The transforming Rho family GTPase Wrch-1 disrupts epithelial cell tight junctions and epithelial morphogenesis: Mol.Cell Biol.

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TypeArticle
Journal titleMol.Cell Biol.
Volume29
Issue4
Pages10351049; # of pages: 15
Subject3D; Actins; Adaptor Proteins,Signal Transducing; Animals; binding; cell; Cell Adhesion; Cell Polarity; Cell Proliferation; Cell Shape; CELLS; Cercopithecus aethiops; chemistry; Cos Cells; cytology; Dogs; DOMAIN; drug effects; embryology; Enzyme Activation; enzymology; Epithelial Cells; Epithelium; genetics; Guanosine Triphosphate; Human; Humans; kinetic; Kinetics; membrane; Membranes; metabolism; Morphogenesis; MUTANT; Mutation; ORGANIZATION; pharmacology; protein; Protein Binding; Protein Structure,Tertiary; Protein Transport; Proteins; rho GTP-Binding Proteins; Tight Junctions
AbstractWrch-1, an atypical and transforming Rho GTPase, regulates cellular activities including proliferation and actin organization, but its functions and effectors remain poorly characterized. We show here that Wrch-1 distributes along the apical and basolateral membranes in MDCK cells and binds the cell polarity protein Par6 in a GTP-dependent manner. Activated Wrch-1 negatively regulates the kinetics of tight junction (TJ) assembly during epithelial cell polarization but has no detectable effect on overall cell polarity in confluent monolayers. It also causes a dramatic cytoskeletal reorganization and multilayering in cells grown in two-dimensional culture and disrupts cystogenesis of cells grown in three-dimensional (3D) culture. Similarly, short hairpin RNA-mediated knockdown of Wrch-1 perturbs cystogenesis in 3D culture, suggesting that tight regulation of Wrch-1 activity is necessary for normal epithelial morphogenesis. A weakly transforming effector domain mutant of activated Wrch-1 that inhibits Par6 binding abrogates the ability of Wrch-1 to disrupt TJ formation, actin organization, and epithelial morphogenesis. We hypothesize that Wrch-1-induced morphological and growth transformation may occur in part through Par6-mediated disruption of TJs and actin organization
Publication date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberBRADY2009
NPARC number9368084
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Record identifierb9dde1de-9583-4b91-8483-f621c297cc40
Record created2009-07-10
Record modified2016-05-09
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