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Molecular and Cellular Biology, February 2009, p. 1035-1049, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.00336-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Transforming Rho Family GTPase Wrch-1 Disrupts Epithelial Cell Tight Junctions and Epithelial Morphogenesis{triangledown}

Donita C. Brady,1 Jamie K. Alan,1 James P. Madigan,2 Alan S. Fanning,3 and Adrienne D. Cox1,2,4,5*

Department of Pharmacology,1 Curriculum in Genetics and Molecular Biology,2 Department of Cell and Molecular Physiology,3 Department of Radiation Oncology,4 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275995

Received 27 February 2008/ Returned for modification 17 March 2008/ Accepted 20 November 2008

Wrch-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.

* Corresponding author. Mailing address: Departments of Radiation Oncology and Pharmacology, 1028 NCCCC, 101 Manning Drive, CB # 7512, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7512. Phone: (919) 966-7713, ext. 305. Fax: (919) 966-7681. E-mail: adrienne_cox{at}med.unc.edu

{triangledown} Published ahead of print on 8 December 2008.

Molecular and Cellular Biology, February 2009, p. 1035-1049, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.00336-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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