2,858
Views
43
CrossRef citations to date
0
Altmetric
Review

Phosphorylation of tight junction transmembrane proteins: Many sites, much to do

&
Article: e1382671 | Received 24 Aug 2017, Accepted 15 Sep 2017, Published online: 30 Oct 2017

References

  • Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17(9):564–80. https://doi.org/10.1038/nrm.2016.80 PMID:27353478
  • Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol. 2014;36:157–65. https://doi.org/10.1016/j.semcdb.2014.08.011 PMID:25171873
  • Chretien I., Robert J, Marcuz A, Garcia-Sanz JA, Courtet M, Du Pasquier L. CTX, a novel molecule specifically expressed on the surface of cortical thymocytes in Xenopus. Eur J Immunol. 1996;26(4):780–91. https://doi.org/10.1002/eji.1830260409 PMID:8625968
  • Rodgers LS, Fanning AS. Regulation of epithelial permeability by the actin cytoskeleton. Cytoskeleton. 2011;68(12):653–60. https://doi.org/10.1002/cm.20547 PMID:22083950
  • Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol. 1994;127(6 Pt 1):1617–26. https://doi.org/10.1083/jcb.127.6.1617 PMID:7798316
  • 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. J Cell Biol. 1999;147(6):1351–63. https://doi.org/10.1083/jcb.147.6.1351 PMID:10601346
  • Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem. 1998;273(45):29745–53. https://doi.org/10.1074/jbc.273.45.29745 PMID:9792688
  • Ebnet K, Schulz CU, Meyer Zu Brickwedde MK, Pendl GG, Vestweber D. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem. 2000;275(36):27979–88. PMID:10856295
  • Bazzoni G, Martinez-Estrada OM, Orsenigo F, Cordenonsi M, Citi S, Dejana E. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem. 2000;275(27):20520–6. https://doi.org/10.1074/jbc.M905251199 PMID:10877843
  • Riazuddin S., Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, Khan SN, Chattaraj P, Friedman PL, Anderson JM, et al. Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet. 2006;79(6):1040–51. https://doi.org/10.1086/510022 PMID:17186462
  • Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, et al. Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010;3(104):ra3. https://doi.org/10.1126/scisignal.2000475 PMID:20068231
  • Nishi H, Hashimoto K, Panchenko AR. Phosphorylation in protein-protein binding: effect on stability and function. Structure. 2011;19(12):1807–15. https://doi.org/10.1016/j.str.2011.09.021 PMID:22153503
  • Narayanan A, Jacobson MP. Computational studies of protein regulation by post-translational phosphorylation. Curr Opin Struct Biol. 2009;19(2):156–63. https://doi.org/10.1016/j.sbi.2009.02.007 PMID:19339172
  • Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 2015;43(Database issue):D512–20. https://doi.org/10.1093/nar/gku1267 PMID:25514926
  • Willott E, Balda MS, Fanning AS, Jameson B, Van Itallie C, Anderson JM. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc Natl Acad Sci U S A. 1993;90(16):7834–8. https://doi.org/10.1073/pnas.90.16.7834 PMID:8395056
  • Beatch M, Jesaitis LA, Gallin WJ, Goodenough DA, Stevenson BR. The tight junction protein ZO-2 contains three PDZ (PSD-95/Discs-Large/ZO-1) domains and an alternatively spliced region. J Biol Chem. 1996;271(42):25723–6. https://doi.org/10.1074/jbc.271.42.25723 PMID:8824195
  • Haskins J, Gu L, Wittchen ES, Hibbard J, Stevenson BR. ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J Cell Biol. 1998;141(1):199–208. https://doi.org/10.1083/jcb.141.1.199 PMID:9531559
  • 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. J Biol Chem. 2002;277(1):455–61. https://doi.org/10.1074/jbc.M109005200 PMID:11689568
  • Yamamoto T, Harada N, Kano K, Taya S, Canaani E, Matsuura Y, Mizoguchi A, Ide C, Kaibuchi K. The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells. J Cell Biol. 1997;139(3):785–95. https://doi.org/10.1083/jcb.139.3.785 PMID:9348294
  • Dobrosotskaya I, Guy RK, James GL. MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of protein-protein interaction domains. J Biol Chem. 1997;272(50):31589–97. https://doi.org/10.1074/jbc.272.50.31589 PMID:9395497
  • Wu X, Hepner K, Castelino-Prabhu S, Do D, Kaye MB, Yuan XJ, Wood J, Ross C, Sawyers CL, Whang YE. Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci U S A. 2000;97(8):4233–8. https://doi.org/10.1073/pnas.97.8.4233 PMID:10760291
  • Wu Y, Dowbenko D, Spencer S, Laura R, Lee J, Gu Q, Lasky LA. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem. 2000;275(28):21477–85. https://doi.org/10.1074/jbc.M909741199 PMID:10748157
  • Gao L, Macara IG, Joberty G. Multiple splice variants of Par3 and of a novel related gene, Par3L, produce proteins with different binding properties. Gene. 2002;294(1-2):99–107. https://doi.org/10.1016/S0378-1119(02)00681-9 PMID:12234671
  • Roh MH, Makarova O, Liu CJ, Shin K, Lee S, Laurinec S, Goyal M, Wiggins R, Margolis B. The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost. J Cell Biol. 2002;157(1):161–72. https://doi.org/10.1083/jcb.200109010 PMID:11927608
  • Lemmers C, Médina E, Delgrossi MH, Michel D, Arsanto JP, Le Bivic A. hINADl/PATJ, a homolog of discs lost, interacts with crumbs and localizes to tight junctions in human epithelial cells. J Biol Chem. 2002;277(28):25408–15. https://doi.org/10.1074/jbc.M202196200 PMID:11964389
  • Cho KO, Hunt CA, Kennedy MB. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. Neuron. 1992;9(5):929–42. https://doi.org/10.1016/0896-6273(92)90245-9 PMID:1419001
  • Songyang Z, Fanning AS, Fu C, Xu J, Marfatia SM, Chishti AH, Crompton A, Chan AC, Anderson JM, Cantley LC. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science. 1997;275(5296):73–7. https://doi.org/10.1126/science.275.5296.73 PMID:8974395
  • Zhang Y, Yeh S, Appleton BA, Held HA, Kausalya PJ, Phua DC, Wong WL, Lasky LA, Wiesmann C, Hunziker W, et al. Convergent and divergent ligand specificity among PDZ domains of the LAP and zonula occludens (ZO) families. J Biol Chem. 2006;281(31):22299–311. https://doi.org/10.1074/jbc.M602902200 PMID:16737968
  • Luck K, Charbonnier S, Trave G. The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains. FEBS letters. 2012;586(17):2648–61. https://doi.org/10.1016/j.febslet.2012.03.056 PMID:22709956
  • Poliak S, Matlis S, Ullmer C, Scherer SS, Peles E. Distinct claudins and associated PDZ proteins form different autotypic tight junctions in myelinating Schwann cells. J Cell Biol. 2002;159(2):361–72. https://doi.org/10.1083/jcb.200207050 PMID:12403818
  • Van Itallie CM, Tietgens AJ, LoGrande K, Aponte A, Gucek M, Anderson JM. Phosphorylation of claudin-2 on serine 208 promotes membrane retention and reduces trafficking to lysosomes. J Cell Sci. 2012;125(Pt 20):4902–12. https://doi.org/10.1242/jcs.111237 PMID:22825868
  • Liu X, Shepherd TR, Murray AM, Xu Z, Fuentes EJ. The structure of the Tiam1 PDZ domain/ phospho-syndecan1 complex reveals a ligand conformation that modulates protein dynamics. Structure 2013;21(3):342–54. https://doi.org/10.1016/j.str.2013.01.004 PMID:23395182
  • Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005;280(51):42375–82. https://doi.org/10.1074/jbc.M503786200 PMID:16236711
  • Nomme J, Antanasijevic A, Caffrey M, Van Itallie CM, Anderson JM, Fanning AS, Lavie A. Structural Basis of a Key Factor Regulating the Affinity between the Zonula Occludens First PDZ Domain and Claudins. J Biol Chem. 2015;290(27):16595–606. https://doi.org/10.1074/jbc.M115.646695 PMID:26023235
  • Twiss F, Oldenkamp M, Hiemstra A, Zhou H, Matheron L, Mohammed S, de Rooij J. HGF signaling regulates Claudin-3 dynamics through its C-terminal tyrosine residues. Tissue barriers. 2013;1(4):e27425. https://doi.org/10.4161/tisb.27425 PMID:24665413
  • D'Souza T, Indig FE, Morin PJ. Phosphorylation of claudin-4 by PKCepsilon regulates tight junction barrier function in ovarian cancer cells. Exp Cell Res. 2007;313(15):3364–75. https://doi.org/10.1016/j.yexcr.2007.06.026 PMID:17678893
  • D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem. 2005;280(28):26233–40. https://doi.org/10.1074/jbc.M502003200 PMID:15905176
  • Aono S, Hirai Y. Phosphorylation of claudin-4 is required for tight junction formation in a human keratinocyte cell line. Exp Cell Res. 2008;314(18):3326–39. https://doi.org/10.1016/j.yexcr.2008.08.012 PMID:18786529
  • Fujii N, Matsuo Y, Matsunaga T, Endo S, Sakai H, Yamaguchi M, Yamazaki Y, Sugatani J, Ikari A. Hypotonic Stress-induced Down-regulation of Claudin-1 and -2 Mediated by Dephosphorylation and Clathrin-dependent Endocytosis in Renal Tubular Epithelial Cells. J Biol Chem. 2016;291(47):24787–24799. https://doi.org/10.1074/jbc.M116.728196 PMID:27733684
  • Shiomi R, Shigetomi K, Inai T, Sakai M, Ikenouchi J. CaMKII regulates the strength of the epithelial barrier. Sci Rep. 2015;5:13262. https://doi.org/10.1038/srep13262 PMID:26281891
  • Ikari A, Matsumoto S, Harada H, Takagi K, Hayashi H, Suzuki Y, Degawa M, Miwa M. Phosphorylation of paracellin-1 at Ser217 by protein kinase A is essential for localization in tight junctions. J Cell Sci. 2006;119(Pt 9):1781–9. https://doi.org/10.1242/jcs.02901 PMID:16608877
  • Ikari A, Tonegawa C, Sanada A, Kimura T, Sakai H, Hayashi H, Hasegawa H, Yamaguchi M, Yamazaki Y, Endo S, et al. Tight junctional localization of claudin-16 is regulated by syntaxin 8 in renal tubular epithelial cells. J Biol Chem. 2014;289(19):13112–23. https://doi.org/10.1074/jbc.M113.541193 PMID:24659781
  • Marunaka K, Furukawa C, Fujii N, Kimura T, Furuta T, Matsunaga T, Endo S, Hasegawa H, Anzai N, Yamazaki Y, et al. The RING finger- and PDZ domain-containing protein PDZRN3 controls localization of the Mg2+ regulator claudin-16 in renal tube epithelial cells. J Biol Chem. 2017;292(31):13034–13044. https://doi.org/10.1074/jbc.M117.779405 PMID:28623232
  • Sewduth RN, Kovacic H, Jaspard-Vinassa B, Jecko V, Wavasseur T, Fritsch N, Pernot M, Jeaningros S, Roux E, Dufourcq P, et al. PDZRN3 destabilizes endothelial cell-cell junctions through a PKCzeta-containing polarity complex to increase vascular permeability. Sci Signal. 2017;10(464). https://doi.org/10.1126/scisignal.aag3209 PMID:28143902
  • Cong X, Zhang Y, Li J, Mei M, Ding C, Xiang RL, Zhang LW, Wang Y, Wu LL, Yu GY. Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells. J Cell Sci. 2015;128(12):2271–86. https://doi.org/10.1242/jcs.165878 PMID:25948584
  • Luissint AC, Nusrat A, Parkos CA. JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol. 2014;36(2):211–26. https://doi.org/10.1007/s00281-014-0421-0 PMID:24667924
  • Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci. 2004;117(Pt 1):19–29. https://doi.org/10.1242/jcs.00930 PMID:14657270
  • Nomme J, Fanning AS, Caffrey M, Lye MF, Anderson JM, Lavie A. 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. 2011;286(50):43352–60. https://doi.org/10.1074/jbc.M111.304089 PMID:22030391
  • Braiterman LT, Heffernan S, Nyasae L, Johns D, See AP, Yutzy R, McNickle A, Herman M, Sharma A, Naik UP, et al. JAM-A is both essential and inhibitory to development of hepatic polarity in WIF-B cells. Am J Physiol Gastrointest Liver Physiol. 2008;294(2):G576–88. https://doi.org/10.1152/ajpgi.00159.2007 PMID:18096610
  • Iden S, Misselwitz S, Peddibhotla SS, Tuncay H, Rehder D, Gerke V, Robenek H, Suzuki A, Ebnet K. aPKC phosphorylates JAM-A at Ser285 to promote cell contact maturation and tight junction formation. J Cell Biol. 2012;196(5):623–39. https://doi.org/10.1083/jcb.201104143 PMID:22371556
  • Nunbhakdi-Craig V, Machleidt T, Ogris E, Bellotto D, White CL 3rd, Sontag E. Protein phosphatase 2A associates with and regulates atypical PKC and the epithelial tight junction complex. J Cell Biol. 2002;158(5):967–78. https://doi.org/10.1083/jcb.200206114 PMID:12196510
  • Scott DW, Tolbert CE, Burridge K. Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF. Mol Biol Cell. 2016;27(9):1420–30. https://doi.org/10.1091/mbc.E15-12-0833 PMID:26985018
  • Hopkins AM, Li D, Mrsny RJ, Walsh SV, Nusrat A. Modulation of tight junction function by G protein-coupled events. Adv Drug Deliv Rev. 2000;41(3):329–40. https://doi.org/10.1016/S0169-409X(00)00050-8 PMID:10854690
  • Naik MU, Mousa SA, Parkos CA, Naik UP. Signaling through JAM-1 and alphavbeta3 is required for the angiogenic action of bFGF: dissociation of the JAM-1 and alphavbeta3 complex. Blood. 2003;102(6):2108–14. https://doi.org/10.1182/blood-2003-04-1114 PMID:12750158
  • Naik MU, Caplan JL, Naik UP, Junctional adhesion molecule-A suppresses platelet integrin alphaIIbbeta3 signaling by recruiting Csk to the integrin-c-Src complex. Blood. 2014;123(9):1393–402. https://doi.org/10.1182/blood-2013-04-496232 PMID:24300854
  • Zen K, Babbin BA, Liu Y, Whelan JB, Nusrat A, Parkos CA. JAM-C is a component of desmosomes and a ligand for CD11b/CD18-mediated neutrophil transepithelial migration. Mol Biol Cell. 2004;15(8):3926–37. https://doi.org/10.1091/mbc.E04-04-0317 PMID:15194813
  • Chavakis T, Keiper T, Matz-Westphal R, Hersemeyer K, Sachs UJ, Nawroth PP, Preissner KT, Santoso S. The junctional adhesion molecule-C promotes neutrophil transendothelial migration in vitro and in vivo. J Biol Chem. 2004;279(53):55602–8. https://doi.org/10.1074/jbc.M404676200 PMID:15485832
  • Santoso S, Orlova VV, Song K, Sachs UJ, Andrei-Selmer CL, Chavakis T. The homophilic binding of junctional adhesion molecule-C mediates tumor cell-endothelial cell interactions. J Biol Chem. 2005;280(43):36326–33. https://doi.org/10.1074/jbc.M505059200 PMID:16118203
  • Mandicourt G, Iden S, Ebnet K, Aurrand-Lions M, Imhof BA. JAM-C regulates tight junctions and integrin-mediated cell adhesion and migration. J Biol Chem. 2007;282(3):1830–7. https://doi.org/10.1074/jbc.M605666200 PMID:17099249
  • Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM. The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction. Proc Natl Acad Sci U S A. 2001;98(26):15191–6. https://doi.org/10.1073/pnas.261452898 PMID:11734628
  • Coyne CB, Voelker T, Pichla SL, Bergelson JM. The coxsackievirus and adenovirus receptor interacts with the multi-PDZ domain protein-1 (MUPP-1) within the tight junction. J Biol Chem. 2004;279(46):48079–84. https://doi.org/10.1074/jbc.M409061200 PMID:15364909
  • Morton PE, Hicks A, Nastos T, Santis G, Parsons M. CAR regulates epithelial cell junction stability through control of E-cadherin trafficking. Sci Rep. 2013;3:2889. https://doi.org/10.1038/srep02889 PMID:24096322
