Review Article | Published:

Organization and execution of the epithelial polarity programme

Nature Reviews Molecular Cell Biology volume 15, pages 225242 (2014) | Download Citation

Abstract

Epithelial cells require apical–basal plasma membrane polarity to carry out crucial vectorial transport functions and cytoplasmic polarity to generate different cell progenies for tissue morphogenesis. The establishment and maintenance of a polarized epithelial cell with apical, basolateral and ciliary surface domains is guided by an epithelial polarity programme (EPP) that is controlled by a network of protein and lipid regulators. The EPP is organized in response to extracellular cues and is executed through the establishment of an apical–basal axis, intercellular junctions, epithelial-specific cytoskeletal rearrangements and a polarized trafficking machinery. Recent studies have provided insight into the interactions of the EPP with the polarized trafficking machinery and how these regulate epithelial polarization and depolarization.

Key points

  • The epithelium is the first tissue to develop during phylogenesis and ontogenesis; the evolutionary appearance of modern epithelia reflects the requirement of Metazoa for a tissue structure that can segregate their internal medium from the outside environment.

  • Epithelial cells form tight monolayers with an apical junctional complex, which segregate apical and basolateral plasma membrane domains with different lipids and protein composition that are required to act as active barriers between the body and the environment.

  • In higher vertebrates there are more than 150 different types of epithelia that form the key functional components of most body organs; in part because of their exposure to external noxa, epithelia are the main sources of cancer and other human diseases.

  • The epithelial phenotype can be lost and acquired during development through mechanisms called epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET), respectively; a process similar to EMT might account for dissemination of cancers, which, in humans, arise mainly from epithelial cells.

  • The acquisition and maintenance of the epithelial phenotype is guided by an epithelial polarity programme (EPP), which is regulated by a network of polarity proteins and lipids; although these regulators have been highly conserved during evolution, the execution of the EPP is highly variable and context dependent.

  • The EPP proteins and lipids organize themselves into primordial apical and basolateral domains in response to external cues from other cells and the substratum; execution of the EPP results in the formation of the apical junctional complex, the reorganization of the cytoskeleton and the secretory and endosomal organelles in order to generate apical–basal polarity required for vectorial transport functions.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & A polarized epithelium organized by β- and α-catenin predates cadherin and metazoan origins. Science 331, 1336–1339 (2011). An important contribution to our understanding of the evolution of epithelial tissues in animals.

  2. 2.

    , & Cell adhesion, polarity, and epithelia in the dawn of metazoans. Physiol. Rev. 84, 1229–1262 (2004).

  3. 3.

    & Cell-cell adhesion in the cnidaria: insights into the evolution of tissue morphogenesis. Biol. Bull. 214, 218–232 (2008).

  4. 4.

    Cell biology: the endless frontier. Mol. Biol. Cell 21, 3785 (2010).

  5. 5.

    & From cells to organs: building polarized tissue. Nature Rev. Mol. Cell Biol. 9, 887–901 (2008).

  6. 6.

    et al. Apical constriction: a cell shape change that can drive morphogenesis. Dev. Biol. 341, 5–19 (2010).

  7. 7.

    & Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

  8. 8.

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

  9. 9.

    & Epithelial-mesenchymal transitions: insights from development. Development 139, 3471–3486 (2012).

  10. 10.

    & Epithelial organization, cell polarity, and tumorigenesis. Trends Cell Biol. 21, 727–735 (2011).

  11. 11.

    & Cell polarity as a regulator of cancer cell behavior plasticity. Annu. Rev. Cell Dev. Biol. 28, 599–625 (2012).

  12. 12.

    , , , & Polarity complex proteins. Biochim. Biophys. Acta 1778, 614–630 (2008).

  13. 13.

    & The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007).

  14. 14.

    & Cell polarity in eggs and epithelia: parallels and diversity. Cell 141, 757–774 (2010).

  15. 15.

    The apical polarity protein network in Drosophila epithelial cells: regulation of polarity, junctions, morphogenesis, cell growth, and survival. Annu. Rev. Cell Dev. Biol. 28, 655–685 (2012).

  16. 16.

    & Coordinated protein sorting, targeting and distribution in polarized cells. Nature Rev. Mol. Cell Biol. 9, 833–845 (2008).

  17. 17.

    , & Role of membrane traffic in the generation of epithelial cell asymmetry. Nature Cell Biol. 14, 1235–1243 (2012).

  18. 18.

    , & Organization of vesicular trafficking in epithelia. Nature Rev. Mol. Cell Biol. 6, 233–247 (2005).

  19. 19.

    , , & Identification of genes required for cytoplasmic localization in early C. elegans embryos. Cell 52, 311–320 (1988). Identification of PAR genes by an elegant screen.

  20. 20.

    et al. Regulation of neurocoel morphogenesis by Pard6γb. Dev. Biol. 324, 41–54 (2008).

  21. 21.

    , & Integrated activity of PDZ protein complexes regulates epithelial polarity. Nature Cell Biol. 5, 53–58 (2003). The first description of genetic interactions between different groups of polarity genes.

  22. 22.

    , & Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).

  23. 23.

    et al. Yurt, Coracle, Neurexin IV and the Na+,K+-ATPase form a novel group of epithelial polarity proteins. Nature 459, 1141–1145 (2009). Describes the discovery of a new set of genes that is involved in epithelial polarity.

  24. 24.

    & Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

  25. 25.

    & Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62 (1995).

  26. 26.

    & Crosstalk between small GTPases and polarity proteins in cell polarization. Nature Rev. Mol. Cell Biol. 9, 846–859 (2008).

  27. 27.

    , , , & Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J. Cell Biol. 147, 1009–1022 (1999).

  28. 28.

    Adaptation of core mechanisms to generate cell polarity. Nature 422, 766–774 (2003).

  29. 29.

    & Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).

  30. 30.

    & Phosphoinositide signaling pathways: promising role as builders of epithelial cell polarity. Int. Rev. Cell. Mol. Biol. 273, 313–343 (2009).

  31. 31.

    & Phosphoinositide lipids and cell polarity: linking the plasma membrane to the cytocortex. Essays Biochem. 53, 15–27 (2012).

  32. 32.

    , & Phosphoinositides in cell architecture. Cold Spring Harb. Perspect. Biol. 3, a004796 (2011).

  33. 33.

    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).

  34. 34.

    et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128, 383–397 (2007). References 33 and 34 provide evidence that phospholipids can directly alter the identity of membrane domains.

  35. 35.

    , , , & 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).

  36. 36.

    et al. Apicobasal domain identities of expanding tubular membranes depend on glycosphingolipid biosynthesis. Nature Cell Biol. 13, 1189–1201 (2011).

  37. 37.

    & Revitalizing membrane rafts: new tools and insights. Nature Rev. Mol. Cell Biol. 11, 688–699 (2010).

  38. 38.

    , , & Phosphatidylserine is polarized and required for proper Cdc42 localization and for development of cell polarity. Nature Cell Biol. 13, 1424–1430 (2011).

  39. 39.

    et al. Par3 controls epithelial spindle orientation by aPKC-mediated phosphorylation of apical Pins. Curr. Biol. 20, 1809–1818 (2010).

  40. 40.

    et al. aPKC-mediated phosphorylation regulates asymmetric membrane localization of the cell fate determinant Numb. EMBO J. 26, 468–480 (2007).

  41. 41.

    et al. A lateral belt of cortical LGN and NuMA guides mitotic spindle movements and planar division in neuroepithelial cells. J. Cell Biol. 193, 141–154 (2011).

  42. 42.

    , & Discs large links spindle orientation to apical–basal polarity in Drosophila epithelia. Curr. Biol. 23, 1707–1712 (2013).

  43. 43.

    & Drosophila PAR-1 and 14-3-3 inhibit bazooka/PAR-3 to establish complementary cortical domains in polarized cells. Cell 115, 691–704 (2003). One of the first papers to describe the concept of mutual exclusion by polarity proteins in different plasma membrane territories.

  44. 44.

    , & Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr. Biol. 14, 736–741 (2004).

  45. 45.

    et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr. Biol. 14, 1425–1435 (2004).

  46. 46.

    & The polarity-inducing kinase Par-1 controls Xenopus gastrulation in cooperation with 14-3-3 and aPKC. EMBO J. 23, 4190–4201 (2004).

  47. 47.

    et al. PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells 6, 721–731 (2001).

  48. 48.

    , , & Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement. J. Biol. Chem. 287, 21003–21011 (2012).

  49. 49.

    , , & Tuba, a Cdc42 GEF, is required for polarized spindle orientation during epithelial cyst formation. J. Cell Biol. 189, 661–669 (2010).

  50. 50.

    et al. Dbl3 drives Cdc42 signaling at the apical margin to regulate junction position and apical differentiation. J. Cell Biol. 204, 111–127 (2014).

  51. 51.

    & aPKC phosphorylation of Bazooka defines the apical/lateral border in Drosophila epithelial cells. Cell 141, 509–523 (2010).

  52. 52.

    , , & Formation of a Bazooka-Stardust complex is essential for plasma membrane polarity in epithelia. J. Cell Biol. 190, 751–760 (2010).

  53. 53.

    et al. Protein phosphatase 1 regulates the phosphorylation state of the polarity scaffold Par-3. Proc. Natl Acad. Sci. USA 105, 10402–10407 (2008).

  54. 54.

    , , & Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. Cancer Cell 22, 601–614 (2012). Evidence that polarity proteins are important tumour growth and invasion suppressors.

  55. 55.

    , , & Expression of crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 82, 67–76 (1995).

  56. 56.

    et al. Trafficking of Crumbs3 during cytokinesis is crucial for lumen formation. Mol. Biol. Cell 20, 4652–4663 (2009).

  57. 57.

    , & Crumbs controls epithelial integrity by inhibiting Rac1 and PI3K. J. Cell Sci. 124, 3393–3398 (2011).

  58. 58.

    , , & Activation of the protein kinase Akt/PKB by the formation of E-cadherin-mediated cell-cell junctions. Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex. J. Biol. Chem. 274, 19347–19351 (1999).

  59. 59.

    & Cell surface interaction induces polarization of mouse 8-cell blastomeres at compaction. Cell 21, 935–942 (1980).

  60. 60.

    Remodeling epithelial cell organization: transitions between front-rear and apical–basal polarity. Cold Spring Harb. Perspect. Biol. 1, a000513 (2009).

  61. 61.

    & How one becomes many: blastoderm cellularization in Drosophila melanogaster. Bioessays 24, 1012–1022 (2002).

  62. 62.

    , & 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).

  63. 63.

    , & Steps in the morphogenesis of a polarized epithelium. II. Disassembly and assembly of plasma membrane domains during reversal of epithelial cell polarity in multicellular epithelial (MDCK) cysts. J. Cell Sci. 95, 153–165 (1990).

  64. 64.

    et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3, 831–838 (2001).

  65. 65.

    et al. β1-integrin orients epithelial polarity via Rac1 and laminin. Mol. Biol. Cell 16, 433–445 (2005).

  66. 66.

    et al. Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity. EMBO Rep. 9, 923–929 (2008).

  67. 67.

    et al. A molecular network for de novo generation of the apical surface and lumen. Nature Cell Biol. 12, 1035–1045 (2010). Characterization of the mechanisms involved in the establishment of the apical–basal polarity axis and lumen in MDCK cysts.

  68. 68.

    & An integrin-ILK-microtubule network orients cell polarity and lumen formation in glandular epithelium. Nature Cell Biol. 15, 17–27 (2013).

  69. 69.

    et al. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005). Discovery of a key mechanism in EMT.

  70. 70.

    & Beyond polymer polarity: how the cytoskeleton builds a polarized cell. Nature Rev. Mol. Cell Biol. 9, 860–873 (2008).

  71. 71.

    Polarity proteins in migration and invasion. Oncogene 27, 6970–6980 (2008).

  72. 72.

    , & Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).

  73. 73.

    & Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003).

  74. 74.

    , , & Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J. Cell Biol. 164, 717–727 (2004).

  75. 75.

    et al. Par1b links lumen polarity with LGN-NuMA positioning for distinct epithelial cell division phenotypes. J. Cell Biol. 203, 251–264 (2013).

  76. 76.

    , , & Expression and distribution of cell adhesion molecule uvomorulin in mouse preimplantation embryos. Dev. Biol. 124, 451–456 (1987).

  77. 77.

    , & Quantitative analysis of cadherin-catenin-actin reorganization during development of cell-cell adhesion. J. Cell Biol. 135, 1899–1911 (1996).

  78. 78.

    , , , & Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123, 903–915 (2005).

  79. 79.

    , , , & Deconstructing the cadherin-catenin-actin complex. Cell 123, 889–901 (2005). References 78 and 79 propose an alternative to the 'standard' mechanism that links E-cadherin to the actin cytoskeleton.

  80. 80.

    , & Independent cadherin-catenin and Bazooka clusters interact to assemble adherens junctions. J. Cell Biol. 185, 787–796 (2009).

  81. 81.

    & Rab11 in recycling endosomes regulates the sorting and basolateral transport of E-cadherin. Mol. Biol. Cell 16, 1744–1755 (2005).

  82. 82.

    , , , & Drosophila Cip4 and WASp define a branch of the Cdc42-Par6-aPKC pathway regulating E-cadherin endocytosis. Curr. Biol. 18, 1639–1648 (2008).

  83. 83.

    , , & Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability. Curr. Biol. 18, 1631–1638 (2008).

  84. 84.

    et al. Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes Dev. 20, 571–585 (2006).

  85. 85.

    , , & The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin. J. Cell Biol. 171, 1061–1071 (2005).

  86. 86.

    , , & Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions. J. Cell Biol. 132, 451–463 (1996).

  87. 87.

    & Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nature Cell Biol. 7, 262–269 (2005). Describes a role for PAR3 in tight junction assembly.

  88. 88.

    , & PALS1 regulates E-cadherin trafficking in mammalian epithelial cells. Mol. Biol. Cell 18, 874–885 (2007).

  89. 89.

    , & Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J. Cell Sci. 118, 2859–2869 (2005).

  90. 90.

    & Biogenesis of tight junctions: the C-terminal domain of occludin mediates basolateral targeting. J. Cell Sci. 111, 511–519 (1998).

  91. 91.

    , , & Rab11 helps maintain apical crumbs and adherens junctions in the Drosophila embryonic ectoderm. PLoS ONE 4, e7634 (2009).

  92. 92.

    & The role of uvomorulin in the formation of epithelial occluding junctions. Ciba Found. Symp. 125, 168–186 (1987).

  93. 93.

    & A molecular mechanism directly linking E-cadherin adhesion to initiation of epithelial cell surface polarity. J. Cell Biol. 178, 323–335 (2007).

  94. 94.

    et al. E-cadherin polarity is determined by a multifunction motif mediating lateral membrane retention through ankyrin-G and apical–lateral transcytosis through clathrin. J. Biol. Chem. 288, 14018–14031 (2013).

  95. 95.

    et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116, 457–466 (2004). Provides evidence that polarization can occur in the absence of cell–cell contacts.

  96. 96.

    , , & Cytoskeletal control of centrioles movement during the establishment of polarity in Madin-Darby canine kidney cells. J. Cell Biol. 110, 1123–1135 (1990).

  97. 97.

    , & Control of microtubule nucleation and stability in Madin-Darby canine kidney cells: the occurrence of noncentrosomal, stable detyrosinated microtubules. J. Cell Biol. 105, 1283–1296 (1987).

  98. 98.

    , , & GCP6 binds to intermediate filaments: a novel function of keratins in the organization of microtubules in epithelial cells. Mol. Biol. Cell 18, 781–794 (2007).

  99. 99.

    , , & Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell-cell contacts. Cell 135, 948–959 (2008).

  100. 100.

    , & Cadherin-mediated regulation of microtubule dynamics. Nature Cell Biol. 2, 797–804 (2000).

  101. 101.

    & KIF17 stabilizes microtubules and contributes to epithelial morphogenesis by acting at MT plus ends with EB1 and APC. J. Cell Biol. 190, 443–460 (2010).

  102. 102.

    & APC is a component of an organizing template for cortical microtubule networks. Nature Cell Biol. 7, 463–473 (2005).

  103. 103.

    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).

  104. 104.

    , , & Microtubular organization and its involvement in the biogenetic pathways of plasma membrane proteins in Caco-2 intestinal epithelial cells. J. Cell Biol. 113, 275–288 (1991).

  105. 105.

    , , & Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. Dev. Cell 13, 511–522 (2007).

  106. 106.

    et al. The kinesin KIF16B mediates apical transcytosis of transferrin receptor in AP-1B-deficient epithelia. EMBO J. 32, 2125–2139 (2013).

  107. 107.

    et al. The Golgi complex is a microtubule-organizing organelle. Mol. Biol. Cell 12, 2047–2060 (2001).

  108. 108.

    et al. Asymmetric CLASP-dependent nucleation of noncentrosomal microtubules at the trans-Golgi network. Dev. Cell 12, 917–930 (2007).

  109. 109.

    & Apical trafficking in epithelial cells: signals, clusters and motors. J. Cell Sci. 122, 4253–4266 (2009).

  110. 110.

    PAR proteins and the establishment of cell polarity during C. elegans development. Bioessays 27, 126–135 (2005).

  111. 111.

    , & The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 101, 377–388 (2000).

  112. 112.

    FERM proteins in animal morphogenesis. Curr. Opin. Genet. Dev. 19, 357–367 (2009).

  113. 113.

    et al. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex. Dev. Cell 16, 551–562 (2009).

  114. 114.

    , , , & Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes Dev. 26, 2709–2723 (2012).

  115. 115.

    , , & Local phosphocycling mediated by LOK/SLK restricts ezrin function to the apical aspect of epithelial cells. J. Cell Biol. 199, 969–984 (2012).

  116. 116.

    , & Interaction of cadherin with the actin cytoskeleton. Novartis Found. Symp. 269, 159–168; discussion 168 77, 223–230 (2005).

  117. 117.

    , , , & Mammalian Cdc42 is a brefeldin A-sensitive component of the Golgi apparatus. J. Biol. Chem. 271, 26850–26854 (1996).

  118. 118.

    , & Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cells. Nature Cell Biol. 1, 8–13 (1999).

  119. 119.

    , , & cdc42 regulates the exit of apical and basolateral proteins from the trans-Golgi network. EMBO J. 20, 2171–2179 (2001).

  120. 120.

    et al. LIM kinase 1 and cofilin regulate actin filament population required for dynamin-dependent apical carrier fission from the trans-Golgi network. Mol. Biol. Cell 20, 438–451 (2009).

  121. 121.

    et al. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch. 447, 465–468 (2004).

  122. 122.

    , & N-glycans as apical sorting signals in epithelial cells. Nature 378, 96–98 (1995).

  123. 123.

    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). References 122 and 123 describe the role of N- and O-glycans as apical sorting signals.

  124. 124.

    , & Interaction of influenza virus hemagglutinin with sphingolipid-cholesterol membrane rafts via its transmembrane domain. EMBO J. 16, 5501–5508 (1997).

  125. 125.

    , , & A glycophospholipid membrane anchor acts as an apical targeting signal in polarized epithelial cells. J. Cell Biol. 109, 2145–2156 (1989).

  126. 126.

    , , & Transmembrane and GPI anchored forms of NCAM are targeted to opposite domains of a polarized epithelial cell. Nature 353, 76–77 (1991).

  127. 127.

    & Rhodopsin trafficking and its role in retinal dystrophies. Int. Rev. Cytol. 195, 215–267 (2000).

  128. 128.

    , , , & Rhodopsin's carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell 97, 877–887 (1999).

  129. 129.

    , & Cytoplasmic dynein regulation by subunit heterogeneity and its role in apical transport. J. Cell Biol. 153, 1499–1509 (2001).

  130. 130.

    , & Identification of an apical sorting determinant in the cytoplasmic tail of megalin. Am. J. Physiol. Cell Physiol. 284, C1105–c1113 (2003).

  131. 131.

    et al. Differential distribution of low-density lipoprotein-receptor-related protein (LRP) and megalin in polarized epithelial cells is determined by their cytoplasmic domains. Traffic 4, 273–288 (2003).

