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Multifunctional strands in tight junctions


Tight junctions are one mode of cell–cell adhesion in epithelial and endothelial cellular sheets. They act as a primary barrier to the diffusion of solutes through the intercellular space, create a boundary between the apical and the basolateral plasma membrane domains, and recruit various cytoskeletal as well as signalling molecules at their cytoplasmic surface. New insights into the molecular architecture of tight junctions allow us to now discuss the structure and functions of this unique cell–cell adhesion apparatus in molecular terms.

Key Points

  • Tight junctions provide one type of cell-cell adhesion, acting as a barrier against solute diffusion through the intercellular space, providing boundaries between different membrane domains and recruiting cytoskeletal and signalling molecules.

  • Tight-junction morphology has been studied thoroughly by freeze-fracture replica electron microscopy, revealing that they are composed of sets of continuous intramembranous strands. Two models have been proposed to explain the chemical make-up of these strands - a 'protein model' and a 'lipid model'.

  • Integral membrane proteins that localize to tight junctions include occludin, claudins and junctional adhesion molecule (JAM).

  • Tight junctions vary in tightness. The number of strands correlates well with tightness, but the molecular mechanisms that regulate tight-junction strand number are not known. A possible role for different claudin types is discussed.

  • The existence of aqueous pores, taking open and closed states, has been proposed to exist within paired tight-junction strands. In addition to forming the backbone of tight-junction strands, claudins have been proposed to form extracellular aqueous pores.

  • Claudins bind numerous PDZ-containing proteins through their carboxyl termini. As a result, tight junction-strands are thought to have a magnetic bar function, recruiting cytoskeletal and signalling molecules to their cytoplasmic surface, which might contribute to signalling and polarization of the cell.

  • Tight-junction strands probably form a fence that limits diffusion of lipids and proteins between the apical and basolateral membrance domains.

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Figure 1: Junctional complex and tight junctions.
Figure 2: Structure of tight junctions.
Figure 3: Protein versus lipid models.
Figure 4: Integral membrane proteins localized at tight junctions.
Figure 5: Multiple functions of tight-junction strands.
Figure 6: PDZ-containing proteins localized at tight junctions.


  1. 1

    Farquhar, M. G. & Palade, G. E. Junctional complexes in various epithelia. J. Cell Biol. 17, 375–412 (1963).This is the first electron microscopic description of the junctional complex consisting of tight junctions, adherens junctions and desmosomes.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Schneeberger, E. E. & Lynch, R. D. Structure, function, and regulation of cellular tight junctions. Am. J. Physiol. 262, L647–L661 (1992).

    CAS  PubMed  Google Scholar 

  3. 3

    Gumbiner, B. Breaking through the tight junction barrier. J. Cell Biol. 123, 1631–1633 (1993).

    CAS  PubMed  Google Scholar 

  4. 4

    Spring, K. Routes and mechanism of fluid transport by epithelia. Annu. Rev. Physiol. 60, 105–119 ( 1998).

    CAS  PubMed  Google Scholar 

  5. 5

    Reuss, L. in Tight Junctions (ed. Cereijido, M.) 49–66 (CRC, London, 1992).

    Google Scholar 

  6. 6

    Staehelin, L. A. Further observations on the fine structure of freeze-cleaved tight junctions . J. Cell Sci. 13, 763– 786 (1973).

    CAS  PubMed  Google Scholar 

  7. 7

    Kachar, B. & Reese, T. S. Evidence for the lipidic nature of tight junction strands. Nature 296, 464 –466 (1982).

    CAS  PubMed  Google Scholar 

  8. 8

    Furuse, M. et al. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777– 1788 (1993).This paper reports identification of occludin as a first component of tight-junction strands.

    CAS  PubMed  Google Scholar 

  9. 9

    Ando-Akatsuka,Y. et al. Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologues. J. Cell Biol. 133, 43–47 ( 1996).

    CAS  PubMed  Google Scholar 

  10. 10

    Muresan, Z., Paul, D. L. & Goodenough, D. A. Occludin1B, a variant of the tight junction protein . Mol. Biol. Cell 11, 627– 634 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Saitou, M. et al. Mammalian occludin in epithelial cells: its expression and subcellular distribution. Eur. J. Cell Biol. 73, 222–231 (1997).

    CAS  PubMed  Google Scholar 

  12. 12

    Hirase, T. et al. Occludin as a possible determinant of tight junction permeability in endothelial cells. J. Cell Sci. 110, 1603–1613 (1997).

