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J. Biol. Chem., Vol. 283, Issue 34, 23440-23449, August 22, 2008

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Par-3-mediated Junctional Localization of the Lipid Phosphatase PTEN Is Required for Cell Polarity Establishment^*

From the Department of Biochemistry, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

PDZ domain-containing scaffold protein Par-3 is the central organizer of the evolutionarily conserved cell polarity-regulatory Par-3·Par-6·atypical protein kinase C complex. The PDZ domains of Par-3 have also been implicated as potential phosphoinositide signaling integrators, since its second PDZ domain binds to phosphoinositides, and the third PDZ interacts with phosphoinositide phosphatase PTEN. However, the molecular basis of Par-3/PTEN interaction is still poorly understood. Additionally, it is not known whether the regulatory function of PTEN in cell polarity is specifically mediated by its interaction with Par-3. The structures of Par-3 PDZ3 in both its free and PTEN tail peptide-bound forms determined in this work reveal that Par-3 PDZ3 binds to PTEN with two discrete binding sites: a canonical PDZ-ligand interaction site and a distal, opposite charge-charge interaction site. This distinct target recognition mechanism confers the interaction specificity of the Par-3·PTEN complex. We show that the Par-3 PDZ3-PTEN binding is required for the enrichment of PTEN at the junctional membranes of Madin-Darby canine kidney cells. Finally, we demonstrate that the junctional membrane-localized PTEN is specifically required for the polarization of Madin-Darby canine kidney cells. These results, together with earlier data, firmly establish that Par-3 functions as a scaffold in integrating phosphoinositide signaling events during cellular polarization.

Received for publication, March 31, 2008 , and in revised form, May 28, 2008.

The atomic coordinates and structure factors (code 2k1z and 2k20) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Research Grants Council of Hong Kong Grants HKUST6419/05M, 6442/06M, 663407, AoE/B-15/01-II, and CA07/08.SC01 (to M. Z.). The NMR spectrometer used in this work was purchased with funds donated to the Biotechnology Research Institute by the Hong Kong Jockey Club. 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 supplemental Figs. 1-5.

¹ Both authors contributed equally to this work.

² Recipient of the Croucher Foundation Senior Research Fellow Award. To whom correspondence should be addressed. Tel.: 852-2358-8709; Fax: 852-2358-1552; E-mail: mzhang{at}ust.hk.

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