  132. 132.

    et al. Galectin-4-regulated delivery of glycoproteins to the brush border membrane of enterocyte-like cells. Traffic 10, 438–450 (2009).

  133. 133.

    , , , & Galectin-9 trafficking regulates apical–basal polarity in Madin-Darby canine kidney epithelial cells. Proc. Natl Acad. Sci. USA 107, 17633–17638 (2010). References 132 and 133 Identify a role of galectins in apical trafficking, thus consolidating the concept of glycans as apical sorting signals.

  134. 134.

    et al. The MAL proteolipid is necessary for normal apical transport and accurate sorting of the influenza virus hemagglutinin in Madin-Darby canine kidney cells. J. Cell Biol. 145, 141–151 (1999).

  135. 135.

    et al. Protein oligomerization modulates raft partitioning and apical sorting of GPI-anchored proteins. J. Cell Biol. 167, 699–709 (2004).

  136. 136.

    , , & 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).

  137. 137.

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

  138. 138.

    , , & VIP17/MAL, a lipid raft-associated protein, is involved in apical transport in MDCK cells. Proc. Natl Acad. Sci. USA 96, 6241–6248 (1999).

  139. 139.

    & Clathrin and AP1B: key roles in basolateral trafficking through trans-endosomal routes. FEBS Lett. 583, 3784–3795 (2009).

  140. 140.

    & Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu. Rev. Biochem. 72, 395–447 (2003).

  141. 141.

    et al. Clathrin is a key regulator of basolateral polarity. Nature 452, 719–723 (2008). Reports a major role of clathrin in basolateral trafficking.

  142. 142.

    et al. Basolateral sorting of the coxsackie and adenovirus receptor through interaction of a canonical YXXPhi motif with the clathrin adaptors AP-1A and AP-1B. Proc. Natl Acad. Sci. USA 109, 3820–3825 (2012).

  143. 143.

    et al. Mu1B, a novel adaptor medium chain expressed in polarized epithelial cells. FEBS Lett. 449, 215–220 (1999).

  144. 144.

    , , & A novel clathrin adaptor complex mediates basolateral targeting in polarized epithelial cells. Cell 99, 189–198 (1999). References 143 and 144 report the discovery of the first basolateral sorting adaptor.

  145. 145.

    , , & Response: the “tail” of the twin adaptors. Dev. Cell 27, 247–248 (2013).

  146. 146.

    Adaptor proteins involved in polarized sorting. J. Cell Biol. 204, 7–17 (2014).

  147. 147.

    et al. The adaptor protein-1 mu1B subunit expands the repertoire of basolateral sorting signal recognition in epithelial cells. Dev. Cell 27, 353–366 (2013).

  148. 148.

    , & The epithelial-specific adaptor AP1B mediates post-endocytic recycling to the basolateral membrane. Nature Cell Biol. 4, 605–609 (2002).

  149. 149.

    et al. Antibody to AP1B adaptor blocks biosynthetic and recycling routes of basolateral proteins at recycling endosomes. Mol. Biol. Cell 18, 4872–4884 (2007).

  150. 150.

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

  151. 151.

    et al. The clathrin adaptor AP-1A mediates basolateral polarity. Dev. Cell 22, 811–823 (2012).

  152. 152.

    , & A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell 105, 575–585 (2001).

  153. 153.

    et al. Clathrin adaptor AP1B controls adenovirus infectivity of epithelial cells. Proc. Natl Acad. Sci. USA 106, 11143–11148 (2009).

  154. 154.

    et al. The absence of a clathrin adapter confers unique polarity essential to proximal tubule function. Kidney Int. 78, 382–388 (2010).

  155. 155.

    et al. Signal-mediated, AP-1/clathrin-dependent sorting of transmembrane receptors to the somatodendritic domain of hippocampal neurons. Neuron 75, 810–823 (2012).

  156. 156.

    & 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).

  157. 157.

    et al. The basolateral targeting signal of CD147 (EMMPRIN) consists of a single leucine and is not recognized by retinal pigment epithelium. Mol. Biol. Cell 15, 4148–4165 (2004).

  158. 158.

    , , , & AP-4 binds basolateral signals and participates in basolateral sorting in epithelial MDCK cells. Nature Cell Biol. 4, 154–159 (2002).

  159. 159.

    , , & The delta subunit of AP-3 is required for efficient transport of VSV-G from the trans-Golgi network to the cell surface. Proc. Natl Acad. Sci. USA 99, 6755–6760 (2002).

  160. 160.

    & ARH cooperates with AP-1B in the exocytosis of LDLR in polarized epithelial cells. J. Cell Biol. 193, 51–60 (2011).

  161. 161.

    et al. Naked2 acts as a cargo recognition and targeting protein to ensure proper delivery and fusion of TGF-α containing exocytic vesicles at the lower lateral membrane of polarized MDCK cells. Mol. Biol. Cell 18, 3081–3093 (2007).

  162. 162.

    et al. Protein kinase D regulates basolateral membrane protein exit from trans-Golgi network. Nature Cell Biol. 6, 106–112 (2004).

