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J. Biol. Chem., Vol. 281, Issue 49, 37738-37747, December 8, 2006

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Mammalian Lin-7 Stabilizes Polarity Protein Complexes^*

Samuel W. Straight¹², Jay N. Pieczynski¹, Eileen L. Whiteman³, Chia-Jen Liu, and Ben Margolis⁴

From the Departments of Internal Medicine and Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109

Mammalian Lin-7 forms a complex with several proteins, including PALS1, that have a role in polarity determination in epithelial cells. In this study we have found that loss of Lin-7 protein from the polarized epithelial cell line Madin-Darby canine kidney II by small hairpin RNA results in defects in tight junction formation as indicated by lowered transepithelial electrical resistance and mislocalization of the tight junction protein ZO-1 after calcium switch. The knock down of Lin-7 also resulted in the loss of expression of several Lin-7 binding partners, including PALS1 and the polarity protein PATJ. The effects of Lin-7 knock down were rescued by the exogenous expression of murine Lin-7 constructs that contained the L27 domain, but not the PDZ domain alone. Furthermore, exogenously expressed PALS1, but not other Lin-7 binding partners, also rescued the effects of Lin-7 knock down, including the restoration of PATJ protein in rescued cell lines. Finally, the effects of Lin-7 knock down appeared to be due to instability of PALS1 protein in the absence of Lin-7, as indicated by an increased rate of PALS1 protein degradation. Taken together, these results indicate that Lin-7 functions in tight junction formation by stabilizing its membrane-associated guanylate kinase binding partner PALS1.

Received for publication, July 25, 2006 , and in revised form, September 20, 2006.

^* This work was supported in part by National Institutes of Health Grants DK58208 and DK39255. This work utilized the Morphology and Image Analysis Core of the Michigan Diabetes Research and Training Center funded by NIH5P60 DK20572 from NIDDK, National Institutes of Health. 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.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Microbiology and Immunology, University of Michigan, 5631 Med. Sci. II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0620.

³ Supported by the Cancer Biology Training Program at the University of Michigan Comprehensive Cancer Center, 5-T32-CA09676.

⁴ To whom correspondence should be addressed: 1528 BSRB, 109 Zina Pitcher Pl., University of Michigan Medical School, Ann Arbor, MI 48109. Tel.: 734-764-3567; E-mail: bmargoli{at}umich.edu.

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