CoChat
Sign Up
Cited by 585Barrier Structure and Function StudiesCell Adhesion Molecules ResearchCellular Mechanics and Interactions

ZO-1 controls endothelial adherens junctions, cell–cell tension, angiogenesis, and barrier formation

Open access
Tornavaca, Olga, Chia, Minghao, Dufton, Neil, Almagro, Lourdes Osuna, Conway, Daniel E., Randi, Anna M., Schwartz, Martin A., Matter, Karl +1 more·2015·Journal of Cell Biology
DOI 10.1083/jcb.201404140PMC PMC4362456
Open this paper in CoChat — free accountOpen PDF

Abstract

Intercellular junctions are crucial for mechanotransduction, but whether tight junctions contribute to the regulation of cell–cell tension and adherens junctions is unknown. Here, we demonstrate that the tight junction protein ZO-1 regulates tension acting on VE-cadherin–based adherens junctions, cell migration, and barrier formation of primary endothelial cells, as well as angiogenesis in vitro and in vivo. ZO-1 depletion led to tight junction disruption, redistribution of active myosin II from junctions to stress fibers, reduced tension on VE-cadherin and loss of junctional mechanotransducers such as vinculin and PAK2, and induced vinculin dissociation from the α-catenin–VE-cadherin complex. Claudin-5 depletion only mimicked ZO-1 effects on barrier formation, whereas the effects on mechanotransducers were rescued by inhibition of ROCK and phenocopied by JAM-A, JACOP, or p114RhoGEF down-regulation. ZO-1 was required for junctional recruitment of JACOP, which, in turn, recruited p114RhoGEF. ZO-1 is thus a central regulator of VE-cadherin–dependent endothelial junctions that orchestrates the spatial actomyosin organization, tuning cell–cell tension, migration, angiogenesis, and barrier formation.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1083/jcb.201404140

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Tight junction proteins are connected to actin and vinculin-based cytoskeletal filaments via scaffolding proteins ZO-1, ZO-2, and ZO-3.

    “TJ proteins are connected to the actin and vinculin-based cytoskeletal filaments via scaffolding proteins of the membrane-associated guanylate kinase family ZO-1, -2, and -3 (595, 608) (FIGURE 2) .”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [595]

