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Wibbe, N.; Ebnet, K. Integral Membrane Proteins at the Tight Junctions. Encyclopedia. Available online: https://encyclopedia.pub/entry/52565 (accessed on 01 July 2024).
Wibbe N, Ebnet K. Integral Membrane Proteins at the Tight Junctions. Encyclopedia. Available at: https://encyclopedia.pub/entry/52565. Accessed July 01, 2024.
Wibbe, Nicolina, Klaus Ebnet. "Integral Membrane Proteins at the Tight Junctions" Encyclopedia, https://encyclopedia.pub/entry/52565 (accessed July 01, 2024).
Wibbe, N., & Ebnet, K. (2023, December 11). Integral Membrane Proteins at the Tight Junctions. In Encyclopedia. https://encyclopedia.pub/entry/52565
Wibbe, Nicolina and Klaus Ebnet. "Integral Membrane Proteins at the Tight Junctions." Encyclopedia. Web. 11 December, 2023.
Integral Membrane Proteins at the Tight Junctions
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This entry is adapted from the peer-reviewed paper 10.3390/cells12232701

Tight junctions (TJ) are cell–cell adhesive structures that define the permeability of barrier-forming epithelia and endothelia. In contrast to this seemingly static function, TJs display a surprisingly high molecular complexity and unexpected dynamic regulation, which allows the TJs to maintain a barrier in the presence of physiological forces and in response to perturbations. Cell–cell adhesion receptors play key roles during the dynamic regulation of TJs. They connect individual cells within cellular sheets and link sites of cell–cell contacts to the underlying actin cytoskeleton.

cell–cell adhesion JAM-A tight junction integral membrane proteins CRB3 claudins TAMPs IgSF proteins

1. Introduction

The intercellular junctions of epithelial and endothelial cells are specializations of the cell membrane that physically integrate individual cells into tissues. These junctions consist of distinct substructures visible via ultrastructural analysis, such as tight junctions (TJs), adherens junctions (AJs), or desmosomes, with different functions at the level of the individual cell, of the organ, and of the entire organism, which, for example, include apical-basal polarity, barrier formation, resistance to the mechanical strain and propagation of mechanical forces, and morphogenesis [1][2][3][4][5]. The integrity of these junctions is necessary for the maintenance of functional tissues. Abnormalities in the organization or function of the junctions are frequently associated with disorders like inflammation and malignant transformation [6][7][8]. Consistent with the necessity to develop adhesive systems as a prerequisite for the development of multicellular organisms, the origination of proteins mediating cell–cell adhesion dates back to the closest extant unicellular relative of multicellular organisms [9][10]. Interestingly, while AJs are used to mediate adhesion in the earliest metazoa, both desmosomes and TJs exist only in vertebrates [11][12]. Desmosomes have probably evolved from AJs as they use similar molecular components to link adjacent cells [12], whereas TJs have probably evolved from the Septate Junctions (SJs) of invertebrates, which are morphologically different from TJs but are functionally homologous to TJs and contain molecular components that are related to the components found in vertebrate TJs [13].
All three types of junctions are composed of several multiprotein complexes. These complexes consist of at least one integral membrane protein that interacts with a cytoplasmic protein which, together with other scaffolding proteins, forms a junctional plaque that is linked to the actin cytoskeleton, the intermediate filament system, or the microtubule system [14][15][16]. In addition to their role in connecting the cellular filamental systems to the cell–cell junctions, all three types of cell junctions serve as hubs for signaling events that regulate proliferation, differentiation, or cell migration [17][18][19]. The integral membrane proteins localized at the different types of junctions thus not only physically link adjacent cells to form a structural continuum of epithelial cells, but also regulate the specific localization of signaling hubs along the intercellular junctions.
Interestingly, the most diverse repertoire of adhesion molecules and integral membrane proteins is localized at the TJs. As opposed to AJs and desmosomes, which use cadherins and members of the nectin family of the immunoglobulin superfamily (IgSF) to interact with adjacent cells, TJs make use of various members of the IgSF, members of the claudin family, members of the TJ-associated Marvel protein (TAMP) family, and members of the Crumbs family of integral membrane proteins to regulate their function.
Integral membrane proteins localized at the TJs can be classified into four major groups: Crumbs homolog 3 (CRB3), a member of the Crumbs family of proteins; claudins; TAMPs; and members of the IgSF of adhesion molecules (Figure 1).
Cells 12 02701 g001
Figure 1. Integral membrane proteins at TJs and their interaction with scaffolding proteins. Tight junctions contain a number of membrane proteins including Crumbs3 (CRB3), claudins, TJ-associated marvel proteins (Occludin, MarvelD3, Tricellulin), and members of the immunoglobulin superfamily (JAMs, CAR, ESAM, Angulins). All membrane proteins at the TJ directly interact with one or several scaffolding proteins (depicted in grey color). Some scaffolding proteins interact with several integral membrane proteins, as well as with other scaffolding proteins. For example, MUPP1 can interact with JAM-A, CAR, and claudins, as well as with PALS-1, PAR-6, and ZO-3 (indicated by arrows). Tricellulin and angulins are specifically localized at tricellular TJs.