  • Alves MM, Halim D, Maroofian R, de Graaf BM, Rooman R, van der Werf CS, Van de Vijver E, Mehrjardi MY, Aflatoonian M, Chioza BA, et al. Genetic screening of Congenital Short Bowel Syndrome patients confirms CLMP as the major gene involved in the recessive form of this disorder. Eur J Hum Genet. 2016;24(11):1627–1629. https://doi.org/10.1038/ejhg.2016.58 PMID:27352967
  • Van Der Werf CS, Wabbersen TD, Hsiao NH, Paredes J, Etchevers HC, Kroisel PM, Tibboel D, Babarit C, Schreiber RA, Hoffenberg EJ, et al. CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome. Gastroenterology. 2012;142(3):453–462 e3. https://doi.org/10.1053/j.gastro.2011.11.038 PMID:22155368
  • Raschperger E, Engstrom U, Pettersson RF, Fuxe J. CLMP, a novel member of the CTX family and a new component of epithelial tight junctions. J Biol Chem. 2004;279(1):796–804. https://doi.org/10.1074/jbc.M308249200 PMID:14573622
  • van der Werf CS, Hsiao NH, Conroy S, Paredes J, Ribeiro AS, Sribudiani Y, Seruca R, Hofstra RM, Westers H, van Ijzendoorn SC. CLMP is essential for intestinal development, but does not play a key role in cellular processes involved in intestinal epithelial development. PloS one. 2013;8(2):e54649. https://doi.org/10.1371/journal.pone.0054649 PMID:23460781
  • Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6 Pt 2):1777–88. https://doi.org/10.1083/jcb.123.6.1777 PMID:8276896
  • Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S. Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol. 1997;137(6):1393–401. https://doi.org/10.1083/jcb.137.6.1393 PMID:9182670
  • Wong V. Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am J Physiol. 1997;273(6 Pt 1):C1859–67. PMID:9435490
  • Cordenonsi M, Mazzon E, De Rigo L, Baraldo S, Meggio F, Citi S. Occludin dephosphorylation in early development of Xenopus laevis. J Cell Sci. 1997;110(Pt 24):3131–9. PMID:9365283
  • Tsukamoto T, Nigam SK. Role of tyrosine phosphorylation in the reassembly of occludin and other tight junction proteins. Am J Physiol. 1999;276(5 Pt 2):F737–50. PMID:10330056
  • Farshori P, Kachar B. Redistribution and phosphorylation of occludin during opening and resealing of tight junctions in cultured epithelial cells. J Membr Biol. 1999;170(2):147–56. https://doi.org/10.1007/s002329900544 PMID:10430658
  • Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem. 1999;274(33):23463–7. https://doi.org/10.1074/jbc.274.33.23463 PMID:10438525
  • Feldman GJ, Mullin JM, Ryan MP. Occludin: structure, function and regulation. Adv Drug Deliv Rev. 2005;57(6):883–917. https://doi.org/10.1016/j.addr.2005.01.009 PMID:15820558
  • Cordenonsi M, Turco F, D'atri F, Hammar E, Martinucci G, Meggio F, Citi S. Xenopus laevis occludin. Identification of in vitro phosphorylation sites by protein kinase CK2 and association with cingulin. Eur J Biochem. 1999;264(2):374–84. https://doi.org/10.1046/j.1432-1327.1999.00616.x PMID:10491082
  • Chen YH, Lu Q, Goodenough DA, Jeansonne B. Nonreceptor tyrosine kinase c-Yes interacts with occludin during tight junction formation in canine kidney epithelial cells. Mol Biol Cell. 2002;13(4):1227–37. https://doi.org/10.1091/mbc.01-08-0423 PMID:11950934
  • McKenzie JA, Riento K, Ridley AJ. Casein kinase I epsilon associates with and phosphorylates the tight junction protein occludin. FEBS letters. 2006;580(9):2388–94. https://doi.org/10.1016/j.febslet.2006.03.048 PMID:16616143
  • Andreeva AY, Krause E, Müller EC, Blasig IE, Utepbergenov DI. Protein kinase C regulates the phosphorylation and cellular localization of occludin. J Biol Chem. 2001;276(42):38480–6. https://doi.org/10.1074/jbc.M104923200 PMID:11502742
  • Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol. 2008;172(2):521–33. https://doi.org/10.2353/ajpath.2008.070076 PMID:18187566
  • Du D, Xu F, Yu L, Zhang C, Lu X, Yuan H, Huang Q, Zhang F, Bao H, Jia L, et al. The tight junction protein, occludin, regulates the directional migration of epithelial cells. Dev Cell. 2010;18(1):52–63. https://doi.org/10.1016/j.devcel.2009.12.008 PMID:20152177
  • Bolinger MT, Ramshekar A, Waldschmidt HV, Larsen SD, Bewley MC, Flanagan JM, Antonetti DA. Occludin S471 Phosphorylation Contributes to Epithelial Monolayer Maturation. Mol Cell Biol. 2016;36(15):2051–66. https://doi.org/10.1128/MCB.00053-16 PMID:27185880
  • Sallee JL, Burridge K. Density-enhanced phosphatase 1 regulates phosphorylation of tight junction proteins and enhances barrier function of epithelial cells. J Biol Chem. 2009;284(22):14997–5006. https://doi.org/10.1074/jbc.M901901200 PMID:19332538
  • Siddiqui MR, Mayanil CS, Kim KS, Tomita T. Angiopoietin-1 Regulates Brain Endothelial Permeability through PTPN-2 Mediated Tyrosine Dephosphorylation of Occludin. PloS one. 2015;10(6):e0130857. https://doi.org/10.1371/journal.pone.0130857 PMID:26090670
  • Sundstrom JM, Tash BR, Murakami T, Flanagan JM, Bewley MC, Stanley BA, Gonsar KB, Antonetti DA. Identification and analysis of occludin phosphosites: a combined mass spectrometry and bioinformatics approach. J Proteome Res. 2009;8(2):808–17. https://doi.org/10.1021/pr7007913 PMID:19125584
  • Murakami T, Felinski EA, Antonetti DA. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem. 2009;284(31):21036–46. https://doi.org/10.1074/jbc.M109.016766 PMID:19478092
  • Murakami T, Frey T, Lin C, Antonetti DA. Protein kinase cbeta phosphorylates occludin regulating tight junction trafficking in vascular endothelial growth factor-induced permeability in vivo. Diabetes. 2012;61(6):1573–83. https://doi.org/10.2337/db11-1367 PMID:22438576
  • Runkle EA, Sundstrom JM, Runkle KB, Liu X, Antonetti DA. Occludin localizes to centrosomes and modifies mitotic entry. J Biol Chem. 2011;286(35):30847–58. https://doi.org/10.1074/jbc.M111.262857 PMID:21757728
  • Liu X, Dreffs A, Díaz-Coránguez M, Runkle EA, Gardner TW, Chiodo VA, Hauswirth WW, Antonetti DA. Occludin S490 Phosphorylation Regulates Vascular Endothelial Growth Factor-Induced Retinal Neovascularization. Am J Pathol. 2016;186(9):2486–99. https://doi.org/10.1016/j.ajpath.2016.04.018 PMID:27423695
  • Tash BR, Bewley MC, Russo M, Keil JM, Griffin KA, Sundstrom JM, Antonetti DA, Tian F, Flanagan JM, The occludin and ZO-1 complex, defined by small angle X-ray scattering and NMR, has implications for modulating tight junction permeability. Proc Natl Acad Sci U S A. 2012;109(27):10855–60. https://doi.org/10.1073/pnas.1121390109 PMID:22711802
  • Dorfel MJ, Huber O. A phosphorylation hotspot within the occludin C-terminal domain. Ann N Y Acad Sci. 2012;1257:38–44. https://doi.org/10.1111/j.1749-6632.2012.06536.x PMID:22671587
  • Raleigh DR, Boe DM, Yu D, Weber CR, Marchiando AM, Bradford EM, Wang Y, Wu L, Schneeberger EE, Shen L, et al. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J Cell Biol. 2011;193(3):565–82. https://doi.org/10.1083/jcb.201010065 PMID:21536752
  • Dorfel MJ, Westphal JK, Bellmann C, Krug SM, Cording J, Mittag S, Tauber R, Fromm M, Blasig IE, Huber O. CK2-dependent phosphorylation of occludin regulates the interaction with ZO-proteins and tight junction integrity. Cell Commun Signal. 2013;11(1):40. https://doi.org/10.1186/1478-811X-11-40 PMID:23758859
  • Suzuki T, Elias BC, Seth A, Shen L, Turner JR, Giorgianni F, Desiderio D, Guntaka R, Rao R. PKC eta regulates occludin phosphorylation and epithelial tight junction integrity. Proc Natl Acad Sci U S A. 2009;106(1):61–6. https://doi.org/10.1073/pnas.0802741106 PMID:19114660
