Par-3-mediated junctional localization of the lipid phosphatase PTEN is required for cell polarity establishment.
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.
Feng
Wei
W
Department of Biochemistry, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Wu
Hao
H
Chan
Ling-Nga
LN
Zhang
Mingjie
M
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D051059:PTEN Phosphohydrolase / Q000378:metabolism / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C472451:Pard3 protein, rat; C504908:Pard6a protein, rat; D010455:Peptides; D011493:Protein Kinase C; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat