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Cited by 92Ubiquitin and proteasome pathwaysProtein Kinase Regulation and GTPase SignalingTGF-β signaling in diseases

A new mechanism of RhoA ubiquitination and degradation: Roles of SCF(FBXL19) E3 ligase and Erk2

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Wei, Jianxin, Mialki, Rachel K., Dong, Su, Khoo, Andrew, Mallampalli, Rama K., Zhao, Yutong, Zhao, Jing·2013·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
DOI 10.1016/j.bbamcr.2013.07.005PMC PMC3834026
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Abstract

RhoA is a small GTPase multifunctional protein that regulates cell proliferation and cytoskeletal reorganization. Regulation of its protein stability plays an important role in its biological functions. We have shown that a Skp1-Cul1-F-box (SCF) FBXL19 E3 ubiquitin ligase targets Rac1, a related member of the Rho family for ubiquitination and degradation. Here, SCF(FBXL19) mediates RhoA ubiquitination and proteasomal degradation in lung epithelial cells. Ectopically expressed FBXL19 decreased RhoA wild type, active, and inactive forms. Cellular depletion of FBXL19 increased RhoA protein levels and extended its half-life. FBXL19 bound the small GTPase in the cytoplasm leading to RhoA ubiquitination at Lys(135). A RhoA(K135R) mutant protein was resistant to SCF(FBXL19)-mediated ubiquitination and degradation and exhibited a longer lifespan. Protein kinase Erk2-mediated phosphorylation of RhoA was both sufficient and required for SCF(FBXL19)-mediated RhoA ubiquitination and degradation. Thus, SCF(FBXL19) targets RhoA for its disposal, a process regulated by Erk2. Ectopically expressed FBXL19 reduced phosphorylation of p27 and cell proliferation, a process mediated by RhoA. Further, FBXL19 cellular expression diminished lysophosphatidic acid (LPA)-induced phosphorylation of myosin light chain (MLC) and stress fiber formation. Hence, SCF(FBXL19) functions as a RhoA antagonist during cell proliferation and cytoskeleton rearrangement. These results provide the first evidence of an F-box protein targeting RhoA thereby modulating its cellular lifespan that impacts cell proliferation and cytoskeleton rearrangement.

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  • SCFFBXL19 targets both the active and inactive forms of RhoA on Lys135, but the process is dependent on prior Erk2-mediated phosphorylation of RhoA.

    “In contrast, SCFFBXL19 targets both the active and inactive forms of RhoA on Lys135, but the process is dependent on prior Erk2-mediated phosphorylation of RhoA [62].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [62]

  • 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 [62]

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Cited by

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Authors
Wei, J., Mialki, R. K., Dong, S., Khoo, A., Mallampalli, R. K., Zhao, Y., & Zhao, J.
Affiliations
University of Pittsburgh (US)
Corresponding author
Zhao, Jing
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2013-12
Volume
1833
Issue
12
Pages
2757-2764
ISSN
0167-4889 (ISSN-L)
DOI
10.1016/j.bbamcr.2013.07.005
PMC
PMC3834026
OpenAlex
W1980894239
Cited by
92
References
0
Citations by year
2026: 2 · 2025: 7 · 2024: 7 · 2023: 11 · 2022: 9 · 2021: 2 · 2020: 8 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 8 · 2013: 1
FWCI
3.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • US National Institutes of Health (RO1 HL01916, HL112791, HL096376, HL097376, HL098174)
  • American Heart Association (12SDG9050005)
  • Merit Review Award
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
RhoA, SCF ubiquitin ligase, ubiquitination, proteasomal degradation, ERK2 phosphorylation, p27 phosphorylation, cell proliferation, cytoskeleton rearrangement, lysophosphatidic acid, myosin light chain phosphorylation, stress fiber formation, lung epithelial cells, Rho GTPases
MeSH terms
Animals, Cell Line, DNA-Binding Proteins, Enzyme Stability, Epithelial Cells, Lung, Lysine, Phosphorylation, Protein Binding, Mitogen-Activated Protein Kinase 1, rhoA GTP-Binding Protein, Stress Fibers, Ubiquitin, Ubiquitin-Protein Ligases, F-Box Proteins, Proteasome Endopeptidase Complex, Cell Proliferation, Mice, Ubiquitination, Proteolysis

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