  163. 163.

    et al. CtBP3/BARS drives membrane fission in dynamin-independent transport pathways. Nature Cell Biol. 7, 570–580 (2005).

  164. 164.

    et al. Four-dimensional live imaging of apical biosynthetic trafficking reveals a post-Golgi sorting role of apical endosomal intermediates. Proc. Natl Acad. Sci. USA (2014).

  165. 165.

    , & Involvement of microtubule motors in basolateral and apical transport in kidney cells. Nature 372, 801–803 (1994).

  166. 166.

    et al. KIFC3, a microtubule minus end-directed motor for the apical transport of annexin XIIIb-associated Triton-insoluble membranes. J. Cell Biol. 155, 77–88 (2001).

  167. 167.

    , , & PH-domain-dependent selective transport of p75 by kinesin-3 family motors in non-polarized MDCK cells. J. Cell Sci. 123, 1732–1741 (2010). References 101 and 167 show that the same apical plasma membrane protein may be carried by different kinesin motors in non-polarized and in polarized epithelial cells.

  168. 168.

    , & Myosin II is involved in the production of constitutive transport vesicles from the TGN. J. Cell Biol. 138, 291–306 (1997).

  169. 169.

    , , , & Myosin VI is required for sorting of AP-1B-dependent cargo to the basolateral domain in polarized MDCK cells. J. Cell Biol. 177, 103–114 (2007).

  170. 170.

    et al. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc. Natl Acad. Sci. USA 108, 2789–2794 (2011).

  171. 171.

    et al. Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model. Hum. Mutat. 31, 544–551 (2010).

  172. 172.

    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).

  173. 173.

    et al. Exocyst requirement for endocytic traffic directed toward the apical and basolateral poles of polarized MDCK cells. Mol. Biol. Cell 18, 3978–3992 (2007). References 172 and 173 report the involvement of the exocyst in apical and basolateral trafficking.

  174. 174.

    et al. Three-dimensional analysis of post-Golgi carrier exocytosis in epithelial cells. Nature Cell Biol. 5, 126–136 (2003).

  175. 175.

    , , , & Apical targeting of syntaxin 3 is essential for epithelial cell polarity. J. Cell Biol. 173, 937–948 (2006).

  176. 176.

    , , , & Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity. PLoS ONE 6, e21181 (2011).

  177. 177.

    & Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

  178. 178.

    & Role of Rab GTPases in membrane traffic and cell physiology. Physiol. Rev. 91, 119–149 (2011).

  179. 179.

    et al. Rab5 is necessary for the biogenesis of the endolysosomal system in vivo. Nature 485, 465–470 (2012). RAB5 as a master endosomal organizer.

  180. 180.

    , , & Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nature Cell Biol. 9, 1066–1073 (2007). Screen reveals a link between polarity proteins and vesicle traffic.

  181. 181.

    et al. Caenorhabditis elegans screen reveals role of PAR-5 in RAB-11-recycling endosome positioning and apicobasal cell polarity. Nature Cell Biol. 14, 666–676 (2012).

  182. 182.

    & Cdc42 and Par proteins stabilize dynamic adherens junctions in the Drosophila neuroectoderm through regulation of apical endocytosis. J. Cell Biol. 183, 1129–1143 (2008).

  183. 183.

    , & The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol. Biol. Cell 20, 2522–2529 (2009).

  184. 184.

    et al. Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells. Nature Cell Biol. 14, 838–849 (2012).

  185. 185.

    , , & Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells. J. Cell Biol. 168, 303–313 (2005).

  186. 186.

    , & The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. J. Cell Sci. 120, 3099–3110 (2007).

  187. 187.

    , , , & Positive feedback and mutual antagonism combine to polarize Crumbs in the Drosophila follicle cell epithelium. Curr. Biol. 22, 1116–1122 (2012).

  188. 188.

    , , , & Retromer controls epithelial cell polarity by trafficking the apical determinant Crumbs. Curr. Biol. 21, 1111–1117 (2011).

  189. 189.

    , & Upstream regulation of the hippo size control pathway. Curr. Biol. 20, R574–582 (2010).

  190. 190.

    & Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008).

  191. 191.

    et al. A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 329, 436–439 (2010).

  192. 192.

    et al. A size-exclusion permeability barrier and nucleoporins characterize a ciliary pore complex that regulates transport into cilia. Nature Cell Biol. 14, 431–437 (2012). References 191 and 192 identify key protein complexes that control ciliary access.

  193. 193.

    & The primary cilium at the crossroads of mammalian hedgehog signaling. Curr. Top. Dev. Biol. 85, 225–260 (2008).

  194. 194.

    et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468, 310–315 (2010).

  195. 195.

    et al. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell 147, 539–553 (2011). References 194 and 195 identify regulatory roles of endothelial cells in epithelial regeneration.

  196. 196.

    et al. Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis. Development 140, 1330–1341 (2013).

  197. 197.

    et al. A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145, 1129–1141 (2011).

  198. 198.

    , , , & Atypical protein kinase C controls sea urchin ciliogenesis. Mol. Biol. Cell 22, 2042–2053 (2011).

  199. 199.

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

  200. 200.

    , , , & GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature 494, 484–488 (2013).

  201. 201.

    et al. Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Hum. Mol. Genet. 18, 4711–4723 (2009).

  202. 202.

    et al. The exocyst protein Sec10 interacts with Polycystin-2 and knockdown causes PKD-phenotypes. PLoS Genet. 7, e1001361 (2011).

  203. 203.

    , , , & Evolving endosomes: how many varieties and why? Curr. Opin. Cell Biol. 17, 423–434 (2005).

  204. 204.

    et al. Apical and basolateral endocytic pathways of MDCK cells meet in acidic common endosomes distinct from a nearly-neutral apical recycling endosome. Traffic 1, 480–493 (2000).

  205. 205.

    et al. Definition of distinct compartments in polarized Madin-Darby canine kidney (MDCK) cells for membrane-volume sorting, polarized sorting and apical recycling. Traffic 1, 124–140 (2000).

  206. 206.

    , , , & Meeting of the apical and basolateral endocytic pathways of the Madin-Darby canine kidney cell in late endosomes. J. Cell Biol. 109, 3259–3272 (1989).

  207. 207.

    & Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol. 18, 199–209 (2008).

  208. 208.

    , , & Newly synthesized transferrin receptors can be detected in the endosome before they appear on the cell surface. J. Biol. Chem. 270, 10999–11003 (1995).

  209. 209.

    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).

  210. 210.

    et al. Differential involvement of endocytic compartments in the biosynthetic traffic of apical proteins. EMBO J. 26, 3737–3748 (2007).

  211. 211.

    , , , & A centrosomal antigen localized on intermediate filaments and mitotic spindle poles. J. Cell Sci. 97, 259–271 (1990).

  212. 212.

    et al. Mammalian homolog of Drosophila tumor suppressor lethal (2) giant larvae interacts with basolateral exocytic machinery in Madin-Darby canine kidney cells. Mol. Biol. Cell 13, 158–168 (2002).

  213. 213.

    & Endocytic control of epithelial polarity and proliferation in Drosophila. Nature Cell Biol. 7, 1232–1239 (2005).

  214. 214.

    & Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell-cell adhesion. J. Cell Biol. 178, 517–527 (2007).

  215. 215.

    , , , & Differential roles for actin polymerization and a myosin II motor in assembly of the epithelial apical junctional complex. Mol. Biol. Cell 16, 2636–2650 (2005).

  216. 216.

    , , & Overexpression of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-dependent maintenance of membrane organelle distribution. J. Cell Biol. 139, 469–484 (1997).

  217. 217.

    et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–450 (2005).

  218. 218.

    et al. AP-1 and KIF13A coordinate endosomal sorting and positioning during melanosome biogenesis. J. Cell Biol. 187, 247–264 (2009).

  219. 219.

    , , & mDia mediates Rho-regulated formation and orientation of stable microtubules. Nature Cell Biol. 3, 723–729 (2001).

  220. 220.

    , , , & The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401–410 (1992).

  221. 221.

    , , , & Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts. Nature Cell Biol. 1, 45–50 (1999).

  222. 222.

    , , & The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions. J. Cell Biol. 145, 123–139 (1999).

  223. 223.

    et al. Rab5a is a common component of the apical and basolateral endocytic machinery in polarized epithelial cells. Proc. Natl Acad. Sci. USA 91, 5061–5065 (1994).

  224. 224.

    et al. Rab and actomyosin-dependent fission of transport vesicles at the Golgi complex. Nature Cell Biol. 12, 645–654 (2010).

  225. 225.

    et al. Rab8, a small GTPase involved in vesicular traffic between the TGN and the basolateral plasma membrane. J. Cell Biol. 123, 35–45 (1993).

  226. 226.

    , , , & The Rab8 GTPase selectively regulates AP-1B-dependent basolateral transport in polarized Madin-Darby canine kidney cells. J. Cell Biol. 163, 339–350 (2003).

  227. 227.

    et al. The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport. J. Cell Sci. 123, 3966–3977 (2010).

  228. 228.

    et al. Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol. Biol. Cell 12, 2341–2351 (2001).

  229. 229.

    et al. Rab10 is involved in basolateral transport in polarized Madin-Darby canine kidney cells. Traffic 8, 47–60 (2007).

  230. 230.

    et al. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol. Biol. Cell 10, 47–61 (1999).

  231. 231.

    , & Sorting of membrane and fluid at the apical pole of polarized Madin-Darby canine kidney cells. Mol. Biol. Cell 11, 2131–2150 (2000).

  232. 232.

    et al. A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nature Cell Biol. 12, 1143–1153 (2010).

  233. 233.

    , , & Rab13 regulates membrane trafficking between TGN and recycling endosomes in polarized epithelial cells. J. Cell Biol. 182, 845–853 (2008).

  234. 234.

    & Rab17 localizes to recycling endosomes and regulates receptor-mediated transcytosis in epithelial cells. J. Biol. Chem. 273, 15734–15741 (1998).

  235. 235.

    et al. Rab17 regulates membrane trafficking through apical recycling endosomes in polarized epithelial cells. J. Cell Biol. 140, 1039–1053 (1998).