2. CRB3

CRB3 is a member of the vertebrate Crumbs family of proteins, which are homologous to Drosophila Crumbs. CRB3 and has a very short extracellular region that consists of 33 amino acids (AA), a single transmembrane region, and a short cytoplasmic region of 40 AA [20]. In addition to its localization at TJs, CRB3 is also localized at the apical membrane domain of epithelial cells [21]. As opposed to Drosophila Crumbs, the vertebrate CRB3 isoform localized at the TJs is most likely not involved in homophilic or heterophilic interactions [22].

3. Claudins

Claudins are a family of tetraspan transmembrane proteins comprising 27 members [23][24]. Notably, claudins support cell aggregation when expressed in fibroblasts, indicating that their adhesive activity not only regulates their localization at homotypic cell–cell contacts but also contributes to the physical cell–cell adhesion at the TJs [25]. A central property of claudins is their ability to multimerize by interacting both in cis and in trans with either the same or a different claudin family member to form strands that are visible via freeze-fracture electron microscopy (EM) [26][27]. Claudin-based strands can act as occluding barriers for water and small solutes, as well as anion- or cation-selective paracellular channels, and are the principal paracellular permeability regulators of epithelial and endothelial barriers [28].

4. TAMPs

Members of the TAMP family include occludin, tricellulin/MarvelD2, and MarvelD3 [29]. Similar to claudins, TAMPs are tetraspan transmembrane proteins, but based on their sequence homologies, they are not related to claudins. Their characteristic feature is a conserved four-transmembrane “MAL and related proteins for vesicle trafficking and membrane link” (Marvel) domain [30]. Of the three TAMPs, tricellulin is unique as it is enriched at sites of contact between three cells (tricellular TJs, tTJs) [31]. Heterotypic interactions between tricellulin and MarvelD3, as well as between occludin and MarvelD3, have been described via co-immunoprecipitation (CoIP) and via Förster resonance energy transfer (FRET) experiments. These interactions most likely occur in cis [29][32]. A homophilic interaction in trans has been found for occludin but not for tricellulin or MarvelD3 [32][33]. While several studies have suggested that TAMPs per se are not essential for the development of an epithelial barrier function [34][35][36], recent findings indicate that tricellulin is required for the establishment of the barrier function in mammary gland-derived epithelial cells [37].

