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Coordinated protein sorting, targeting and distribution in polarized cells

Nature Reviews Molecular Cell Biology volume 9, pages 833–845 (2008)Cite this article

Key Points

  • Cell polarity is defined as the segregation of specific biological functions to different plasma membrane domains. Cell polarity is essential for the survival of all multicellular and many unicellular organisms.

  • The polarized distribution of biological functions requires the coordinated interaction of three machineries that modify basic mechanisms of intracellular protein trafficking and distribution.

  • First, intrinsic protein-sorting signals and cellular decoding machineries regulate protein trafficking to selected plasma membrane domains. Correctly sorted proteins regulate functional specialization of the membrane domain.

  • Second, intracellular signalling complexes define the plasma membrane domains to which proteins are delivered.

  • Third, proteins involved in cell–cell and cell–substrate adhesion orientate the distribution of intracellular signalling complexes and membrane traffic in three-dimensional space.

  • The integration of these mechanisms into a complex and dynamic network is crucial for normal tissue function and is often defective in disease states.

Abstract

The polarized distribution of functions in polarized cells requires the coordinated interaction of three machineries that modify the basic mechanisms of intracellular protein trafficking and distribution. First, intrinsic protein-sorting signals and cellular decoding machineries regulate protein trafficking to plasma membrane domains; second, intracellular signalling complexes define the plasma membrane domains to which proteins are delivered; and third, proteins that are involved in cell–cell and cell–substrate adhesion orientate the three-dimensional distribution of intracellular signalling complexes and, accordingly, the direction of membrane traffic. The integration of these mechanisms into a complex and dynamic network is crucial for normal tissue function and is often defective in disease states.

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Figure 1: A generic post-translational pathway for protein trafficking to the plasma membrane.
Figure 2: Superimposing protein sorting demands on the generic trafficking pathway.
Figure 3: Signalling complexes and scaffolds on the cytosolic face of the membrane define and stabilize membrane domains.
Figure 4: Roles of signalling complexes on the cytosolic face of the membrane control phosphoinositide distribution and vesicle trafficking.
Figure 5: Polarized cells form from the hierarchical integration of three fundamental mechanisms.

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References

  1. Palade, G. Intracellular aspects of the process of protein synthesis. Science 189, 867 (1975).

    CAS  PubMed  Google Scholar 

  2. Shook, D. & Keller, R. Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development. Mech. Dev. 120, 1351–1383 (2003).

    CAS  PubMed  Google Scholar 

  3. Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial–mesenchymal transitions. Nature Rev. Mol. Cell Biol. 7, 131–142 (2006).

    CAS  Google Scholar 

  4. Wodarz, A. & Nathke, I. Cell polarity in development and cancer. Nature Cell Biol. 9, 1016–1024 (2007).

    CAS  PubMed  Google Scholar 

  5. Rothman, J. E. Mechanisms of intracellular protein transport. Nature 372, 55–63 (1994).

    CAS  PubMed  Google Scholar 

  6. Lee, M. C., Miller, E. A., Goldberg, J., Orci, L. & Schekman, R. Bi-directional protein transport between the ER and Golgi. Annu. Rev. Cell Dev. Biol. 20, 87–123 (2004).

    CAS  PubMed  Google Scholar 

  7. Pearse, B. M. & Robinson, M. S. Clathrin, adaptors, and sorting. Annu. Rev. Cell Biol. 6, 151–171 (1990).

    CAS  PubMed  Google Scholar 

  8. Edeling, M. A., Smith, C. & Owen, D. Life of a clathrin coat: insights from clathrin and AP structures. Nature Rev. Mol. Cell Biol. 7, 32–44 (2006).

    CAS  Google Scholar 

  9. Hehnly, H. & Stamnes, M. Regulating cytoskeleton-based vesicle motility. FEBS Lett. 581, 2112–2118 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Grosshans, B. L., Ortiz, D. & Novick, P. Rabs and their effectors: achieving specificity in membrane traffic. Proc. Natl Acad. Sci. USA 103, 11821–11827 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Robinson, M. S. Adaptable adaptors for coated vesicles. Trends Cell Biol. 14, 167–174 (2004).

    CAS  PubMed  Google Scholar 

  12. Ohno, H. et al. Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269, 1872–1875 (1995).

    CAS  PubMed  Google Scholar 

  13. Matter, K., Hunziker, W. & Mellman, I. Basolateral sorting of LDL receptor in MDCK cells: the cytoplasmic domain contains two tyrosine-dependent targeting determinants. Cell 71, 741–753 (1992). Provides a detailed analysis of sorting of LDLR in polarized MDCK epithelial cells, and defines two Tyr-based basolateral sorting signals.