  236. 236.

    et al. The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J. Cell Biol. 185, 673–684 (2009).

  237. 237.

    et al. Mechanism of polarized lysosome exocytosis in epithelial cells. J. Cell Sci. 125, 5937–5943 (2012).

  238. 238.

    et al. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biol. 14, 61–72 (2011).

  239. 239.

    et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biol. 12, 19–30 (2010).

  240. 240.

    , , , & Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote. Dev Dyn. 229, 422–32 (2004).

Download references

Acknowledgements

Research in E.R.B.'s laboratory was supported by US National Institutes of Health (NIH) grants EY08538, EY022165 and GM34107, and by the Dyson, Research to Prevent Blindness, Beckman and Starr Foundations. Research in I.G.M.'s laboratory was supported by NIH grants CA132898 and GM50526, and by a grant from the Susan Komen Breast Cancer Foundation.

Author information

Affiliations

  1. Margaret Dyson Vision Research Institute, Weill Cornell Medical College, 1300 York Avenue, LC-301 New York City, New York 10065, USA.

    • Enrique Rodriguez-Boulan
  2. Department of Cell & Developmental Biology, Vanderbilt University Medical Center, 465 21st Avenue South, U 3209 MRB III, Nashville Tennessee 37232, USA.

    • Ian G. Macara

Authors

  1. Search for Enrique Rodriguez-Boulan in:

  2. Search for Ian G. Macara in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Enrique Rodriguez-Boulan or Ian G. Macara.

Glossary

Phylogenesis

Refers to the evolutionary history of species. Embryo development reflects the course of evolution, partially supporting Hackel's proposal that ontogenesis recapitulates phylogenesis; however, the more generalized form of this concept has been mostly discredited.

Polarized trafficking machinery

The special configuration that has been adopted by the secretory pathway and endosomes in polarized epithelia cells.

Ontogenesis

The origin and development of an organism from the fertilized egg to mature form.

Primary cilium

A protrusion at the free surface of most interphase vertebrate cells that disassembles during mitosis. It is based on nine pairs of microtubules that emerge from a basal body. It houses a number of signalling pathways that are important for development, such as Hedgehog.

Planar polarity

The polarization of epithelial cells along the plane of the epithelium (orthogonal to the apical–basal axis), which directs the orientation of cell shape, division, movement and differentiation. Non-epithelial cells can also exhibit planar polarity.

Epithelial–mesenchymal transition

(EMT). A developmental programme during which epithelial cells adopt a mesenchymal phenotype that is marked by the loss of intercellular adhesion and by increased cell migration. During EMT, markers such as epithelial cadherin (E-cadherin), Crumbs and cytokeratins are downregulated, whereas mesenchymal markers such as vimentin are upregulated.

MDCK

(Madin Darby canine kidney). A polarized epithelial cell line that is widely used for the study of polarity, membrane trafficking and cell adhesion.

Apical–basal polarity

The polarity axis along the apical (uppermost) and basal plasma membrane domains. In epithelial cells the two plasma membrane domains have different protein and lipid composition, which are required to carry out directional transport of nutrients and waste between the two sides of the epithelium.

Basement membrane

The condensation of extracellular matrix components (collagens, laminins, distroglycans, elastins and others) that are secreted partly by epithelial cells and underlie connective tissue and vascular cells, to which epithelial cells attach through integrin receptors.

Integrin

Transmembrane proteins composed of two (α- and β-) subunits that link the actin cytoskeleton with extracellular components such as the basement membrane.

Front–rear polarity

A morphological characteristic of migratory cells wherein the front (leading edge) and the rear (uropod) show morphological and functional asymmetry.

Apical junctional complex

A belt-like structure at the border between apical and lateral domains that are formed by adherens junctions with a predominantly adhesive function and tight junctions (septate junctions in invertebrates) with a predominantly sealing role. Both junctions are formed by adhesive transmembrane proteins (claudin and occludin for tight junctions and E-cadherin for adherens junctions) and cytoplasmic 'plaque' proteins that link these junctions with the actin cytoskeleton.

Microvilli

Small plasma membrane protrusions at the surface of cells that increase the surface area and facilitate absorption and secretion.

Clathrin-mediated endocytosis

Formation of some types of endocytic vesicles at the plasma membrane, which is mediated by clathrin and clathrin adaptors such as adaptor protein 2 (AP-2).

Exosomes

Small vesicles that are released from cells by fusion of multivesicular bodies with the plasma membrane. They have multiple communication roles between cells.

Microtubule motors

A family of plus end and minus end directed kinesins and minus end directed dyneins that move transport vesicles and organelles along the cytoskeleton and across the viscous cytoplasm using ATP as an energy source.

Exocyst

A highly conserved octameric protein complex, which is part of a large group of 'tethering factors', that regulates the docking and fusion of transport vesicles with the plasma membrane.

SNAREs

Proteins that regulate secretory vesicle fusion.

Coat protein

Eukaryotic cells express coatomer protein and the clathrin family of coat proteins; they fold membranes to generate transport vesicles in cooperation with adaptors selecting specific cargo proteins that will be passengers during the transport to a different membrane.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrm3775

Further reading