    CAS  PubMed  Google Scholar 

  13. 13

    Moroi, S. et al. Occludin is concentrated at tight junctions of mouse/rat but not human/guinea pig Sertoli cells in testes. Am. J. Physiol. 274, C1708–C1717 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    Saitou, M. et al. Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J. Cell Biol. 141, 397–408 ( 1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K. & Tsukita, S. Claudin-1 and-2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J. Cell Biol. 141, 1539–1550 (1998).Identification and cloning of the genes encoding claudin-1 and claudin-2.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Morita, K., Furuse, M., Fujimoto, K. & Tsukita, S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc. Natl Acad. Sci. USA 96, 511 –516 (1999).

    CAS  PubMed  Google Scholar 

  17. 17

    Tsukita, S. & Furuse, M. Occludin and claudins in tight junction strands: leading or supporting players? Trend. Cell Biol. 9, 268–273 (1999).

    CAS  Google Scholar 

  18. 18

    Morita, K., Sasaki, H., Fujimoto, K., Furuse, M. & Tsukita, S. Claudin-11/OSP-based tight junctions in myelinated sheaths of oligodendrocytes and Sertoli cells in testis. J. Cell Biol. 145, 579–588 ( 1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Morita, K., Sasaki, H., Furuse, M. & Tsukita, S. Endothelial claudin: Claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J. Cell Biol. 147, 185–194 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Kubota, K. et al. Ca2+-independent cell adhesion activity of claudins, integral membrane proteins of tight junctions. Curr. Biol. 9, 1035–1038 ( 1999).

    CAS  PubMed  Google Scholar 

  21. 21

    Furuse, M., Sasaki, H., Fujimoto, K. & Tsukita, S. A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J. Cell Biol. 143, 391–401 (1998).First report that tight-junction strands can be reconstituted within plasma membranes of cultured fibroblasts by a single gene product, claudin-1 or claudin-2.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Furuse, M., Sasaki, H. & Tsukita, S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J. Cell Biol. 147, 891–903 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Tsukita, S. & Furuse, M. Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J. Cell Biol. 149, 13–16 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Martin-Padura, I. et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol. 142, 117– 127 (1998).Identification and cloning of genes that encode JAM.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Palmeri, D., van Zante, A., Huang, C. C., Hemmerich, S. & Rosen, S. D. Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J. Biol. Chem. 275, 19139–19145 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Aurrand-Lons, M. A., Duncn, L., Du Pasquire, L. & Imhof, B. A. Cloning of JAM-2 and JAM-3; an emerging junctional adhesion molecular family? Curr. Top. Microbiol. Immunol. 251, 91– 98 (2000).

    Google Scholar 

  27. 27

    Bazzoni, G. et al. Homophilic interaction of junctional adhesion molecule. J. Biol. Chem. 275, 30970–30976 (2000).

    CAS  PubMed  Google Scholar 

  28. 28

    Liu, Y. et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J. Cell Sci. 113, 2363– 2374 (2000).

    CAS  PubMed  Google Scholar 

  29. 29

    Claude, P. & Goodenough, D. A. Fracture faces of zonulae occludentes from 'tight' and 'leaky' epithelia. J. Cell Biol. 58, 390–400 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Claude, P. Morphological factors influencing transepithelial permeability: a model for the resistance of the zonula occludens. J. Membr. Biol. 10, 219–232 (1978).

    Google Scholar 

  31. 31

    Martinez-Palomo, A. & Erlij, D. Structure of tight junctions in epithelia with different permeability. Proc. Natl Acad. Sci. USA 72, 4487–4491 (1975).

    CAS  PubMed  Google Scholar 

  32. 32

    Mollgard, K., Malinowski, D. N. & Saunders, N. R. Lack of correlation between tight junction morphology and permeability properties in developing choroid plexus. Nature 264, 293–294 ( 1976).

    CAS  PubMed  Google Scholar 

  33. 33

    Stevenson, B. R., Anderson, J. M., Goodenough, D. A. & Mooseker, M. S. Tight junction structure and ZO-1 content are identical in two strains of Madin–Darby canine kidney cells which differ in transepithelial resistance . J. Cell Biol. 107, 2401– 2408 (1988).Comprehensive examination of the tightness and structure of tight-junction strands in MDCK I and II cells.

    CAS  PubMed  Google Scholar 

  34. 34

    Sonoda, N. et al. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J. Cell Biol. 147, 195–204 (1999).