    CAS  PubMed  Google Scholar 

  14. Jareb, M. & Banker, G. The polarized sorting of membrane proteins expressed in cultured hippocampal neurons using viral vectors. Neuron 20, 855–867 (1998). Provides evidence that sorting signals that are important for protein delivery to the apical and basolateral membranes of polarized epithelial cells also function in sorting to the axonal and somatodendritic domains, respectively, of polarized hippocampal neurons.

    CAS  PubMed  Google Scholar 

  15. Rodriguez-Boulan, E. & Musch, A. Protein sorting in the Golgi complex: shifting paradigms. Biochim. Biophys. Acta 1744, 455–464 (2005).

    CAS  PubMed  Google Scholar 

  16. Folsch, H. Regulation of membrane trafficking in polarized epithelial cells. Curr. Opin. Cell Biol. 20, 208–213 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hunziker, W. & Fumey, C. A di-leucine motif mediates endocytosis and basolateral sorting of macrophage IgG Fc receptors in MDCK cells. EMBO J. 13, 2963–2969 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Odorizzi, G. & Trowbridge, I. S. Structural requirements for basolateral sorting of the human transferrin receptor in the biosynthetic and endocytic pathways of Madin–Darby canine kidney cells. J. Cell Biol. 137, 1255–1264 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mostov, K. E., de Bruyn Kops, A. & Deitcher, D. L. Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis. Cell 47, 359–364 (1986). Early study of cytoplasmic domain sorting motifs in the poly-IgA-receptor, which is involved in basolateral targeting and transcytosis.

    CAS  PubMed  Google Scholar 

  20. Folsch, H., Ohno, H., Bonifacino, J. S. & Mellman, I. A novel clathrin adaptor complex mediates basolateral targeting in polarized epithelial cells. Cell 99, 189–198 (1999). Identification of AP-1B as an epithelial specific adaptor protein that is required for basolateral protein sorting.

    CAS  PubMed  Google Scholar 

  21. Gan, Y., McGraw, T. E. & Rodriguez-Boulan, E. The epithelial-specific adaptor AP1B mediates post-endocytic recycling to the basolateral membrane. Nature Cell Biol. 4, 605–609 (2002). Identification of the recycling endosome as a site for AP-1B control of basolateral sorting of LDLR.

    CAS  PubMed  Google Scholar 

  22. Simmen, T., Honing, S., Icking, A., Tikkanen, R. & Hunziker, W. AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells. Nature Cell Biol. 4, 154–9 (2002).

    CAS  PubMed  Google Scholar 

  23. Koivisto, U. M., Hubbard, A. L. & Mellman, I. A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell 105, 575–585 (2001).

    CAS  PubMed  Google Scholar 

  24. Deborde, S. et al. Clathrin is a key regulator of basolateral polarity. Nature 452, 719–723 (2008). Analysis of the effects of siRNA knockdown of clathrin on apical and basolateral membrane protein sorting in polarized epithelial cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bennett, V. & Healy, J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol. Med. 14, 28–36 (2008).

    CAS  PubMed  Google Scholar 

  26. Kizhatil, K. et al. Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. J. Biol. Chem. 282, 26552–26561 (2007).

    CAS  PubMed  Google Scholar 

  27. Schuck, S. & Simons, K. Polarized sorting in epithelial cells: raft clustering and the biogenesis of the apical membrane. J. Cell Sci. 117, 5955–5964 (2004).

    CAS  PubMed  Google Scholar 

  28. Yeaman, C. et al. The O-glycosylated stalk domain is required for apical sorting of neurotrophin receptors in polarized MDCK cells. J. Cell Biol. 139, 929–940 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Spodsberg, N., Jacob, R., Alfalah, M., Zimmer, K. P. & Naim, H. Y. Molecular basis of aberrant apical protein transport in an intestinal enzyme disorder. J. Biol. Chem. 276, 23506–23510 (2001).

    CAS  PubMed  Google Scholar 

  30. Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997). Overview of the organization and functions of lipid rafts.

    CAS  PubMed  Google Scholar 

  31. Paladino, S., Sarnataro, D., Tivodar, S. & Zurzolo, C. Oligomerization is a specific requirement for apical sorting of glycosyl-phosphatidylinositol-anchored proteins but not for non-raft-associated apical proteins. Traffic 8, 251–258 (2007). Analysis of the mechanisms that are involved in GPI-protein sorting in the secretory pathway in polarized MDCK epithelial cells, and evidence for oligomerization in the late Golgi.