5. IgSF Proteins

IgSF members localized at the TJs include the junctional adhesion molecule (JAM) family members JAM-A and JAM-C [38], and the JAM-related adhesion molecules Coxsackie- and Adenovirus-Receptor (CAR), JAM4, CAR-like membrane protein (CLMP), and Endothelial Cell-Selective Adhesion Molecule (ESAM, in endothelial cells) [39][40][41][42]. All these IgSF proteins can undergo trans-homophilic interactions which stabilize their localization at cell–cell contacts. In addition, the trans-homophilic activities of CAR, JAM4, CLMP, and ESAM support cell aggregation after transfection in cells [39][40][41][43], suggesting that their adhesive activities contribute to the strength of the physical interaction at the TJs. Angulins (Angulin-1, -2, -3) are IgSF proteins with a single N-terminal Ig-like domain [44]. Among all other IgSF proteins localized at the TJs, angulins are unique in that they are enriched at the tTJs [45]. A main function of all three angulins is to recruit tricellulin to the tTJs [45][46]. The ectopic expression of angulin-1 in L cell fibroblasts resulted in angulin-1 enrichment at cell–cell contacts, suggesting that angulin-1 is engaged in homophilic or heterophilic trans interactions [46].
Strikingly, many of the integral membrane proteins localized at the TJs contain a C-terminal PDZ domain-binding motif (PBM), through which they can interact with the PDZ domains present in many TJ-localized scaffolding proteins (Table 1).
Table 1. PDZ domain binding motifs of integral membrane proteins at TJs. The figure shows integral membrane proteins localized at the TJs. The total number of AA and the number of amino acids comprising the cytoplasmic regions are indicated. The five C-terminal AA comprising the PDZ domain binding motifs are also shown. A classification of PDZ domain binding motifs (PBM) is provided in reference [47]. The nomenclature applies to human proteins. AA are shown in single letter code. X refers to any AA. Abbreviations: PBM, PDZ domain binding motiv.
Integral Membrane Protein Size (AA) Cytoplasmic Region (AA) COOH-Terminal Residues (PBM)
CRB3 120 40 - EERLI (+)
JAM-A 299 40 - SSFLV (+)
JAM-C 310 48 - SSFVI (+)
CAR 365 107 - DGSIV (+)
JAM4 407 122 - NTTVV (+)
ESAM 390 121 - AGSLV (+)
Angulin-1/LSR 649 369 - ESLVV (+)
Angulin-2/ILDR1 546 358 - RSVVI (+)
Angulin-3/ILDR2 639 432 - MSLVV (+)
Claudins (1–26) 207–305 27–66 - XXXYF (+)
Occludin 522 257 - DRQKT (−)
Tricellulin 558 196 - VQGYS (−)
MarvelD3 401 20 - EMFEF (+)

The presence of multiple PDZ domains in many scaffolding proteins localized at the TJs (Figure 1), combined with the promiscuity of PDZ domains in ligand binding, allows for the incorporation of several integral membrane proteins in a single scaffolding protein-organized complex. Vice versa, individual membrane proteins can recruit and assemble distinct protein complexes at the TJ. These biochemical properties may, in part, explain the high complexity and dynamics of protein complexes at the TJs [21].