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Gow, A. et al. CNS myelin and Sertoli cell tight junction strands are absent in OSP/claudin-11 null mice. Cell 99, 649– 659 (1999).Generation of mice lacking one claudin gene, confirming the importance of claudin and tight junctions at the level of the whole organism.

    CAS  PubMed  Google Scholar 

  36. 36

    McCarthy, K. M. et al. Occludin is a functional component of the tight junction. J. Cell Sci. 109, 2287–2298 (1996).

    CAS  PubMed  Google Scholar 

  37. 37

    McCarthy, K. M. et al. Inducible expression of claudin-1–myc but not occludin–VSV-G results in aberrant tight junction strand formation in MDCK cells. J. Cell Sci. 113, 3387–3398 (2000).

    CAS  PubMed  Google Scholar 

  38. 38

    Cereijido, M., Gonzales–Mariscal, L. & Contreras, G. Tight junction: barrier between higher organisms and environment. News in Physiol. Sci. 4, 72 (1989).

    Google Scholar 

  39. 39

    Simon, D. B. et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285, 103–106 (1999). Report that mutations in claudin molecules cause a human hereditary disease, and that claudins might be involved in the formation of aqueous pores within tight-junction strands.

    CAS  PubMed  Google Scholar 

  40. 40

    Furuse, M., Furuse, K., Sasaki, H. & Tsukita, S. Conversion of zonula occludentes from tight to leaky strand type by introducing claudin–2 into MDCK I cells. J. Cell Biol. (in the press).

  41. 41

    Balda, M. S. et al. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical–basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein . J. Cell Biol. 134, 1031– 1049 (1996).

    CAS  PubMed  Google Scholar 

  42. 42

    Wong, V. & Gumbiner, B. M. A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J. Cell Biol. 136, 399– 409 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Saitou, M. et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Stevenson, B. R., Siliciano, J. D., Mooseker, M. S. & Goodenough, D. A. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J. Cell Biol. 103, 755–766 (1986).Identification and characterization of ZO-1 as a first component of tight junctions.

    CAS  PubMed  Google Scholar 

  45. 45

    Gumbiner, B., Lowenkopf, T. & Apatira, D. Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1. Proc. Natl Acad. Sci. USA 88, 3460–3464 (1991).

    CAS  PubMed  Google Scholar 

  46. 46

    Balda, M. S., González-Mariscal, L., Matter, K., Cereijido, M. & Anderson, J. M. Assembly of the tight junction: the role of diacylglycerol. J. Cell Biol. 123, 293–302 (1993).

    CAS  PubMed  Google Scholar 

  47. 47

    Itoh, M. et al. The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J. Cell Biol. 121, 491–502 ( 1993).

    CAS  PubMed  Google Scholar 

  48. 48

    Willott, E. et al. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppresser protein of septate junctions. Proc. Natl Acad. Sci. USA 90, 7834– 7838 (1993).

    CAS  PubMed  Google Scholar 

  49. 49

    Jesaitis, L. A. & Goodenough, D. A. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppresser protein. J. Cell Biol. 124, 949– 961 (1994).

    CAS  PubMed  Google Scholar 

  50. 50

    Haskins, J., Gu, L., Wittchen, E. S., Hibbard, J. & Stevenson, B. R. ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J. Cell Biol. 141, 199–208 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Itoh, M. et al. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J. Cell Biol. 147, 1351–1367 ( 1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Furuse, M. et al. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J. Cell Biol. 127, 1617–1626 (1994).

    CAS  PubMed  Google Scholar 

  53. 53

    Itoh, M., Morita, K. & Tsukita, S. Characterization of ZO-2 as a MAGUK family member associated with tight and adherens junctions with a binding affinity to occludin and α-catenin . J. Biol. Chem. 274, 5981– 5986 (1999).

    CAS  PubMed  Google Scholar 

  54. 54

    Fanning, A. S., Jameson, B. J., Jesaitis, L. A. & Anderson, J. M. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J. Biol. Chem. 273, 29745–29753 (1998).

    CAS  PubMed  Google Scholar 

  55. 55

    Bazzoni, G. et al. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J. Biol. Chem. 275, 20520–20526 ( 2000).

    CAS  PubMed  Google Scholar 

  56. 56

    Ebnet, K., Schulz, C. U., Meyer Zu Brickwedde, M. K., Pendle, G. G. & Vestweber, D. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J. Biol. Chem. 275, 27979–27988 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Martinez-Estrada, O. M. et al. Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (CASK/LIN-2) in human epithelial Caco-2 cells. J. Biol. Chem. (in the press).