    CAS  PubMed  Google Scholar 

  32. Hannan, L. A., Lisanti, M. P., Rodriguez-Boulan, E. & Edidin, M. Correctly sorted molecules of a GPI-anchored protein are clustered and immobile when they arrive at the apical surface of MDCK cells. J. Cell Biol. 120, 353–358 (1993).

    CAS  PubMed  Google Scholar 

  33. Vieira, O. V., Verkade, P., Manninen, A. & Simons, K. FAPP2 is involved in the transport of apical cargo in polarized MDCK cells. J. Cell Biol. 170, 521–526 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Delacour, D. et al. Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells. J. Cell Biol. 169, 491–501 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chuang, J. Z. & Sung, C. H. The cytoplasmic tail of rhodopsin acts as a novel apical sorting signal in polarized MDCK cells. J. Cell Biol. 142, 1245–1256 (1998). Explains a role for sorting motifs in the cytoplasmic domain of rhodopsin during apical trafficking in polarized cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tai, A. W., Chuang, J. Z. & Sung, C. H. Cytoplasmic dynein regulation by subunit heterogeneity and its role in apical transport. J. Cell Biol. 153, 1499–1509 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wisco, D. et al. Uncovering multiple axonal targeting pathways in hippocampal neurons. J. Cell Biol. 162, 1317–1328 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Casanova, J. E., Breitfeld, P. P., Ross, S. A. & Mostov, K. E. Phosphorylation of the polymeric immunoglobulin receptor required for its efficient transcytosis. Science 248, 742–745 (1990). Explains the role of cytoplasmic sorting motif phosphorylation in the poly-IgA-receptor during transcytosis in polarized MDCK epithelial cells.

    CAS  PubMed  Google Scholar 

  39. Gravotta, D. et al. AP1B sorts basolateral proteins in recycling and biosynthetic routes of MDCK cells. Proc. Natl Acad. Sci. USA 104, 1564–1569 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rodriguez-Boulan, E., Kreitzer, G. & Musch, A. Organization of vesicular trafficking in epithelia. Nature Rev. Mol. Cell Biol. 6, 233–247 (2005). Detailed review of the mechanisms involved in protein sorting in polarized cells.

    CAS  Google Scholar 

  41. Kizhatil, K. et al. Ankyrin-G and β2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J. Biol. Chem. 282, 2029–2037 (2007). Evidence of a role of the ankyrin–spectrin complex in protein sorting and trafficking in polarized epithelial cells.

    CAS  PubMed  Google Scholar 

  42. Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bacallao, R. et al. The subcellular organization of Madin–Darby canine kidney cells during the formation of a polarized epithelium. J. Cell Biol. 109, 2817–2832 (1989).

    CAS  PubMed  Google Scholar 

  44. Grindstaff, K. K., Bacallao, R. L. & Nelson, W. J. Apiconuclear organization of microtubules does not specify protein delivery from the trans-Golgi network to different membrane domains in polarized epithelial cells. Mol. Biol. Cell 9, 685–699 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jaulin, F., Xue, X., Rodriguez-Boulan, E. & Kreitzer, G. Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. Dev. Cell 13, 511–522 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lafont, F., Burkhardt, J. K. & Simons, K. Involvement of microtubule motors in basolateral and apical transport in kidney cells. Nature 372, 801–803 (1994).

    CAS  PubMed  Google Scholar 

  47. Hirokawa, N. & Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci. 6, 201–214 (2005).

    CAS  Google Scholar 

  48. Grindstaff, K. K. et al. Sec6/8 complex is recruited to cell–cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell 93, 731–740 (1998). Describes the localization of the SEC6–SEC8 (exocyst) complex in polarized epithelial cells and evidence for a role in the delivery of transport vesicles to the basolateral membrane.

    CAS  PubMed  Google Scholar 

  49. Hazuka, C. D. et al. The Sec6/8 complex is located at neurite outgrowth and axonal synapse-assembly domains. J. Neurosci. 19, 1324–1334 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Folsch, H., Pypaert, M., Schu, P. & Mellman, I. Distribution and function of AP-1 clathrin adaptor complexes in polarized epithelial cells. J. Cell Biol. 152, 595–606 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ang, A. L. et al. Recycling endosomes can serve as intermediates during transport from the Golgi to the plasma membrane of MDCK cells. J. Cell Biol. 167, 531–543 (2004). Provides evidence that protein delivery between the Golgi complex and plasma membrane might involve an intermediate step through the recycling endosome.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gerke, V., Creutz, C. E. & Moss, S. E. Annexins: linking Ca2+ signalling to membrane dynamics. Nature Rev. Mol. Cell Biol. 6, 449–461 (2005).

