Andrew T Lombardo, Cameron AR Mitchell, Riasat Zaman, David J McDermitt, Anthony Bretscher

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

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine
  • General Neuroscience

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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