  58. 58

    Dobrosotskaya, I., Guy, R. K. & James, G. L. MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of protein-protein interaction domains. J. Biol. Chem. 272, 31589–31597 (1997).

    CAS  PubMed  Google Scholar 

  59. 59

    Ide, N. et al. Localization of membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells. Oncogene 18, 7810–7815 ( 1999).

    CAS  PubMed  Google Scholar 

  60. 60

    Wu, X. et al. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc. Natl Acad. Sci. USA 97, 4233–4238 (2000).

    CAS  PubMed  Google Scholar 

  61. 61

    Wu, X. et al. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J. Biol. Chem. 275, 21477–21485 ( 2000).

    CAS  PubMed  Google Scholar 

  62. 62

    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 

  63. 63

    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  PubMed Central  Google Scholar 

  64. 64

    Lin, D. et al. A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Qiu, R. G., Abo, A. & Steven Martin, G. A human homolog of the C. elegans polarity determinant par-6 links rac and cdc42 to PKCζ signaling and cell transformation. Curr. Biol. 10, 697–707 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Itoh, M., Nagafuchi, A., Moroi, S. & Tsukita, S. Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to α catenin and actin filaments. J. Cell Biol. 138, 181–192 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Hata, Y., Nakanishi, H. & Takai, Y. Synaptic PDZ domain-containing proteins. Neurosci. Res. 32, 1–7 ( 1998).

    CAS  PubMed  Google Scholar 

  68. 68

    Giancotti, F. G. & Ruoslahti, E. Integrin signaling . Science 285a, 1028–1032 (1999).

    Google Scholar 

  69. 69

    Weber, E. et al. Expression and polarized targeting of a rab3 isoform in epithelial cells. J. Cell Biol. 125, 583– 594 (1994).

    CAS  PubMed  Google Scholar 

  70. 70

    Zahraoui, A. et al. A small rab GTPase is distributed in cytoplasmic vesicles in non polarized cells but colocalizes with the tight junction marker ZO-1 in polarized epithelial cells. J. Cell Biol. 124, 101–115 (1994).

    CAS  PubMed  Google Scholar 

  71. 71

    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).Indicates that the tight junction region might function as a specific site for the polarized delivery of exocytic vesicles during epithelial cell polarization.

    CAS  Google Scholar 

  72. 72

    Forstner, G. G. & Wherrett, J. R. Plasma membrane and mucosal glycosphingolipids in the rat intestine. Biochim. Biophys. Acta 306, 446–459 ( 1973).

    CAS  PubMed  Google Scholar 

  73. 73

    Chapelle, S. & Gilles-Baillien, M. Phospholipids and cholesterol in brush border and basolateral membranes from rat intestinal mucosa. Biochim. Biophys. Acta 753, 269–271 (1983).

    CAS  PubMed  Google Scholar 

  74. 74

    Barsukov, L. I., Bergelson, L. D., Spiess, M., Hauser, H. & Semenza, G. Phospholipid topology and flip-flop in intestinal brush-border membrane. Biochim. Biophys. Acta 862, 87–99 (1986).

    CAS  PubMed  Google Scholar 

  75. 75

    Rothman, J. E., Tsai, D. K., Dawidowicz, E. A. & Lenard, J. Transbilayer phospholipid asymmetry and its maintenance in the membrane of influenza virus. Biochemistry 15, 2361– 2370 (1976).

    CAS  PubMed  Google Scholar 

  76. 76

    Dragsten, P. R., Blumenthal, R. & Handler, J. S. Membrane asymmetry in epithelia: is the tight junction a barrier to diffusion in the plasma membrane? Nature 294, 718–722 (1981).

    CAS  PubMed  Google Scholar 

  77. 77

    van Meer, G. & Simon, K. The function of tight junctions in maintaining differences in lipid composition between the apical and basolateral cell surface domains of MDCK cells. EMBO J. 5, 1455–1464 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Nelson, W. J. Regulation of cell surface polarity from bacteria to mammals. Science 258, 948–954 ( 1992).

    CAS  PubMed  Google Scholar 

  79. 79

    Pisam, M. & Ripoche, P. Redistribution of surface macromolecules in dissociated epithelial cells. J. Cell Biol. 71, 909–920 (1976).