    CAS  Google Scholar 

  53. Jacob, R. et al. Annexin II is required for apical transport in polarized epithelial cells. J. Biol. Chem. 279, 3680–3684 (2004).

    CAS  PubMed  Google Scholar 

  54. Pocard, T., Le Bivic, A., Galli, T. & Zurzolo, C. Distinct v-SNAREs regulate direct and indirect apical delivery in polarized epithelial cells. J. Cell Sci. 120, 3309–3320 (2007).

    CAS  PubMed  Google Scholar 

  55. Low, S. H. et al. Differential localization of syntaxin isoforms in polarized Madin–Darby canine kidney cells. Mol. Biol. Cell 7, 2007–2018 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fujita, H., Tuma, P. L., Finnegan, C. M., Locco, L. & Hubbard, A. L. Endogenous syntaxins 2, 3 and 4 exhibit distinct but overlapping patterns of expression at the hepatocyte plasma membrane. Biochem. J. 329, 527–538 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sharma, N., Low, S. H., Misra, S., Pallavi, B. & Weimbs, T. Apical targeting of syntaxin 3 is essential for epithelial cell polarity. J. Cell Biol. 173, 937–948 (2006). Functional analysis of apical vesicle trafficking and the role of the t-SNARE syntaxin-3 in specifying vesicle fusion at the (apical) plasma membrane.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. ter Beest, M. B., Chapin, S. J., Avrahami, D. & Mostov, K. E. The role of syntaxins in the specificity of vesicle targeting in polarized epithelial cells. Mol. Biol. Cell 16, 5784–5792 (2005).

    CAS  PubMed  Google Scholar 

  59. Fields, I. C. et al. v-SNARE cellubrevin is required for basolateral sorting of AP-1B-dependent cargo in polarized epithelial cells. J. Cell Biol. 177, 477–488 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hammerton, R. W. et al. Mechanism for regulating cell surface distribution of Na+, K+-ATPase in polarized epithelial cells. Science 254, 847–850 (1991).

    CAS  PubMed  Google Scholar 

  61. Mays, R. W., Beck, K. A. & Nelson, W. J. Organization and function of the cytoskeleton in polarized epithelial cells: a component of the protein sorting machinery. Curr. Opin. Cell Biol. 6, 16–24 (1994).

    CAS  PubMed  Google Scholar 

  62. Nelson, W. J. & Veshnock, P. J. Dynamics of membrane-skeleton (fodrin) organization during development of polarity in Madin–Darby canine kidney epithelial cells. J. Cell Biol. 103, 1751–1765 (1986).

    CAS  PubMed  Google Scholar 

  63. Nelson, W. J. & Lazarides, E. The patterns of expression of two ankyrin isoforms demonstrate distinct steps in the assembly of the membrane skeleton in neuronal morphogenesis. Cell 39, 309–320 (1984).

    CAS  PubMed  Google Scholar 

  64. Shin, K., Fogg, V. C. & Margolis, B. Tight junctions and cell polarity. Annu. Rev. Cell Dev. Biol. 22, 207–235 (2006). A review of the molecular organization and function of tight junctions in polarized epithelial cells.

    CAS  PubMed  Google Scholar 

  65. Winckler, B., Forscher, P. & Mellman, I. A diffusion barrier maintains distribution of membrane proteins in polarized neurons. Nature 397, 698–701 (1999). Evidence for a diffusion barrier at the axonal hillock that controls the diffusion of proteins between the axonal and somatodendritic membrane domains.

    CAS  PubMed  Google Scholar 

  66. Kemphues, K. J., Priess, J. R., Morton, D. G. & Cheng, N. S. Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988). The genetic screen that identified the identity and function of the PAR complex in early C. elegans development.

    CAS  PubMed  Google Scholar 

  67. Baas, A. F. et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004). Evidence that activated LKB1 (PAR-4) can lead to polarization of epithelial cells in the absence of cell–cell and cell–extracellular matrix adhesion.

