Pathway Map Details

Cell adhesion_Tight junctions

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Object list (links open in MetaCore):

Actin, Claudin-16, MUPP1, WNK4, Cingulin, Claudin-5, JAM2, LYRIC, CSDA, ZO-1, ZO-3, Claudin 1, Claudin 19, JAM3, AF-6, ITGB1, Claudin 3, Claudin 2, Claudin 4, Claudin-8, CDX1, Tcf(Lef), Myosin II, ZO-2, CDX2, Occludin, SP1, Occludin, Caveolin-1, Prr1, SNAIL1, Claudin 7, Claudin 3, Claudin-5, TITF1, Claudin-18, Claudin 1, Claudin-14, Claudin 2, JAM1, Claudin-11, Claudin-14


Tight junctions

Multicellular organisms are separated from external environment by a layer of epithelial cells whose integrity is maintained by intercellular junction complexes composed of tight junctions (TJ), adherens junctions, and desmosomes. Tight cell junctions serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets.

A group of integral membrane proteins, Occludin, Claudins, and Junction adhesion molecules ( JAM 1, JAM 2 and JAM3 ), interact with an increasingly complex array of tight junction plaque proteins to regulate paracellular solute and water flux and integrate other diverse cell functions [1].

TJ plaque proteins, such as Zonula occludens ZO-1, ZO-2 and ZO-3, serve as links between the integral TJ proteins and the Actin cytoskeleton and as adapters for the recruitment of cytosolic molecules implicated in cell signaling [2].

Actin filament-binding protein AF-6 serves as a linker of the Actin cytoskeleton to the plasma membrane at the TJ sites [3].

Cingulin is a functionally important component of TJ. It links the submembrane plaque domain of TJ to the actomyosin cytoskeleton [4].

Multi-PDZ domain protein 1 ( MUPP1 ) accumulates at the TJ in epithelial cells through its binding to Claudins and JAMs. MUPP1 is believed to function as a multivalent scaffold protein that recruits various proteins to TJ [5].

Metadherin ( LYRIC ) colocalizes with ZO-1 and Occludin in polarized epithelial cells. This protein is most likely not involved in the TJ formation as a structural component. However, it is required for the maturation of the TJ complex [6].

Interactions between Nectin ( Prr1 ), AF-6 and Occludin suggest a role of the nectin-afadin system in the organization of TJs in epithelial cells [7].

WNK lysine deficient protein kinase 4 ( WNK4 ) phosphorylates Claudins 1-4 involved in the regulation of paracellular ion permeability [8].

ZO-1 -associated Y-box factor ZONAB ( CSDA ) regulates epithelial cell proliferation and cell density [9].

Transcription factors Tcf(Lef), TITF1, CDX1, CDX2 and SNAIL1 are involved in the transcriptional regulation of expression of the genes encoding TJ proteins [1].


  1. Schneeberger EE, Lynch RD
    The tight junction: a multifunctional complex. American journal of physiology. Cell physiology. 2004 Jun;286(6):C1213-28
  2. Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S
    Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. The Journal of cell biology 1999 Dec 13;147(6):1351-63
  3. Mandai K, Nakanishi H, Satoh A, Obaishi H, Wada M, Nishioka H, Itoh M, Mizoguchi A, Aoki T, Fujimoto T, Matsuda Y, Tsukita S, Takai Y
    Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction. The Journal of cell biology 1997 Oct 20;139(2):517-28
  4. Cordenonsi M, D'Atri F, Hammar E, Parry DA, Kendrick-Jones J, Shore D, Citi S
    Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin. The Journal of cell biology 1999 Dec 27;147(7):1569-82
  5. Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S
    Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. The Journal of biological chemistry 2002 Jan 4;277(1):455-61
  6. Britt DE, Yang DF, Yang DQ, Flanagan D, Callanan H, Lim YP, Lin SH, Hixson DC
    Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells. Experimental cell research 2004 Oct 15;300(1):134-48
  7. Fukuhara A, Irie K, Yamada A, Katata T, Honda T, Shimizu K, Nakanishi H, Takai Y
    Role of nectin in organization of tight junctions in epithelial cells. Genes to cells : devoted to molecular & cellular mechanisms 2002 Oct;7(10):1059-72
  8. Yamauchi K, Rai T, Kobayashi K, Sohara E, Suzuki T, Itoh T, Suda S, Hayama A, Sasaki S, Uchida S
    Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proceedings of the National Academy of Sciences of the United States of America 2004 Mar 30;101(13):4690-4
  9. Balda MS, Garrett MD, Matter K
    The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density. The Journal of cell biology 2003 Feb 3;160(3):423-32