    The Introduction (page unavailable) says ZO-1 interacts with tight-junction proteins, binds F-actin, and has functional redundancy with ZO-2. The Discussion (page unavailable) links ZO-1 to the recruitment of vinculin, but the paper does not establish the claimed connection through all three ZO proteins or describe vinculin-based filaments. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. Bazzoni G. 2011 Pathobiology of junctional adhesion molecules. Antioxid. Redox Signal. 15: 1221– 1234 10.1089/ars.2010.3867 21254840 · DOI
  2. Bazzoni G., Martinez-Estrada O.M., Orsenigo F., Cordenonsi M., Citi S., and Dejana E. 2000 Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J. Biol. Chem. 275: 20520– 20526 10.1074/jbc.M905251199 10877843 · DOI
  3. Benais-Pont G., Punn A., Flores-Maldonado C., Eckert J., Raposo G., Fleming T.P., Cereijido M., Balda M.S., and Matter K. 2003 Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability. J. Cell Biol. 160: 729– 740 10.1083/jcb.200211047 12604587 PMC2173357 · DOI
  4. Birdsey G.M., Dryden N.H., Amsellem V., Gebhardt F., Sahnan K., Haskard D.O., Dejana E., Mason J.C., and Randi A.M. 2008 Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood. 111: 3498– 3506 10.1182/blood-2007-08-105346 18195090 PMC2275018 · DOI
  5. Cavallaro U., and Dejana E. 2011 Adhesion molecule signalling: not always a sticky business. Nat. Rev. Mol. Cell Biol. 12: 189– 197 10.1038/nrm3068 21346732 · DOI
  6. Citi S., Pulimeno P., and Paschoud S. 2012 Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex. Ann. NY Acad. Sci. 1257: 125– 132 10.1111/j.1749-6632.2012.06506.x 22671598 · DOI
  7. Conway D., and Schwartz M.A. 2012 Lessons from the endothelial junctional mechanosensory complex. F1000 Biol. Rep. 4: 1. 22238515 PMC3251317
  8. Conway D.E., Breckenridge M.T., Hinde E., Gratton E., Chen C.S., and Schwartz M.A. 2013 Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr. Biol. 23: 1024– 1030 10.1016/j.cub.2013.04.049 23684974 PMC3676707 · DOI
  9. Cooke V.G., Naik M.U., and Naik U.P. 2006 Fibroblast growth factor-2 failed to induce angiogenesis in junctional adhesion molecule-A-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26: 2005– 2011 10.1161/01.ATV.0000234923.79173.99 16809549 · DOI
  10. Ebnet K., Schulz C.U., Meyer Zu Brickwedde M.K., Pendl G.G., and Vestweber D. 2000 Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J. Biol. Chem. 275: 27979– 27988. 10856295
  11. Elbediwy A., Zihni C., Terry S.J., Clark P., Matter K., and Balda M.S. 2012 Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex. J. Cell Biol. 198: 677– 693 10.1083/jcb.201202094 22891260 PMC3514035 · DOI
  12. Fanning A.S., and Anderson J.M. 2009 Zonula occludens-1 and -2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann. NY Acad. Sci. 1165: 113– 120 10.1111/j.1749-6632.2009.04440.x 19538295 PMC3759978 · DOI
  13. Fanning A.S., Van Itallie C.M., and Anderson J.M. 2012 Zonula occludens-1 and -2 regulate apical cell structure and the zonula adherens cytoskeleton in polarized epithelia. Mol. Biol. Cell. 23: 577– 590 10.1091/mbc.E11-09-0791 22190737 PMC3279387 · DOI
  14. Grashoff C., Hoffman B.D., Brenner M.D., Zhou R., Parsons M., Yang M.T., McLean M.A., Sligar S.G., Chen C.S., Ha T., and Schwartz M.A. 2010 Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature. 466: 263– 266 10.1038/nature09198 20613844 PMC2901888 · DOI
  15. Gutwein P., Schramme A., Voss B., Abdel-Bakky M.S., Doberstein K., Ludwig A., Altevogt P., Hansmann M.L., Moch H., Kristiansen G., and Pfeilschifter J. 2009 Downregulation of junctional adhesion molecule-A is involved in the progression of clear cell renal cell carcinoma. Biochem. Biophys. Res. Commun. 380: 387– 391 10.1016/j.bbrc.2009.01.100 19250634 · DOI
  16. Haskard D.O., Boyle J.J., Evans P.C., Mason J.C., and Randi A.M. 2013 Cytoprotective signaling and gene expression in endothelial cells and macrophages-lessons for atherosclerosis. Microcirculation. 20: 203– 216 10.1111/micc.12020 23121167 · DOI
  17. Hoffman B.D., Grashoff C., and Schwartz M.A. 2011 Dynamic molecular processes mediate cellular mechanotransduction. Nature. 475: 316– 323 10.1038/nature10316 21776077 PMC6449687 · DOI · Paper page
  18. Huveneers S., Oldenburg J., Spanjaard E., van der Krogt G., Grigoriev I., Akhmanova A., Rehmann H., and de Rooij J. 2012 Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. J. Cell Biol. 196: 641– 652 10.1083/jcb.201108120 22391038 PMC3307691 · DOI · Paper page
  19. Itoh M., Tsukita S., Yamazaki Y., and Sugimoto H. 2012 Rho GTP exchange factor ARHGEF11 regulates the integrity of epithelial junctions by connecting ZO-1 and RhoA-myosin II signaling. Proc. Natl. Acad. Sci. USA. 109: 9905– 9910 10.1073/pnas.1115063109 22665792 PMC3382488 · DOI
  20. Katsuno T., Umeda K., Matsui T., Hata M., Tamura A., Itoh M., Takeuchi K., Fujimori T., Nabeshima Y., Noda T., 2008 Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol. Biol. Cell. 19: 2465– 2475 10.1091/mbc.E07-12-1215 18353970 PMC2397322 · DOI
  21. Kreis T.E. 1987 Microtubules containing detyrosinated tubulin are less dynamic. EMBO J. 6: 2597– 2606. 3315650 PMC553680
  22. Lamagna C., Hodivala-Dilke K.M., Imhof B.A., and Aurrand-Lions M. 2005 Antibody against junctional adhesion molecule-C inhibits angiogenesis and tumor growth. Cancer Res. 65: 5703– 5710 10.1158/0008-5472.CAN-04-4012 15994945 · DOI
  23. Lampugnani M.G. 2012 Endothelial cell-to-cell junctions: adhesion and signaling in physiology and pathology. Cold Spring Harb. Perspect. Med. 2: a006528 10.1101/cshperspect.a006528 23028127 PMC3475402 · DOI
  24. Martin T.A. 2014 The role of tight junctions in cancer metastasis. Semin. Cell Dev. Biol. 36: 224– 231 10.1016/j.semcdb.2014.09.008 25239399 · DOI