    Google Scholar 

  80. 80

    Ziomek, C. A., Shulman, S. & Edidin, M. Redistribution of membrane proteins in isolated mouse intestinal epithelial cell. J. Cell Biol. 86, 849–857 (1980).

    CAS  PubMed  Google Scholar 

  81. 81

    Vega-Salas, D. E., Salas, P. J. I., Gundersen, D. & Rodriguez-Boulan, E. Formation of the apical pole of epithelial (Madin–Darby canine kidney) cells: polarity of an apical protein is independent of tight junctions while segregation of a basolateral marker requires cell–cell interaction. J. Cell Biol. 104, 905–916 (1987).

    CAS  PubMed  Google Scholar 

  82. 82

    Jou, T.-S., Schneeberger, E. E. & Nelson, W. J. Structural and functional regulation of tight junctions by RhoA and Rac1 small GTPases. J. Cell Biol. 142, 101–115 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Tsukita, S., Furuse, M. & Itoh, M. Structural and signaling molecules come together at tight junctions. Curr. Opin. Cell Biol. 11, 628 –633 (1999).

    CAS  PubMed  Google Scholar 

  84. 84

    Mankertz, J. et al. Expression from the human occludin promoter is affected by tumor necrosis factor α and interferon γ. J. Cell Sci. 113, 2085–2090 ( 2000).

    CAS  PubMed  Google Scholar 

  85. 85

    Chen, Yh., Lu, Q., Schneeberger, E. E. & Goodenough, D. A. Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells. Mol. Biol. Cell 11, 849–862 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Li, D. & Mrsny, R. J. Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin. J. Cell Biol. 148, 791–800 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Sakakibara, A., Furuse, M., Saitou, M., Ando-Akatsuka, Y. & Tsukita, S. Possible involvement of phosphorylation of occludin in tight junction formation. J. Cell Biol. 137, 1393–1401 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Wilcox, E. R. et al. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 104 , 165–172 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Kinugasa, T., Sakaguchi, T. & Reinecker, H. C. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118, 1001–1011 (2000).

    CAS  PubMed  Google Scholar 

  90. 90

    Hough, C. D. et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res. 60, 6281–6287 (2000).

    CAS  Google Scholar 

  91. 91

    Madara, J. L. Tight junction dynamics: Is paracellular transport regulated? Cell 53, 497–498 ( 1988).

    CAS  PubMed  Google Scholar 

  92. 92

    Powell, D. W. Barrier function of epithelia. Am. J. Physiol. 241, G275–G288 (1981).

    CAS  PubMed  Google Scholar 

  93. 93

    Madara, J. L. Regulation of the movement of solutes across tight junctions. Annu. Rev. Physiol. 60, 143–159 (1998).

    CAS  PubMed  Google Scholar 

  94. 94

    Briehl, M. M. & Miesfeld, R. L. Isolation and characterization of transcripts induced by androgen withdrawal and apoptotic cell death in the rat ventral prostate. Mol. Endocrinol. 5, 1381–1388 (1991).

    CAS  PubMed  Google Scholar 

  95. 95

    Katahira, J., Inoue, N., Horiguchi, Y., Matsuda, M. & Sugimoto, N. Molecular cloning and functional characterization of the receptor for Clostridium perfringens enterotoxin. J. Cell Biol. 136, 1239–1247 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Sirotkin, H. et al. Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 42 , 245–251 (1997).

    CAS  PubMed  Google Scholar 

  97. 97

    Bronstein, J. M., Popper, P., Micevych, P. E. & Farber, D. B. Isolation and characterization of a novel oligodendrocyte-specific protein . Neurology 47, 772–778 (1996).

    CAS  PubMed  Google Scholar 

  98. 98

    Citi, S., Sabanay, H., Jakes, R., Geiger, B. & Kendrick-Jones, J. Cingulin, a new peripheral component of tight junctions . Nature 333, 272–276 (1988).

    CAS  PubMed  Google Scholar 

  99. 99

    Cordenonsi, M. et al. Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. J. Cell Biol. 147 , 1569–1582 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Zhong, Y. et al. Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin, and ZO-2. J. Cell Biol. 120, 477–483 (1993).

    CAS  PubMed  Google Scholar 

  101. 101

    Keon, B. H., Schäfer, S., Kuhn, C., Grund, C. & Franke, W. W. Symplekin, a novel type of tight junction plaque protein. J. Cell Biol. 134, 1003–1018 (1996).