    CAS  PubMed  Google Scholar 

  68. Shelly, M., Cancedda, L., Heilshorn, S., Sumbre, G. & Poo, M. M. LKB1/STRAD promotes axon initiation during neuronal polarization. Cell 129, 565–577 (2007).

    CAS  PubMed  Google Scholar 

  69. Williams, T. & Brenman, J. E. LKB1 and AMPK in cell polarity and division. Trends Cell Biol. 18, 193–198 (2008).

    CAS  PubMed  Google Scholar 

  70. Lee, J. H. et al. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020 (2007).

    CAS  PubMed  Google Scholar 

  71. Illenberger, S. et al. Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics. J. Biol. Chem. 271, 10834–10843 (1996).

    CAS  PubMed  Google Scholar 

  72. Cohen, D., Brennwald, P. J., Rodriguez-Boulan, E. & Musch, A. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J. Cell Biol. 164, 717–727 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cohen, D., Rodriguez-Boulan, E. & Musch, A. Par-1 promotes a hepatic mode of apical protein trafficking in MDCK cells. Proc. Natl Acad. Sci. USA 101, 13792–13797 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Elbert, M., Rossi, G. & Brennwald, P. The yeast Par-1 homologs Kin1 and Kin2 show genetic and physical interactions with components of the exocytic machinery. Mol. Biol. Cell 16, 532–549 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Suzuki, A. & Ohno, S. The PAR–aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).

    CAS  PubMed  Google Scholar 

  76. Goldstein, B. & Macara, I. G. The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007). Recent review of the PAR complex, covering their protein interactions, regulation and functions.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Atwood, S. X., Chabu, C., Penkert, R. R., Doe, C. Q. & Prehoda, K. E. Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6 aPKC. J. Cell Sci. 120, 3200–3206 (2007).

    CAS  PubMed  Google Scholar 

  78. Izumi, Y. et al. An atypical PKC directly associates and colocalizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bilder, D., Schober, M. & Perrimon, N. Integrated activity of PDZ protein complexes regulates epithelial polarity. Nature Cell Biol. 5, 53–58 (2003).

    CAS  PubMed  Google Scholar 

  80. Shi, S. H., Jan, L. Y. & Jan, Y. N. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003).

    CAS  PubMed  Google Scholar 

  81. Tanentzapf, G. & Tepass, U. Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization. Nature Cell Biol. 5, 46–52 (2003). Along with reference 79, provides genetic evidence of the roles of the PAR, Crumbs and Scribble polarity complexes in defining apical and basolateral membrane identity in polarized epithelial cells during D. melanogaster embryogenesis.

    CAS  PubMed  Google Scholar 

  82. Nishimura, T. et al. PAR-6–PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biol. 7, 270–277 (2005).

    CAS  PubMed  Google Scholar 

  83. Roh, M. H. & Margolis, B. Composition and function of PDZ protein complexes during cell polarization. Am. J. Physiol. Renal Physiol. 285, F377–F387 (2003).

    PubMed  Google Scholar 

  84. Sotillos, S., Diaz-Meco, M. T., Caminero, E., Moscat, J. & Campuzano, S. DaPKC-dependent phosphorylation of Crumbs is required for epithelial cell polarity in Drosophila. J. Cell Biol. 166, 549–557 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lemmers, C. et al. CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells. Mol. Biol. Cell 15, 1324–1333 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Nagai-Tamai, Y., Mizuno, K., Hirose, T., Suzuki, A. & Ohno, S. Regulated protein–protein interaction between aPKC and PAR-3 plays an essential role in the polarization of epithelial cells. Genes Cells 7, 1161–1171 (2002).

    CAS  PubMed  Google Scholar 

  87. Benton, R. & St. Johnston, D. Drosophila PAR-1 and 14-3-3 inhibit Bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 115, 691–704 (2003).

    CAS  PubMed  Google Scholar 

  88. Hurov, J. B., Watkins, J. L. & Piwnica-Worms, H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr. Biol. 14, 736–741 (2004).

    CAS  PubMed  Google Scholar 

  89. Betschinger, J., Mechtler, K. & Knoblich, J. A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).

    CAS  PubMed  Google Scholar 

  90. Fan, S. et al. Polarity proteins control ciliogenesis via kinesin motor interactions. Curr. Biol. 14, 1451–1461 (2004).

    CAS  PubMed  Google Scholar 

  91. Sfakianos, J. et al. Par3 functions in the biogenesis of the primary cilium in polarized epithelial cells. J. Cell Biol. 179, 1133–1140 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Singla, V. & Reiter, J. F. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 313, 629–633 (2006).