  25. Naik U.P., and Naik M.U. 2008 Putting the brakes on cancer cell migration: JAM-A restrains integrin activation. Cell Adhes. Migr. 2: 249– 251 10.4161/cam.2.4.6753 PMC2633686 19262151 · DOI
  26. Nehls V., and Drenckhahn D. 1995 A novel, microcarrier-based in vitro assay for rapid and reliable quantification of three-dimensional cell migration and angiogenesis. Microvasc. Res. 50: 311– 322 10.1006/mvre.1995.1061 8583947 · DOI
  27. Nie M., Balda M.S., and Matter K. 2012 Stress- and Rho-activated ZO-1-associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival. Proc. Natl. Acad. Sci. USA. 109: 10897– 10902 10.1073/pnas.1118822109 22711822 PMC3390842 · DOI
  28. Nomme J., Fanning A.S., Caffrey M., Lye M.F., Anderson J.M., and Lavie A. 2011 The Src homology 3 domain is required for junctional adhesion molecule binding to the third PDZ domain of the scaffolding protein ZO-1. J. Biol. Chem. 286: 43352– 43360 10.1074/jbc.M111.304089 22030391 PMC3234847 · DOI
  29. Ohnishi H., Nakahara T., Furuse K., Sasaki H., Tsukita S., and Furuse M. 2004 JACOP, a novel plaque protein localizing at the apical junctional complex with sequence similarity to cingulin. J. Biol. Chem. 279: 46014– 46022 10.1074/jbc.M402616200 15292197 · DOI
  30. Ooshio T., Kobayashi R., Ikeda W., Miyata M., Fukumoto Y., Matsuzawa N., Ogita H., and Takai Y. 2010 Involvement of the interaction of afadin with ZO-1 in the formation of tight junctions in Madin-Darby canine kidney cells. J. Biol. Chem. 285: 5003– 5012 10.1074/jbc.M109.043760 20008323 PMC2836104 · DOI
  31. Peddibhotla S.S., Brinkmann B.F., Kummer D., Tuncay H., Nakayama M., Adams R.H., Gerke V., and Ebnet K. 2013 Tetraspanin CD9 links junctional adhesion molecule-A to αvβ3 integrin to mediate basic fibroblast growth factor-specific angiogenic signaling. Mol. Biol. Cell. 24: 933– 944 10.1091/mbc.E12-06-0481 23389628 PMC3608503 · DOI
  32. Pulimeno P., Paschoud S., and Citi S. 2011 A role for ZO-1 and PLEKHA7 in recruiting paracingulin to tight and adherens junctions of epithelial cells. J. Biol. Chem. 286: 16743– 16750 10.1074/jbc.M111.230862 21454477 PMC3089516 · DOI
  33. Severson E.A., Lee W.Y., Capaldo C.T., Nusrat A., and Parkos C.A. 2009 Junctional adhesion molecule A interacts with Afadin and PDZ-GEF2 to activate Rap1A, regulate β1 integrin levels, and enhance cell migration. Mol. Biol. Cell. 20: 1916– 1925 10.1091/mbc.E08-10-1014 19176753 PMC2663925 · DOI
  34. Sourisseau T., Georgiadis A., Tsapara A., Ali R.R., Pestell R., Matter K., and Balda M.S. 2006 Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA. Mol. Cell. Biol. 26: 2387– 2398 10.1128/MCB.26.6.2387-2398.2006 16508013 PMC1430269 · DOI
  35. Steed E., Rodrigues N.T., Balda M.S., and Matter K. 2009 Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 10: 95 10.1186/1471-2121-10-95 20028514 PMC2805614 · DOI
  36. Stockton R.A., Schaefer E., and Schwartz M.A. 2004 p21-activated kinase regulates endothelial permeability through modulation of contractility. J. Biol. Chem. 279: 46621– 46630 10.1074/jbc.M408877200 15333633 · DOI
  37. Sun X.T., Ding Y.T., Yan X.G., Wu L.Y., Li Q., Cheng N., Qiu Y.D., and Zhang M.Y. 2004 Angiogenic synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in an in vitro quantitative microcarrier-based three-dimensional fibrin angiogenesis system. World J. Gastroenterol. 10: 2524– 2528. 15300897 PMC4572154
  38. Terry S.J., Zihni C., Elbediwy A., Vitiello E., Leefa Chong San I.V., Balda M.S., and Matter K. 2011 Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis. Nat. Cell Biol. 13: 159– 166 10.1038/ncb2156 21258369 PMC3032653 · DOI
  39. Terry S.J., Elbediwy A., Zihni C., Harris A.R., Bailly M., Charras G.T., Balda M.S., and Matter K. 2012 Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion. PLoS ONE. 7: e50188 10.1371/journal.pone.0050188 23185572 PMC3501466 · DOI
  40. Van Itallie C.M., Fanning A.S., Bridges A., and Anderson J.M. 2009 ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. Mol. Biol. Cell. 20: 3930– 3940 10.1091/mbc.E09-04-0320 19605556 PMC2735491 · DOI
  41. Weber C., Fraemohs L., and Dejana E. 2007 The role of junctional adhesion molecules in vascular inflammation. Nat. Rev. Immunol. 7: 467– 477 10.1038/nri2096 17525755 · DOI
  42. Xiao K., Allison D.F., Kottke M.D., Summers S., Sorescu G.P., Faundez V., and Kowalczyk A.P. 2003 Mechanisms of VE-cadherin processing and degradation in microvascular endothelial cells. J. Biol. Chem. 278: 19199– 19208 10.1074/jbc.M211746200 12626512 · DOI
  43. Yamazaki Y., Umeda K., Wada M., Nada S., Okada M., Tsukita S., and Tsukita S. 2008 ZO-1- and ZO-2-dependent integration of myosin-2 to epithelial zonula adherens. Mol. Biol. Cell. 19: 3801– 3811 10.1091/mbc.E08-04-0352 18596233 PMC2526713 · DOI
  44. Yonemura S. 2011 A mechanism of mechanotransduction at the cell-cell interface: emergence of α-catenin as the center of a force-balancing mechanism for morphogenesis in multicellular organisms. BioEssays. 33: 732– 736 10.1002/bies.201100064 21826690 · DOI · Paper page
  45. Yonemura S., Wada Y., Watanabe T., Nagafuchi A., and Shibata M. 2010 α-Catenin as a tension transducer that induces adherens junction development. Nat. Cell Biol. 12: 533– 542 10.1038/ncb2055 20453849 · DOI · Paper page
  46. Yoshizaki H., Ohba Y., Kurokawa K., Itoh R.E., Nakamura T., Mochizuki N., Nagashima K., and Matsuda M. 2003 Activity of Rho-family GTPases during cell division as visualized with FRET-based probes. J. Cell Biol. 162: 223– 232 10.1083/jcb.200212049 12860967 PMC2172791 · DOI
  47. Zemljic-Harpf A.E., Godoy J.C., Platoshyn O., Asfaw E.K., Busija A.R., Domenighetti A.A., and Ross R.S. 2014 Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin-43-containing gap junctions in cardiac myocytes. J. Cell Sci. 127: 1104– 1116 10.1242/jcs.143743 24413171 PMC3937777 · DOI