References

  1. Buckley, C.E.; St Johnston, D. Apical-basal polarity and the control of epithelial form and function. Nat. Rev. Mol. Cell Biol. 2022, 23, 559–577.
  2. Zihni, C.; Mills, C.; Matter, K.; Balda, M.S. Tight junctions: From simple barriers to multifunctional molecular gates. Nat. Rev. Mol. Cell Biol. 2016, 17, 564–580.
  3. Hegazy, M.; Perl, A.L.; Svoboda, S.A.; Green, K.J. Desmosomal Cadherins in Health and Disease. Annu. Rev. Pathol. 2022, 17, 47–72.
  4. Ladoux, B.; Mege, R.M. Mechanobiology of collective cell behaviours. Nat. Rev. Mol. Cell Biol. 2017, 18, 743–757.
  5. Fernandez-Gonzalez, R.; Peifer, M. Powering morphogenesis: Multiscale challenges at the interface of cell adhesion and the cytoskeleton. Mol. Biol. Cell 2022, 33, pe4.
  6. Knauf, F.; Brewer, J.R.; Flavell, R.A. Immunity, microbiota and kidney disease. Nat. Rev. Nephrol. 2019, 15, 263–274.
  7. Lambert, A.W.; Weinberg, R.A. Linking EMT programmes to normal and neoplastic epithelial stem cells. Nat. Rev. Cancer 2021, 21, 325–338.
  8. Martin-Belmonte, F.; Perez-Moreno, M. Epithelial cell polarity, stem cells and cancer. Nat. Rev. Cancer 2011, 12, 23–38.
  9. Miller, P.W.; Clarke, D.N.; Weis, W.I.; Lowe, C.J.; Nelson, W.J. The evolutionary origin of epithelial cell-cell adhesion mechanisms. Curr. Top. Membr. 2013, 72, 267–311.
  10. Murray, P.S.; Zaidel-Bar, R. Pre-metazoan origins and evolution of the cadherin adhesome. Biol. Open 2014, 3, 1183–1195.
  11. Abedin, M.; King, N. Diverse evolutionary paths to cell adhesion. Trends Cell Biol. 2010, 20, 734–742.
  12. Green, K.J.; Roth-Carter, Q.; Niessen, C.M.; Nichols, S.A. Tracing the Evolutionary Origin of Desmosomes. Curr. Biol. 2020, 30, R535–R543.
  13. Rice, C.; De, O.; Alhadyian, H.; Hall, S.; Ward, R.E. Expanding the Junction: New Insights into Non-Occluding Roles for Septate Junction Proteins during Development. J. Dev. Biol. 2021, 9, 11.
  14. Takeichi, M. Dynamic contacts: Rearranging adherens junctions to drive epithelial remodelling. Nat. Rev. Mol. Cell Biol. 2014, 15, 397–410.
  15. Vasileva, E.; Citi, S. The role of microtubules in the regulation of epithelial junctions. Tissue Barriers 2018, 6, 1539596.
  16. Muller, L.; Hatzfeld, M.; Keil, R. Desmosomes as Signaling Hubs in the Regulation of Cell Behavior. Front. Cell Dev. Biol. 2021, 9, 745670.
  17. Zihni, C.; Balda, M.S.; Matter, K. Signalling at tight junctions during epithelial differentiation and microbial pathogenesis. J. Cell Sci. 2014, 127, 3401–3413.
  18. Mendonsa, A.M.; Na, T.Y.; Gumbiner, B.M. E-cadherin in contact inhibition and cancer. Oncogene 2018, 37, 4769–4780.
  19. Broussard, J.A.; Jaiganesh, A.; Zarkoob, H.; Conway, D.E.; Dunn, A.R.; Espinosa, H.D.; Janmey, P.A.; Green, K.J. Scaling up single-cell mechanics to multicellular tissues—The role of the intermediate filament-desmosome network. J. Cell Sci. 2020, 133, jcs228031.
  20. Margolis, B. The Crumbs3 Polarity Protein. Cold Spring Harb. Perspect. Biol. 2018, 10, a027961.
  21. Tan, B.; Yatim, S.; Peng, S.; Gunaratne, J.; Hunziker, W.; Ludwig, A. The Mammalian Crumbs Complex Defines a Distinct Polarity Domain Apical of Epithelial Tight Junctions. Curr. Biol. 2020, 30, 2791–2804.e6.
  22. Fletcher, G.C.; Lucas, E.P.; Brain, R.; Tournier, A.; Thompson, B.J. Positive feedback and mutual antagonism combine to polarize Crumbs in the Drosophila follicle cell epithelium. Curr. Biol. 2012, 22, 1116–1122.
  23. Furuse, M.; Tsukita, S. Claudins in occluding junctions of humans and flies. Trends Cell Biol. 2006, 16, 181–188.
  24. Gunzel, D.; Yu, A.S. Claudins and the modulation of tight junction permeability. Physiol. Rev. 2013, 93, 525–569.
  25. Kubota, K.; Furuse, M.; Sasaki, H.; Sonoda, N.; Fujita, K.; Nagafuchi, A.; Tsukita, S. Ca(2+)-independent cell-adhesion activity of claudins, a family of integral membrane proteins localized at tight junctions. Curr. Biol. 1999, 9, 1035–1038.
  26. 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. 1998, 143, 391–401.
