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Cited by 16Protein Kinase Regulation and GTPase SignalingCellular Mechanics and InteractionsCellular transport and secretion

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ARHGAP18-ezrin functions as an autoregulatory module for RhoA in the assembly of distinct actin-based structures

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Lombardo, Andrew T, Mitchell, Cameron AR, Zaman, Riasat, McDermitt, David J, Bretscher, Anthony·2024·eLife
DOI 10.7554/elife.83526PMC PMC10830128

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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 that 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 outnumber 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., Zaman, R., McDermitt, D. J., & Bretscher, A.
Affiliations
Cornell University (US)
Corresponding author
Lombardo, Andrew T
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-01-09
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.83526
PMC
PMC10830128
OpenAlex
W4390758263
Cited by
16
References
3
Citations by year
2026: 7 · 2025: 3 · 2024: 6
FWCI
2.18
Type
journal article
Language
en
Open access
Licence
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 Institute of General Medical Sciences (R35GM131751)
  • The Sam and Nancy Fleming Research Fellowship
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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