Regulation of the Polarity Protein Par6 by TGFß Receptors Controls Epithelial Cell Plasticity
Abstract
The transition of cells from an epithelial to a mesenchymal phenotype is a critical event during morphogenesis in multicellular organisms and underlies the pathology of many diseases, including the invasive phenotype associated with metastatic carcinomas. Transforming growth factor β (TGFβ) is a key regulator of epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms that control the dissolution of tight junctions, an early event in EMT, remain elusive. We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFβ receptors and is a substrate of the type II receptor, TβRII. Phosphorylation of Par6 is required for TGFβ-dependent EMT in mammary gland epithelial cells and controls the interaction of Par6 with the E3 ubiquitin ligase Smurf1. Smurf1, in turn, targets the guanosine triphosphatase RhoA for degradation, thereby leading to a loss of tight junctions. These studies define how an extracellular cue signals to the polarity machinery to control epithelial cell morphology.
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RhoA is ubiquitylated by three different E3 ubiquitin ligase complexes: SMURF1, SCFFBXL19, and CUL3BACURD.
“RhoA is ubiquitylated by three different E3 ubiquitin ligase complexes: the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), SKP1-CUL1-F-box FBXL19 (SCFFBXL19), and the BTB/POZ domain-containing adaptor for CUL3-mediated RhoA degradation (CUL3BACURD) ligase complex.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [67]
SMURF1 ubiquitinates active GTP-bound RhoA on Lys6 and Lys7, targeting RhoA for proteasomal degradation.
“While SMURF1 ubiquitinates active GTP-bound RhoA on Lys6 and Lys7 targeting RhoA for proteasomal degradation [66,67], CUL3BACURD ubiquitinates only GDP-bound inactive RhoA [68,69].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [67]
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- Authors
- Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H.-R., Zhang, Y., & Wrana, J. L.
- Affiliations
- Mount Sinai Hospital (CA)
- Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Canada.
- Corresponding author
- Ozdamar, Barish
- Bose, Rohit
- Wrana, Jeffrey L.
- Venue
- Science
- Published
- 2005-03-11
- Volume
- 307
- Issue
- 5715
- Pages
- 1603-1609
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2028919524
- Cited by
- 881
- References
- 1
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 21 · 2023: 20 · 2022: 35 · 2021: 24 · 2020: 37 · 2019: 33 · 2018: 38 · 2017: 30 · 2016: 46 · 2015: 40 · 2014: 47 · 2013: 64 · 2012: 70
- FWCI
- 23.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- Par6, TGF-beta signaling, epithelial-mesenchymal transition, epithelial polarity, tight junctions, Smurf1, mammary epithelial cells, cellular plasticity, ubiquitination
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Amino Acid Sequence, Animals, Cell Line, DNA-Binding Proteins, Epithelial Cells, Humans, Mesoderm, Models, Biological, Molecular Sequence Data, Mutation, Phosphorylation, Protein Binding, Protein Kinase C, Proteins, Trans-Activators, Transforming Growth Factor beta, Cell Polarity, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Tight Junctions, rhoA GTP-Binding Protein, Activin Receptors, Type I, Ubiquitin-Protein Ligases, Mice, Protein Kinase C-epsilon, Smad2 Protein
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