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J. Biol. Chem., Vol. 283, Issue 34, 23033-23038, August 22, 2008

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Neph-Nephrin Proteins Bind the Par3-Par6-Atypical Protein Kinase C (aPKC) Complex to Regulate Podocyte Cell Polarity^*

Björn Hartleben, Heiko Schweizer, Pauline Lübben, Malte P. Bartram, Clemens C. Möller^¶1, Ronja Herr, Changli Wei^¶, Elke Neumann-Haefelin, Bernhard Schermer, Hanswalter Zentgraf^||, Dontscho Kerjaschki^**, Jochen Reiser^¶, Gerd Walz, Thomas Benzing², and Tobias B. Huber³

From the Renal Division, University Hospital Freiburg, D-79106 Freiburg, Germany, the Renal Division, University Hospital Cologne, D-50937 Köln, Germany, the ^¶Nephrology Division and Program in Glomerular Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, the ^||Department of Pathology, Medical University of Vienna, A-1090 Vienna, Austria, and the ^**Department of Tumor Virology, German Cancer Research Center, D-69120 Heidelberg, Germany

The kidney filter represents a unique assembly of podocyte epithelial cells that tightly enwrap the glomerular capillaries with their foot processes and the interposed slit diaphragm. So far, very little is known about the guidance cues and polarity signals required to regulate proper development and maintenance of the glomerular filtration barrier. We now identify Par3, Par6, and atypical protein kinase C (aPKC) polarity proteins as novel Neph1-Nephrin-associated proteins. The interaction was mediated through the PDZ domain of Par3 and conserved carboxyl terminal residues in Neph1 and Nephrin. Par3, Par6, and aPKC localized to the slit diaphragm as shown in immunofluorescence and immunoelectron microscopy. Consistent with a critical role for aPKC activity in podocytes, inhibition of glomerular aPKC activity with a pseudosubstrate inhibitor resulted in a loss of regular podocyte foot process architecture. These data provide an important link between cell recognition mediated through the Neph1-Nephrin complex and Par-dependent polarity signaling and suggest that this molecular interaction is essential for establishing the three-dimensional architecture of podocytes at the kidney filtration barrier.

Received for publication, April 24, 2008 , and in revised form, June 2, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK073495 (to J. R). This work was also supported by a grant from the Kristyna M. Driehaus foundation (to J. R.), by Deutsche Forschungsgemeinschaft Grants BE 2212 (to T. B.) and HU 1016/2-1) (to T. B. H.), and by Deutsche Forschungsgemeinschaft Sonderforschungsbereich 592 (to T. B. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures.

¹ Supported by a Deutscher Akademischer Austausch Dienst Predoctoral Scholarship.

² To whom correspondence may be addressed: Renal Division, University Hospital Cologne, Kerpener Str. 62, D-50937 Köln, Germany. Tel.: 49-221-478-4480; Fax: 49-221-478-5959; E-mail: thomas.benzing{at}uk-koeln.de. ³ To whom correspondence may be addressed: Tobias B. Huber, Renal Division, University Hospital Freiburg, Breisacher Str. 66, D-79106 Freiburg, Germany. Tel.: 49-761-270-3559; Fax: 49-761-270-3270; E-mail: tobias.huber{at}uniklinik-freiburg.de.

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