    CAS  PubMed  Google Scholar 

  102. 102

    Saha, C., Nigam, S. K. & Denker, B. M. Involvement of Gαi2 in the maintenance and biogenesis of epithelial cell tight junctions. J. Biol. Chem. 273, 21629–21633 ( 1998).

    CAS  PubMed  Google Scholar 

  103. 103

    Balda, M. S. & Matter, K. The tight junction protein ZO-1 and an interacting transcription factor regulate ErbB-2 expression. EMBO J. 19, 2024–2033 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Nakamura, T. et al. huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell–cell tight junctions. Proc. Natl Acad. Sci. USA 97, 7284–7289 ( 2000).

    CAS  PubMed  Google Scholar 

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Closely packed cells, arranged in one or more layers, that cover the outer surfaces of the body or line any internal cavities or tubes (except the blood vessels, heart and serous cavities).


Thin, flattened cells of mesoblastic origin that are arranged in a single layer lining the blood vessels and some body cavities, for example those of the heart.


Flat cells derived from mesoderm that are arranged in a single layer, found lining some body cavities.


Cell–cell adhesive junctions that are linked to cytoskeletal filaments of the microfilament type.


These patch-like intercellular junctions are found in vertebrate tissue, and are particularly abundant in tissues undergoing mechanical stress. The central plaque contains adhesion molecules, and represents an anchorage point for cytoskeletal filaments of the intermediate filament type.


Transport of macromolecules across a cell, including transport through channels, pumps and transporters, as well as transcytosis (endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side).


An electron-microscopic method that uses metal replicas to visualize the interior of cell membranes. This technique provides a convenient way to visualize the distribution of large integral membrane proteins as intramembranous particles in the plane of a membrane.


Cross-connection between adjacent channels, tubes, fibres or other parts of a network.


When membranes are freeze-fractured, fracture planes run between the cytoplasmic and extracytoplasmic leaflets of plasma membranes, giving the P- or E-face images of membranes. The P (protoplasmic) face is the inner leaflet viewed from the outside, whereas the E (extracytoplasmic) face is the outer leaflet viewed from the inside.


A form of electron microscopy, combining freeze-fracture replica electron microscopy and immune labelling of proteins.


A supporting cell of the mammalian testis that surrounds and nourishes developing sperm cells.


Cells that delineate the yolk sac cavity together with parietal endoderm cells in the egg cylinder stage of the mammalian embryo.


A mouse fibroblast line derived from connective tissue that does not show adhesion activity.


A type of glial cell that forms and supports the myelin sheath around axons in the central nervous system of vertebrates.


Let or force out something from a vessel that naturally contains it.


Large leukocyte of the mononuclear phagocyte system found in bone marrow and the bloodstream. Monocytes are derived from pluripotent stem cells and become macrophages when they enter the tissues.


Electric resistance across epithelial sheets, measured across the apical–basolateral axis of the cell.


The sheath that surrounds the axons of vertebrate nerves to prevent the leakage of electric current. It is formed by Schwann cells in peripheral nerves and by oligodendrocytes in the central nervous system. These cells wrap up to 100 concentric layers of their plasma membrane in a tight spiral around the axons.


U-shaped part of a nephron lying in the renal medulla. It comprises a thin descending tubule and an ascending tubule formed of both a thin and a thick segment. It has a role in the selective reabsorption of fluid and solutes.


The increase in the size of a tissue or organ, resulting from an increase in the total number of cells present. The part that is affected retains its normal form.


A junction between two cells consisting of pores that allow passage of molecules (up to 9 kDa).


Protein–protein interaction domain first described in the proteins PSD-95, DLG and ZO-1.


Higher-order protein structure present in postsynaptic membranes that functions to concentrate neurotransmitter receptors.


A large family of heterodimeric transmembrane proteins that act as receptors for cell-adhesion molecules.


Calcium-dependent adhesion molecules that mediate homophilic adhesions. There are several subfamilies of cadherin.


Any compound containing residues of a sphingoid and at least one monosaccharide.


Any of a class of phospholipids in which the amino group of sphingosine is in amide linkage with a fatty acid, and the terminal hydroxyl group of sphingosine is esterified to phosphorylcholine.


Components of receptor-mediated activation or inhibition of adenylyl cyclase and other second messenger systems.


Signalling cascade that relays signals from the plasma membrane to the nucleus. MAPKs, which represent the first step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals.

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Tsukita, S., Furuse, M. & Itoh, M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2, 285–293 (2001).

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