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J. Biol. Chem., Vol. 279, Issue 40, 41557-41562, October 1, 2004

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Isoforms of the Polarity Protein Par6 Have Distinct Functions^*

Lin Gao and Ian G. Macara

From the Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0577

PAR-6 is essential for asymmetric division of the Caenorhabditis elegans zygote. It is also critical for cell polarization in many other contexts throughout the Metazoa. The Par6 protein contains a PDZ domain and a partial CRIB (Cdc42/Rac interactive binding) domain, which mediate interactions with other polarity proteins such as Par3, Cdc42, Pals1, and Lgl. A family of mammalian Par6 isoforms (Par6A–D) has been described, but the significance of this diversification has been unclear. Here we demonstrate that Par6 family members localize differently when expressed in Madin-Darby canine kidney epithelial cells and have distinct effects on tight junction (TJ) assembly. Par6B localizes to the cytosol and inhibits TJ formation, but Par6A co-localizes predominantly with the TJ marker ZO-1 at cell-cell contacts and does not affect junctions. These functional differences correlate with differences in Pals1 binding; Par6B interacts strongly with Pals1, whereas Par6A binds weakly to Pals1 even in the presence of active Cdc42. Pals1 has a low affinity for the isolated CRIB-PDZ domain of Par6A, but analysis of chimeras showed that in addition Pals1 binding is blocked by an inhibitory property of the N terminus of Par6A. Unexpectedly, the localization of Par6A to cell-cell contacts is Cdc42-independent.

Received for publication, April 5, 2004 , and in revised form, July 23, 2004.

^* This work was supported by National Institutes of Health Grants CA40042 and GM070902. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Center for Cell Signaling, Box 800577, HSC, University of Virginia, Charlottesville, VA 22908-0577. Tel.: 434-982-0074; Fax: 434-924-1236; E-mail: imacara{at}virginia.edu.

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