Cited by

Sorted by citations

Authors
Tornavaca, O., Chia, M., Dufton, N., Almagro, L. O., Conway, D. E., Randi, A. M., Schwartz, M. A., Matter, K., & Balda, M. S.
Affiliations
  • University College London (GB)
  • Hammersmith Hospital (GB)
  • Virginia Commonwealth University (US)
  • Yale University (US)
Corresponding author
Balda, Maria S.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2015-03-09
Volume
208
Issue
6
Pages
821-838
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201404140
PMC
PMC4362456
OpenAlex
W2139671059
Cited by
585
References
3
Citations by year
2026: 42 · 2025: 56 · 2024: 70 · 2023: 51 · 2022: 63 · 2021: 72 · 2020: 66 · 2019: 45 · 2018: 43 · 2017: 45 · 2016: 24 · 2015: 8
FWCI
21.38
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-sa)
Funders
  • Wellcome Trust (099173/Z/12/Z)
  • British Heart Foundation (RG/11/17/29256)
  • Biotechnology and Biological Sciences Research Council (BB/J015032/1, BB/H002294/1, BB/L007584/1)
  • National Heart, Lung, and Blood Institute (R01HL75092, R01HL075092)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
ZO-1, tight junctions, adherens junctions, mechanotransduction, VE-cadherin, endothelial cells, angiogenesis, myosin II, actomyosin, vinculin, PAK2, JAM-A, claudin-5, cell migration, stress fibers
MeSH terms
Cadherin 5, Actomyosin, Animals, Capillary Permeability, Cell Movement, Cells, Cultured, Cytoskeletal Proteins, Cytoskeleton, Humans, Mice, Inbred C57BL, Myosins, Receptors, Cell Surface, Antigens, CD, Cell Adhesion Molecules, Cadherins, Neovascularization, Physiologic, Tight Junctions, Protein Transport, Adherens Junctions, Mechanotransduction, Cellular, Endothelial Cells, Claudin-5, Zonula Occludens-1 Protein

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review