    CAS  PubMed  Google Scholar 

  93. Esch, T., Lemmon, V. & Banker, G. Local presentation of substrate molecules directs axon specification by cultured hippocampal neurons. J. Neurosci. 19, 6417–6426 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Streuli, C. H. et al. Laminin mediates tissue-specific gene expression in mammary epithelia. J. Cell Biol. 129, 591–603 (1995).

    CAS  PubMed  Google Scholar 

  95. O'Brien, L. E. et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3, 831–838 (2001). Evidence that the extracellular matrix component laminin and RAC1 control epithelial cell polarity in 3D space.

    CAS  PubMed  Google Scholar 

  96. Schmidhauser, C. et al. A novel transcriptional enhancer is involved in the prolactin- and extracellular matrix-dependent regulation of β-casein gene expression. Mol. Biol. Cell 3, 699–709 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Halbleib, J. M. & Nelson, W. J. Cadherins in development: cell adhesion, sorting, and tissue morphogenesis. Genes Dev. 20, 3199–3214 (2006).

    CAS  PubMed  Google Scholar 

  98. Wang, A. Z., Ojakian, G. K. & Nelson, W. J. Steps in the morphogenesis of a polarized epithelium. I. Uncoupling the roles of cell–cell and cell–substratum contact in establishing plasma membrane polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95, 137–151 (1990).

    PubMed  Google Scholar 

  99. Larue, L., Ohsugi, M., Hirchenhain, J. & Kemler, R. E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc. Natl Acad. Sci. USA 91, 8263–8267 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Nejsum, L. N. & Nelson, W. J. A molecular mechanism directly linking E-cadherin adhesion to initiation of epithelial cell surface polarity. J. Cell Biol. 178, 323–335 (2007). Direct analysis of vesicle trafficking between the Golgi complex and cell–cell contacts and the role of microtubules, the exocyst and SNARE complexes.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Halbleib, J. M., Saaf, A. M., Brown, P. O. & Nelson, W. J. Transcriptional modulation of genes encoding structural characteristics of differentiating enterocytes during development of a polarized epithelium in vitro. Mol. Biol. Cell 18, 4261–4278 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Harris, T. J. & Peifer, M. Adherens junction-dependent and -independent steps in the establishment of epithelial cell polarity in Drosophila. J. Cell Biol. 167, 135–147 (2004). Genetic dissection of the roles of cadherin-mediated cell–cell adhesion and the PAR complex in epithelial cell polarity in developing D. melanogaster .

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Ebnet, K. et al. The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity. J. Cell Sci. 116, 3879–3891 (2003).

    CAS  PubMed  Google Scholar 

  104. Takekuni, K. et al. Direct binding of cell polarity protein PAR-3 to cell–cell adhesion molecule nectin at neuroepithelial cells of developing mouse. J. Biol. Chem. 278, 5497–5500 (2003).

    CAS  PubMed  Google Scholar 

  105. Wang, Q., Chen, X. W. & Margolis, B. PALS1 regulates E-cadherin trafficking in mammalian epithelial cells. Mol. Biol. Cell 18, 874–885 (2007).

    PubMed  PubMed Central  Google Scholar 

  106. Blankenship, J. T., Fuller, M. T. & Zallen, J. A. The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. J. Cell Sci. 120, 3099–3110 (2007).

    CAS  PubMed  Google Scholar 

  107. Arimura, N. & Kaibuchi, K. Key regulators in neuronal polarity. Neuron 48, 881–884 (2005).

    CAS  PubMed  Google Scholar 

  108. Martin-Belmonte, F. et al. Cell-polarity dynamics controls the mechanism of lumen formation in epithelial morphogenesis. Curr. Biol. 18, 507–513 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Joberty, G., Petersen, C., Gao, L. & Macara, I. G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nature Cell Biol. 2, 531–539 (2000).

    CAS  PubMed  Google Scholar 

  110. Mertens, A. E., Rygiel, T. P., Olivo, C., van der Kammen, R. & Collard, J. G. The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex. J. Cell Biol. 170, 1029–1037 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gassama-Diagne, A. et al. Phosphatidylinositol-3,4, 5-trisphosphate regulates the formation of the basolateral plasma membrane in epithelial cells. Nature Cell Biol. 8, 963–970 (2006).

