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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References
Cabib, E., Drgonova, J. & Drgon, T. Role of small G proteins in yeast cell polarization and wall biosynthesis. Annu. Rev. Biochem. 67, 307–333 (1998).
Johnson, D. I. Cdc42: an essential Rho-type GTPase controlling eukaryotic cell polarity. Microbiol. Mol. Biol. Rev. 63, 54– 105 (1999).
Nobes, C. D. & Hall, A. Rho GTPases control polarity, protrusion and adhesion during cell movement. J. Cell Biol. 144 , 1235–1244 (1999).
Kroschewski, R., Hall, A. & Mellman, I. Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cells. Nature Cell Biol. 1, 8–13 (1999).
Eaton, S., Wepf, R. & Simons, K. Roles for Rac1 and Cdc42 in planar polarization and hair outgrowth in the wing of Drosophila. J. Cell Biol. 135, 1277–1289 (1996).
Hing, H., Xiao, J., Harden, N., Lim, L. & Zipursky, S. L. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila. Cell 97, 853 –863 (1999).
Chen, W., Chen, S., Yap, S. F. & Lim, L. The Caenorhabditis elegans p21-activated kinase (CePAK) colocalises with CeRac1 and CDC42Ce at hypodermal cell boundaries during embryo elongation. J. Biol. Chem. 271, 26362–26368 (1996).
Van Aelst, L. & D’Souza-Schorey, C. Rho GTPases and signalling networks. Genes Dev. 11, 2295–2322 (1997).
Burbelo, P. D., Drechsel, D. & Hall, A. A conserved binding motif defines numerous candidate target proteins for both Cdc42 and Rac GTPases. J. Biol. Chem. 270, 29071–29074 ( 1995).
Nelson, W. J. & Grindstaff, K. K. Cell polarity: par for the polar course. Curr. Biol. 7, R562-R564 (1997).
Etemad-Moghadam, B., Guo, S. & Kemphues, K. J. Asymmetrically distributed PAR-3 protein contributes to cell polarity and spindle alignment in early C. elegans embryos. Cell 83, 743–752 ( 1995).
Fanning, A. S. & Anderson, J. M. Protein–protein interactions — PDZ domain networks. Curr. Biol. 6, 1385–1388 (1996).
Ponting, C. P., Phillips, C., Davies, K. E. & Blake, D. J. PDZ domains: targeting signalling molecules to sub-membranous sites. Bioessays 19, 469–479 ( 1997).
Tabuse, Y. et al. Atypical protein kinase C co-operates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. Development 125, 3607–3614 ( 1998).
Hung, T. J. & Kemphues, K. J. PAR-6 is a conserved PDZ domain-containing protein that colocalises with PAR-3 in Caenorhabditis elegans embryos. Development 126, 127–135 ( 1999).
Kuchinke, U., Grawe, F. & Knust, E. Control of spindle orientation in Drosophila by the Par-3-related PDZ- domain protein Bazooka. Curr. Biol. 8, 1357–1365 (1998).
Izumi, Y. et al. An atypical PKC directly associates and colocalises at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).
Lin, D., Gish, G. D., Songyang, Z. & Pawson, T. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J. Biol. Chem. 274, 3726– 3733 (1999).
Bruckner, K. & Klein, R. Signalling by Eph receptors and their ephrin ligands. Curr. Opin. Neurobiol. 8, 375–382 (1998).
Neudauer, C. L., Joberty, G., Tatsis, N. & Macara, I. G. Distinct cellular effects and interactions of the Rho-family GTPase TC10. Curr. Biol. 8, 1151-1160 (1998).
Rousset, R., Fabre, S., Desbois, C., Bantignies, F. & Jalinot, P. The C-terminus of the HTLV-1 Tax oncoprotein mediates interaction with the PDZ domain of cellular proteins. Oncogene 16, 643-54 (1998).
Hotta, K., Tanaka, K., Mino, A., Kohno, H. & Takai, Y. Interaction of the Rho family small G proteins with kinectin, an anchoring protein of kinesin motor. Biochem. Biophys. Res. Commun. 225, 69-74 (1996).
Hillier, B. J., Christopherson, K. S., Prehoda, K. E., Bredt, D. S. & Lim, W. A. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex. Science 284, 812–815 (1999).
Joberty, G., Perlungher, R. R. & Macara, I. G. The Borgs, a new family of Cdc42 and TC10 GTPase-interacting proteins. Mol.Cell. Biol. 19, 6585– 6597 (1999).
Abdul-Manan, N. et al. Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott–Aldrich syndrome’ protein. Nature 399, 379–383 ( 1999).
Mott, H. R. et al. Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK. Nature 399, 384– 388 (1999).
Stevens, W. K. et al. Conformation of a Cdc42/Rac interactive binding peptide in complex with Cdc42 and analysis of the binding interface. Biochemistry 38, 5968–5975 ( 1999).
Songyang, Z. et al. Recognition of unique carboxyl-terminal motifs by distinct pdz domains. Science 275, 73– 77 (1997).
Daniels, D. L., Cohen, A. R., Anderson, J. M. & Brunger, A. T. Crystal structure of the hCASK PDZ domain reveals the structural basis of class II PDZ domain target recognition. Nature Struct. Biol. 5, 317–325 (1998).
Wu, S. L., Staudinger, J., Olson, E. N. & Rubin, C. S. Structure, expression, and properties of an atypical protein kinase C (PKC3) from Caenorhabditis elegans. PKC3 is required for the normal progression of embryogenesis and viability of the organism. J. Biol. Chem. 273, 1130–1143 (1998).
Kuroda, S., Fukata, M., Nakagawa, M. & Kaibuchi, K. Cdc42, Rac1, and their effector IQGAP1 as molecular switches for cadherin-mediated cell–cell adhesion. Biochem. Biophys. Res. Commun. 262, 1–6 (1999).
Muller, H. A. & Wieschaus, E. Armadillo, Bazooka and Stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. J. Cell Biol. 134, 149–163 ( 1996).
Schober, M., Schaefer, M. & Knoblich, J. A. Bazooka recruits Inscuteable to orient asymmetric cell divisions in Drosophila neuroblasts. Nature 402, 548–551 (1999).
Wodarz, A., Ramrath, A., Kuchinke, U. & Knust, E. Bazooka provides an apical cue for Inscuteable localisation in Drosophila neuroblasts. Nature 402, 544–547 ( 1999).
Schaefer, M., Shevchenko, A. & Knoblich, J. A. A protein complex containing Inscuteable and the Galpha-binding protein PINS orients asymmetric cell divisions in Drosophila. Curr. Biol. 10, 353–362 (2000).
Yu, F., Morin, X., Cai, Y., Yang, X. & Chia, W. Analysis of partner of Inscuteable, a novel player of Drosophila asymmetric divisions, reveals two distinct steps in Inscuteable apical localisation. Cell 100, 399–409 ( 2000).
Coghlan, M. P., Chou, M. M. & Carpenter, C. L. Atypical protein kinases Cλ and -ζ associate with the GTP-binding protein Cdc42 and mediate stress fibre loss. Mol. Cell Biol. 20, 2880–2889 (2000).
Sambrook, J., Fritsch, E. F. & Maniatis, T. in Molecular Cloning: A laboratory Manual. (ed. Nolan, C.) 16.32–16.36 (CSH, Plainview, New York, 1989).
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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DOI: https://doi.org/10.1038/35019573
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