  • Kale G, Naren AP, Sheth P, Rao RK. Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochem Biophys Res Commun. 2003;302(2):324–9. https://doi.org/10.1016/S0006-291X(03)00167-0 PMID:12604349
  • Elias BC, Suzuki T, Seth A, Giorgianni F, Kale G, Shen L, Turner JR, Naren A, Desiderio DM, Rao R. Phosphorylation of Tyr-398 and Tyr-402 in occludin prevents its interaction with ZO-1 and destabilizes its assembly at the tight junctions. J Biol Chem. 2009;284(3):1559–69. https://doi.org/10.1074/jbc.M804783200 PMID:19017651
  • Raleigh DR, Marchiando AM, Zhang Y, Shen L, Sasaki H, Wang Y, Long M, Turner JR. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell. 2010;21(7):1200–13. https://doi.org/10.1091/mbc.E09-08-0734 PMID:20164257
  • Steed E, Rodrigues NT, Balda MS, Matter K. Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 2009;10:95. https://doi.org/10.1186/1471-2121-10-95 PMID:20028514
  • Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell. 2009;20(16):3713–24. https://doi.org/10.1091/mbc.E09-01-0080 PMID:19535456
  • Steed E, Elbediwy A, Vacca B, Dupasquier S, Hemkemeyer SA, Suddason T, Costa AC, Beaudry JB, Zihni C, Gallagher E, et al. MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival. J Cell Biol. 2014;204(5):821–38. https://doi.org/10.1083/jcb.201304115 PMID:24567356
  • Nakatsu D, Kano F, Taguchi Y, Sugawara T, Nishizono T, Nishikawa K, Oda Y, Furuse M, Murata M. JNK1/2-dependent phosphorylation of angulin-1/LSR is required for the exclusive localization of angulin-1/LSR and tricellulin at tricellular contacts in EpH4 epithelial sheet. Genes to Cells: Devoted to Molecular & Cellular Mechanisms. 2014;19(7):565–81. https://doi.org/10.1111/gtc.12158
  • Collins MO, Yu L, Campuzano I, Grant SG, Choudhary JS. Phosphoproteomic analysis of the mouse brain cytosol reveals a predominance of protein phosphorylation in regions of intrinsic sequence disorder. Mol Cell Proteomics. 2008;7(7):1331–48. https://doi.org/10.1074/mcp.M700564-MCP200 PMID:18388127
  • Kjaergaard M, Kragelund BB. Functions of intrinsic disorder in transmembrane proteins. Cell Mol Life Sci. 2017;74(17):3205–3224. https://doi.org/10.1007/s00018-017-2562-5 PMID:28601983
  • Linding R, Jensen LJ, Diella F, Bork P, Gibson TJ, Russell RB. Protein disorder prediction: implications for structural proteomics. Structure. 2003;11(11):1453–9. https://doi.org/10.1016/j.str.2003.10.002 PMID:14604535
  • Ishida T, Kinoshita K, PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res. 2007;35(Web Server issue):W460–4. https://doi.org/10.1093/nar/gkm363 PMID:17567614
  • Chattopadhyay R, Dyukova E, Singh NK, Ohba M, Mobley JA, Rao GN. Vascular endothelial tight junctions and barrier function are disrupted by 15(S)-hydroxyeicosatetraenoic acid partly via protein kinase C epsilon-mediated zona occludens-1 phosphorylation at threonine 770/772. J Biol Chem. 2014;289(6):3148–63. https://doi.org/10.1074/jbc.M113.528190 PMID:24338688
  • Audagnotto M, Dal Peraro M, Protein post-translational modifications: In silico prediction tools and molecular modeling. Comput Struct Biotechnol J. 2017;15:307–319. https://doi.org/10.1016/j.csbj.2017.03.004 PMID:28458782
  • Li Y, Fanning AS, Anderson JM, Lavie A. Structure of the conserved cytoplasmic C-terminal domain of occludin: identification of the ZO-1 binding surface. J Mol Biol. 2005;352(1):151–64. https://doi.org/10.1016/j.jmb.2005.07.017 PMID:16081103

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.