    CAS  PubMed  Google Scholar 

  112. Martin-Belmonte, F. et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128, 383–397 (2007). Analysis of PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 distributions in polarized epithelial cells in 3D cultures, and the effects of mislocalization of these phosphoinositides on apical and basolateral membrane-domain organization.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Rescher, U., Ruhe, D., Ludwig, C., Zobiack, N. & Gerke, V. Annexin 2 is a phosphatidylinositol (4,5)-bisphosphate binding protein recruited to actin assembly sites at cellular membranes. J. Cell Sci. 117, 3473–3480 (2004).

    CAS  PubMed  Google Scholar 

  114. Anderson, D. C., Gill, J. S., Cinalli, R. M. & Nance, J. Polarization of the C. elegans embryo by RhoGAP-mediated exclusion of PAR-6 from cell contacts. Science 320, 1771–1774 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. von Stein, W., Ramrath, A., Grimm, A., Muller-Borg, M. & Wodarz, A. Direct association of Bazooka/PAR-3 with the lipid phosphatase PTEN reveals a link between the PAR/aPKC complex and phosphoinositide signaling. Development 132, 1675–1686 (2005).

    CAS  PubMed  Google Scholar 

  116. Wu, H. et al. PDZ domains of Par-3 as potential phosphoinositide signaling integrators. Mol. Cell 28, 886–898 (2007).

    CAS  PubMed  Google Scholar 

  117. Ridley, A. J. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 16, 522–529 (2006).

    CAS  PubMed  Google Scholar 

  118. Liu, J., Zuo, X., Yue, P. & Guo, W. Phosphatidylinositol 4,5-bisphosphate mediates the targeting of the exocyst to the plasma membrane for exocytosis in mammalian cells. Mol. Biol. Cell 18, 4483–4492 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Audebert, S. et al. Mammalian Scribble forms a tight complex with the βPIX exchange factor. Curr. Biol. 14, 987–995 (2004).

    CAS  PubMed  Google Scholar 

  120. Manser, E. et al. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol. Cell 1, 183–192 (1998).

    CAS  PubMed  Google Scholar 

  121. Zhao, Z. S., Manser, E., Loo, T. H. & Lim, L. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol. Cell Biol. 20, 6354–6363 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Roche, J. P., Packard, M. C., Moeckel-Cole, S. & Budnik, V. Regulation of synaptic plasticity and synaptic vesicle dynamics by the PDZ protein Scribble. J. Neurosci. 22, 6471–6479 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Naesens, M., Steels, P., Verberckmoes, R., Vanrenterghem, Y. & Kuypers, D. Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol. 96, 65–78 (2004).

    Google Scholar 

  124. Staub, O. et al. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J. 16, 6325–6336 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bertrand, C. A. & Frizzell, R. A. The role of regulated CFTR trafficking in epithelial secretion. Am. J. Physiol. Cell Physiol. 285, C1–18 (2003).

    CAS  PubMed  Google Scholar 

  126. Keiser, M., Alfalah, M., Propsting, M. J., Castelletti, D. & Naim, H. Y. Altered folding, turnover, and polarized sorting act in concert to define a novel pathomechanism of congenital sucrase-isomaltase deficiency. J. Biol. Chem. 281, 14393–14399 (2006).

    CAS  PubMed  Google Scholar 

  127. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

    CAS  PubMed  Google Scholar 

  128. Gardiol, D., Zacchi, A., Petrera, F., Stanta, G. & Banks, L. Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int. J. Cancer 119, 1285–1290 (2006).

    CAS  PubMed  Google Scholar 

  129. Sung, C. H. & Tai, A. W. Rhodopsin trafficking and its role in retinal dystrophies. Int. Rev. Cytol. 195, 215–267 (2000).

    CAS  PubMed  Google Scholar 

  130. Jenne, D. E. et al. Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18, 38–43 (1998).

    CAS  PubMed  Google Scholar 

  131. Kleta, R. & Bockenhauer, D. Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol. 104, p73–p80 (2006).

    CAS  PubMed  Google Scholar 

  132. Bilder, D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 18, 1909–1925 (2004).

    CAS  PubMed  Google Scholar 

  133. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev. Cancer 7, 415–428 (2007).

    CAS  Google Scholar 

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Acknowledgements

W.J.N. was supported by a grant from the National Institutes of Health (GM35527).

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Authors and Affiliations

  1. Genentech, Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Ira Mellman

  2. Department of Biology, the Department of Molecular and Cellular Physiology and the Bio-X Program, Stanford University, Stanford, 94305, California, USA

    W. James Nelson

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Glossary

Epithelial–mesenchymal transition

Phenotypic and functional changes in epithelial cells, usually associated with the loss of cell–cell adhesion and increased cell migration, as cells are induced to become fibroblasts.