  27. Furuse, M.; Sasaki, H.; Tsukita, S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J. Cell Biol. 1999, 147, 891–903.
  28. Tsukita, S.; Tanaka, H.; Tamura, A. The Claudins: From Tight Junctions to Biological Systems. Trends Biochem. Sci. 2019, 44, 141–152.
  29. Raleigh, D.R.; Marchiando, A.M.; Zhang, Y.; Shen, L.; Sasaki, H.; Wang, Y.; Long, M.; Turner, J.R. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol. Biol. Cell 2010, 21, 1200–1213.
  30. Sanchez-Pulido, L.; Martin-Belmonte, F.; Valencia, A.; Alonso, M.A. MARVEL: A conserved domain involved in membrane apposition events. Trends Biochem. Sci. 2002, 27, 599–601.
  31. Ikenouchi, J.; Furuse, M.; Furuse, K.; Sasaki, H.; Tsukita, S.; Tsukita, S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J. Cell Biol. 2005, 171, 939–945.
  32. Cording, J.; Berg, J.; Kading, N.; Bellmann, C.; Tscheik, C.; Westphal, J.K.; Milatz, S.; Gunzel, D.; Wolburg, H.; Piontek, J.; et al. In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. J. Cell Sci. 2013, 126, 554–564.
  33. Van Itallie, C.M.; Anderson, J.M. Occludin confers adhesiveness when expressed in fibroblasts. J. Cell Sci. 1997, 110 Pt 9, 1113–1121.
  34. Saitou, M.; Furuse, M.; Sasaki, H.; Schulzke, J.D.; Fromm, M.; Takano, H.; Noda, T.; Tsukita, S. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 2000, 11, 4131–4142.
  35. Steed, E.; Rodrigues, N.T.; Balda, M.S.; Matter, K. Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 2009, 10, 95.
  36. Sugawara, T.; Furuse, K.; Otani, T.; Wakayama, T.; Furuse, M. Angulin-1 seals tricellular contacts independently of tricellulin and claudins. J. Cell Biol. 2021, 220, e202005062.
  37. Cho, Y.; Haraguchi, D.; Shigetomi, K.; Matsuzawa, K.; Uchida, S.; Ikenouchi, J. Tricellulin secures the epithelial barrier at tricellular junctions by interacting with actomyosin. J. Cell Biol. 2022, 221, e202009037.
  38. Ebnet, K. Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development. Physiol. Rev. 2017, 97, 1529–1554.
  39. Cohen, C.J.; Shieh, J.T.; Pickles, R.J.; Okegawa, T.; Hsieh, J.T.; Bergelson, J.M. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc. Natl. Acad. Sci. USA 2001, 98, 15191–15196.
  40. Hirabayashi, S.; Tajima, M.; Yao, I.; Nishimura, W.; Mori, H.; Hata, Y. JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Mol. Cell. Biol. 2003, 23, 4267–4282.
  41. Raschperger, E.; Engstrom, U.; Pettersson, R.F.; Fuxe, J. CLMP, a novel member of the CTX family and a new component of epithelial tight junctions. J. Biol. Chem. 2004, 279, 796–804.
  42. Nasdala, I.; Wolburg-Buchholz, K.; Wolburg, H.; Kuhn, A.; Ebnet, K.; Brachtendorf, G.; Samulowitz, U.; Kuster, B.; Engelhardt, B.; Vestweber, D.; et al. A transmembrane tight junction protein selectively expressed on endothelial cells and platelets. J. Biol. Chem. 2002, 277, 16294–16303.
  43. Hirata, K.; Ishida, T.; Penta, K.; Rezaee, M.; Yang, E.; Wohlgemuth, J.; Quertermous, T. Cloning of an immunoglobulin family adhesion molecule selectively expressed by endothelial cells. J. Biol. Chem. 2001, 276, 16223–16231.
  44. Furuse, M.; Izumi, Y.; Oda, Y.; Higashi, T.; Iwamoto, N. Molecular organization of tricellular tight junctions. Tissue Barriers 2014, 2, e28960.
  45. Higashi, T.; Tokuda, S.; Kitajiri, S.; Masuda, S.; Nakamura, H.; Oda, Y.; Furuse, M. Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2--tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. J. Cell Sci. 2013, 126, 966–977.
  46. Masuda, S.; Oda, Y.; Sasaki, H.; Ikenouchi, J.; Higashi, T.; Akashi, M.; Nishi, E.; Furuse, M. LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 2011, 124, 548–555.
  47. Tonikian, R.; Zhang, Y.; Sazinsky, S.L.; Currell, B.; Yeh, J.H.; Reva, B.; Held, H.A.; Appleton, B.A.; Evangelista, M.; Wu, Y.; et al. A specificity map for the PDZ domain family. PLoS Biol. 2008, 6, e239.
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Subjects: Cell Biology
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Nicolina Wibbe
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Klaus Ebnet
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