Regulation of cell polarity and protrusion formation by targeting RhoA for degradation
Abstract
The Rho family of small guanosine triphosphatases regulates actin cytoskeleton dynamics that underlie cellular functions such as cell shape changes, migration, and polarity. We found that Smurf1, a HECT domain E3 ubiquitin ligase, regulated cell polarity and protrusive activity and was required to maintain the transformed morphology and motility of a tumor cell. Atypical protein kinase C zeta (PKCζ), an effector of the Cdc42/Rac1-PAR6 polarity complex, recruited Smurf1 to cellular protrusions, where it controlled the local level of RhoA. Smurf1 thus links the polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements.
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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 [66]
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 [66]
Cites
Hippocampal Neuronal Polarity Specified by Spatially Localized mPar3/mPar6 and PI 3-Kinase Activity
Shi, S.-H., Jan, L. Y., & Jan, Y.-N. (2003) · Cell · doi:10.1016/s0092-8674(02)01249-7 · Cited by 600 · see citing works
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Development and dynamics of cell polarity at a glance
Campanale, J. P., Sun, T. Y., & Montell, D. J. (2017) · Journal of Cell Science · doi:10.1242/jcs.188599 · Cited by 198 · see citing works
System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes
Zhang, W., Wu, K.-P., Sartori, M. A., Kamadurai, H. B., Ordureau, A., Jiang, C., Mercredi, P. Y., Murchie, R., Hu, J., Persaud, A., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.02.005 · Cited by 168 · see citing works
RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
Wnt signaling and neurite outgrowth: Insights and questions
Endo, Y., & Rubin, J. S. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00536.x · Cited by 40 · see citing works
- Authors
- Wang, H.-R., Zhang, Y., Ozdamar, B., Ogunjimi, A. A., Alexandrova, E., Thomsen, G. H., & Wrana, J. L.
- Affiliations
- Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M56 1×5, Canada.
- Mount Sinai Hospital (CA)
- Corresponding author
- Zhang, Yue
- Wrana, Jeffrey L.
- Venue
- Science
- Published
- 2003-12-05
- Volume
- 302
- Issue
- 5651
- Pages
- 1775-1779
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2063090066
- Cited by
- 551
- References
- 1
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 12 · 2023: 18 · 2022: 16 · 2021: 11 · 2020: 18 · 2019: 18 · 2018: 22 · 2017: 24 · 2016: 27 · 2015: 18 · 2014: 22 · 2013: 39 · 2012: 44
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD032429, HD32429)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- RhoA, Smurf1, E3 ubiquitin ligase, protein degradation, cell polarity, cell protrusions, lamellipodia, filopodia, actin cytoskeleton dynamics, cell motility, tumor cell morphology, Rho GTPase signaling
- MeSH terms
- Protein Kinase C zeta, Animals, Cell Line, Cell Membrane, Cell Movement, Cell Transformation, Neoplastic, Cytoskeleton, Humans, Intercellular Junctions, Protein Kinase C, Pseudopodia, Transfection, Signal Transduction, Cell Polarity, Protein Structure, Tertiary, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, cdc42 GTP-Binding Protein, RNA, Small Interfering, NIH 3T3 Cells, Ubiquitin-Protein Ligases, Cell Line, Tumor, Cell Size, Mice
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