COPII

A specific coat protein complex that initiates the vesicle budding process from the endoplasmic reticulum.

COPI

A specific coat protein complex that initiates the vesicle budding process from membranes of the Golgi complex, and is involved in intra-Golgi and Golgi-to-endoplasmic reticulum vesicle trafficking.

AP–clathrin complex

A complex of proteins that comprises adaptor proteins and structural clathrin (which forms a coat that initiates vesicle budding from membranes).

Rab GTPases

A large family of Ras-like GTPases that have key roles in the secretory and endocytic pathways.

Vesicle-tethering complex

A large protein complex that localizes to various sites of vesicle delivery in the secretory pathway and facilitates the capture, docking and fusion of specific vesicles with different membranes (for example, the exocyst complex at the plasma membrane).

SNARE

(Soluble N-ethyl-maleimide-sensitive fusion protein attachment-protein receptor).These proteins comprise a large protein superfamily and mediate the fusion of transport vesicles with membranes.

Transferrin receptor

A membrane protein that binds soluble transferrin, which is required for the cellular import of iron.

Basolateral membrane

A domain of the plasma membrane that comprises the basal and lateral membranes. It is orientated towards cell–extracellular matrix (basal membrane) and cell–cell contacts (lateral membrane).

Somatodendritic membrane

A part of neuronal cells that comprises the dendritic membranes and soma and excludes the axon.

Apical membrane

A domain of the plasma membrane in polarized epithelial cells that is usually orientated on the luminal side of epithelial tubes (for example, the intestine).

Ankyrin

A large adaptor protein that was originally found in erythrocytes but is ubiquitously expressed in nucleated cells. Ankyrin binds to various membrane proteins, spectrin and actin-binding proteins.

Spectrin

A large protein that comprises subunits (α and β) that form a heterotetramer, (αβ)2. Spectrin binds to ankyrin and to the actin cytoskeleton.

Sucrase-isomaltase

A glycosidase that comprises activities of a sucrase and an isomaltase. Sucrase-isomaltase is found in the apical membrane of intestinal epithelial cells.

Glycosyl phosphoinositol

A modification at the C terminus of membrane proteins that occurs in the endoplasmic reticulum. This modifcation allows the protein to insert into the outer leaflet of the lipid bilayer.

Lipid raft

A membrane subdomain that is enriched in glycosphingolipids, sphingomyelin and cholesterol.

Transcytosis

The delivery of transport vesicles between the apical and basolateral membrane domains of polarized cells.

Trans-Golgi network

The terminal region of the Golgi complex, in which proteins are sorted and packaged into transport vesicles for delivery to the plasma membrane.

Recycling endosome

A membrane compartment in which proteins delivered by transport vesicles are resorted and packaged into vesicles for delivery to different membranes.

Exocyst complex

An example of a vesicle-tethering complex that associates with the plasma membrane and regulates the delivery of transport vesicles to the basolateral membrane domain of polarized epithelial cells.

Immunological synapse

The site of interaction between a lymphocyte and an antigen-presenting cell.

PDZ domain

A common structural domain of ∼80 amino acids that is found in many signalling proteins. It was first found in PSD95, DLG and ZO1.

14-3-3

The characteristic migration pattern of a family of proteins on electrophoretic gels. 14-3-3 proteins bind to kinases, phosphatases and transmembrane receptors.

RING-finger protein

A specialized type of zinc finger of 40–60 residues that binds to 2 atoms of zinc, and is involved in mediating protein–protein binding.

Apical junctional complex

A collection of cell–cell junctions (tight junctions, adherens junctions and junction-associated proteins) that localize to the apex of the lateral membrane of polarized epithelial cells.

Bardet–Biedl syndrome

A complex human genetic disease that is characterized by obesity, retinitis pigmentosa, polydactyly, mental retardation, hypogonadism and renal failure.

GEF

A protein that is involved in locally activating small GTPases, such as the Rab proteins and members of the Rho GTPase family, by catalysing the exchange of GDP for GTP.

GTPase-activating protein

A protein that stimulates the GTPase activity of small GTPases (for example, Rab proteins and Rho family GTPases), leading to their inactivation.

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Mellman, I., Nelson, W. Coordinated protein sorting, targeting and distribution in polarized cells. Nat Rev Mol Cell Biol 9, 833–845 (2008). https://doi.org/10.1038/nrm2525

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