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The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42

Abstract

PAR (partitioning-defective) proteins, which were first identified in the nematode Caenorhabditis elegans, are essential for asymmetric cell division and polarized growth, whereas Cdc42 mediates establishment of cell polarity. Here we describe an unexpected link between these two systems. We have identified a family of mammalian Par6 proteins that are similar to the C. elegans PDZ-domain protein PAR-6. Par6 forms a complex with Cdc42–GTP, with a human homologue of the multi-PDZ protein PAR-3 and with the regulatory domains of atypical protein kinase C (PKC) proteins. This assembly is implicated in the formation of normal tight junctions at epithelial cell–cell contacts. Thus, Par6 is a key adaptor that links Cdc42 and atypical PKCs to Par3.

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Figure 1: Sequence analysis of Par6 proteins.
Figure 2: Interaction of Par6 with Cdc42 and TC10 GTPases.
Figure 3: The semi-CRIB and PDZ domains of Par6 are required for association with the Par3 N terminus.
Figure 4: Cdc42, Par6B, Par3 and PKCι/λ form a quaternary complex.
Figure 5: Par6 binds directly and specifically to atypical PKCs.
Figure 6: Expression of Par6 disrupts tight junctions but not adherens junctions.
Figure 7: Effect of ectopic expression of Myc–Par3 or Cdc42(L61) on localization of ZO-1 or endogenous Par3.

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Acknowledgements

This work was supported by grants P01CA40042 and R01CA38888 from the National Institutes of Health, National Cancer Institute, DHHS. We thank J. Moscat (Madrid, Spain) and T. Biden (Sydney, Australia) for PKCι/λ and ζ plasmids, P. Fort (Montpellier, France) for vectors encoding RhoG and kinectin, C. Hahn (Charlottesville, Virginia) for anti-PKCα and anti-PKCδ antibodies and A. Pawson (Toronto, Ontario) for anti-Par 3 antibody and for sharing information before publication. We also thank D. Brautigan for critical reading of the manuscript, C. J. Meyer for technical help and other members of the Macara laboratory for discussion of this work.

Correspondence and requests for materials should be addressed to G.J. The nucleotide sequences of the open reading frames of Par6 proteins and Par3 have been deposited at GenBank under accession numbers AF252290 (Par6A), AF252291 (Par6B), AF252292 (Par6C) and AF252293 (Par3).

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Joberty, G., Petersen, C., Gao, L. et al. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2, 531–539 (2000). https://doi.org/10.1038/35019573

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