title: Conundrum, an ARHGAP18 orthologue, regulates RhoA and proliferation through interactions with Moesin.
abstract: RhoA, a small GTPase, regulates epithelial integrity and morphogenesis by controlling filamentous actin assembly and actomyosin contractility. Another important cytoskeletal regulator, Moesin (Moe), an ezrin, radixin, and moesin (ERM) protein, has the ability to bind to and organize cortical F-actin, as well as the ability to regulate RhoA activity. ERM proteins have previously been shown to interact with both RhoGEF (guanine nucleotide exchange factors) and RhoGAP (GTPase activating proteins), proteins that control the activation state of RhoA, but the functions of these interactions remain unclear. We demonstrate that Moe interacts with an unusual RhoGAP, Conundrum (Conu), and recruits it to the cell cortex to negatively regulate RhoA activity. In addition, we show that cortically localized Conu can promote cell proliferation and that this function requires RhoGAP activity. Surprisingly, Conu's ability to promote growth also appears dependent on increased Rac activity. Our results reveal a molecular mechanism by which ERM proteins control RhoA activity and suggest a novel linkage between the small GTPases RhoA and Rac in growth control.
authors.affiliation: Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Neisch
authors.forename: Etienne
authors.initials: E
authors.lastname: Formstecher
authors.forename: Richard G
authors.initials: RG
authors.lastname: Fehon
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D054910:Compound Eye, Arthropod / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D060227:Imaginal Discs / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055550:Protein Stability; D021381:Protein Transport; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C542464:ARHGAP18 protein, human; C584365:Conu protein, Drosophila; D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; C099886:moesin, Drosophila; C511153:Rho1 protein, Drosophila; D020741:rho GTP-Binding Proteins