160260
- Cited by
- 1,036
- References
- 2
- Citations by year
- 2026: 28 · 2025: 48 · 2024: 58 · 2023: 50 · 2022: 73 · 2021: 65 · 2020: 76 · 2019: 82 · 2018: 82 · 2017: 65 · 2016: 71 · 2015: 83 · 2014: 81 · 2013: 80 · 2012: 63
- FWCI
- 39.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 905 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- V Foundation for Cancer Research
- Stand Up To Cancer
- National Cancer Institute (R01CA131426)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- YAP, Hippo signaling pathway, alpha-catenin, epidermal stem cells, epidermal proliferation, TEAD transcription factors, 14-3-3 proteins, protein phosphatase 2A, YAP1 phosphorylation, skin regeneration, tissue expansion, cell density sensing
- MeSH terms
- Epidermal Cells, YAP-Signaling Proteins, Animals, Cell Line, Epidermis, Phosphoproteins, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, 14-3-3 Proteins, Cell Proliferation, alpha Catenin, Mice
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