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ARHGAP18-ezrin functions as an autoregulatory module for RhoA in the assembly of distinct actin-based structures
Open accessPreprint — published as 10.7554/elife.83526 · Paper page
Abstract
The location of different actin-based structures is largely regulated by Rho GTPases through specific effectors. We use the apical aspect of epithelial cells as a model system to investigate how RhoA is locally regulated to contribute to two distinct adjacent actin-based structures. Assembly of the non-muscle myosin-2 filaments in the terminal web is dependent on RhoA activity, and assembly of the microvilli also requires active RhoA for phosphorylation and activation of ezrin. We show the RhoGAP, ARHGAP18, is localized by binding active microvillar ezrin, and this interaction enhances ARHGAP18’s RhoGAP activity. We present a model where ezrin-ARHGAP18 acts as a negative autoregulatory module to locally reduce RhoA activity in microvilli. Consistent with this model, loss of ARHGAP18 results in disruption of the distinction between microvilli and the terminal web including aberrant assembly of myosin-2 filaments forming inside microvilli. Thus, ARHGAP18, through its recruitment and activation by ezrin, fine-tunes the local level of RhoA to allow for the appropriate distribution of actin-based structures between the microvilli and terminal web. As RhoGAPs vastly out-number Rho GTPases, this may represent a general mechanism whereby individual Rho effectors drive specific actin-based structures.
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Metadata
- Authors
- Lombardo, A. T., Mitchell, C. A. R., Zaman, R., McDermitt, D. J., & Bretscher, A.
- Affiliations
- Cornell University (US)
- Corresponding author
- Lombardo, Andrew T.
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2022-09-12
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC10830128
- OpenAlex
- W4390758263
- Cited by
- 16
- References
- 1
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 6
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (1428922)
- University of Vermont
- National Institutes of Health (1428922)
- National Institute of General Medical Sciences (R35GM131751)
- 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 › Cell Biology › Cellular transport and secretion
- Keywords
- ARHGAP18, ezrin, RhoA, Rho GTPases, negative autoregulation, microvilli, terminal web, ezrin phosphorylation, actin cytoskeleton regulation
- MeSH terms
- Ezrin, Actins, Cytoskeletal Proteins, Myosins, rho GTP-Binding Proteins
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