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DFG Research Unit FOR 721/2 Molecular Structure and Function of the Tight Junction |
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Project 3 |
Otmar Huber, Prof. PhD1,(2)
1Dept. of Biochemistry II, University Jena
Rudolf Tauber, Prof. MD2
2Central Institute of Laboratory Medicine and Pathobiochemistry,
Campus Benjamin Franklin, Charité, Freie Universität and Humboldt-Universität, Berlin
Posttranslational modulation of the structure and function of the tight junction
The maintenance of tight junction structure is of central importance for the barrier function and polarity of epithelial and endothelial cell layers. Impaired tight junction function has been reported in inflammatory bowel disease or kidney disease as well as damage to the blood-brain barrier. Posttranslational modifications play an important rolein the regulation of tight junction structure and function.
In this context, the functional role of ubiquitination for the stability of tricellulin is investigated. In addition, the amino acids modified by ubiquitination will be determined and then mutated. Thee influence of the mutation on the tight junction structure and function will be studied as well as the regulatory mechanisms that will affect the underlying ubiquitination.
In the second part of the project, the nuclear role of the tight junction protein ZO-2 adapter in the regulation of beta-catenin-mediated transcription will be elucidated and characterized. This includies studies of the mechanisms of the nuclear translocation of ZO-2.
Granted by project 3
Dr. Max J. Dörfel
PhD:
Coworker
Cording J, Berg J, Käding N, Bellmann C, Milatz S, Günzel D, Wolburg H, Piontek J, Huber O, Blasig IE (2013) Tight junctions: Claudins regulate the interactions between occludin, tricellulin, and marvelD3, which, inversely, modulate the claudin oligomerization. J. Cell Sci. 126: 554-564 (IF 6.1) [PubMed] [WebPage] [PDF] [Supplement] TP5+TP7+TP6+TP3
Bautista-Garcia P, Reyes JL, Martin D, Namorado MC, Chavez-Munguia B, Soria-Castro E, Huber O, Gonzalez-Mariscal L (2012) Zona occludens-2 protects against podocyte dysfunction induced by ADR in mice. Am. J. Physiol. Renal Physiol. 304(1): F77-F87 (IF 3.7) [PubMed] [WebPage] [PDF]
Dörfel MJ, Huber O (2012) A phosphorylation hotspot within the occludin C-terminal domain. Ann. N. Y. Acad. Sci. 1257: 38-44 (IF 3.2) [PubMed] [WebPage] [PDF] (Review)
Dörfel MJ, Huber O (2012) Modulation of tight junction structure and function by kinases and phosphatases targeting occludin. J. Biomed. Biotech. 2012: Article ID 807356, 14 pages, doi:10.1155/2012/807356 (Review) (IF 2.4) [PubMed] [WebPage] [PDF] [Full text ePUB]
Hackel D, Krug SM, Sauer RS, Mousa SA, Böcker A, Pflücke D, Wrede EJ, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL (2012) Transient opening of the perineurial barrier for analgesic drug delivery. Proc. Natl. Acad. Sci. USA 109(29): E2018-E2027 (IF 9.7) [PubMed] [WebPage] [PDF]
Blasig IE, Bellmann C, Cording J, del Vecchio G, Zwanziger D, Huber O, Haseloff RF (2011) Occludin protein family: oxidative stress and reducing conditions. Antioxid. Redox Signal. 15(5): 1195-1219 (IF 8.5) [PubMed] [WebPage] [PDF for printing] [PDF with links] (Review)
Westphal JK, Dörfel MJ, Krug SM, Cording JD, Piontek J, Blasig IE, Tauber R, Fromm M, Huber O (2010) Tricellulin forms homomeric and heteromeric tight junctional complexes. Cell. Mol. Life Sci. 67(12): 2057-2068 (IF 7.0) [PubMed] [WebPage] [PDF] [Supplement]
Doctoral thesis
Westphal JK (2010) [Structure, function, and regulation of the tight junction protein tricellulin] Doctoral thesis, Biology, Freie Universität Berlin. 12.02.10: Magna cum laude
Doerfel MJ (2010) [Effect of posttranslational modifications on the function of the tight junction protein occludin] Doctoral Thesis, Biochemistry, Freie Universität Berlin. 21.06.10: Magna cum laude
Award
Doerfel MJ, Westphal JK, Krug SM, Fromm M, Huber O (2010) CKII-dependent phosphorylation of occludin attenuates interaction with ZO-2 and regulates tight junction integrity. Poster award of the Signal Transduction Society, 14th joint meeting, Weimar
Publications 2007 - 2009 (FOR 721/1)
Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to
macromolecules in tricellular tight junctions without affecting ion permeability. Mol. Biol. Cell 20: 3713-3724 [PubMed]
[ePub manuscript] [Supplement text] [Supplement
video]
Tapia R, Huerta M, Islas S, Avila-Flores A, Lopez-Bayghen E, Weiske J, Huber O, González-Mariscal L (2009) ZO-2 inhibits cyclin D1 expression and cell proliferation and exhibits changes in localization along the cell cycle. Mol. Biol. Cell 20(3): 1102-1117 [PubMed] [WebPage] [PDF]
Dörfel MJ, Westphal JK, Huber O (2009) Differential phosphorylation of occludin and tricellulin by CK2 and CK1. Ann. N.Y. Acad. Sci. 1165: 69-73 [PubMed] [WebPage] [PDF]
Dörfel MJ, Huber O (2008) CSNK1A1 (casein kinase 1, alpha 1). Atlas Genet. Cyotgenet. Oncol. Haematol. URL: http://AtlasGeneticsOncology.org/Genes/CSNK1A1ID40168ch5q32.html
Previous work
Angres B, Kim L, Jung R, Gessner R, Tauber R (2001) LI-cadherin gene expression during mouse intestinal development. Dev. Dyn. 221: 182-193.
Bauer A*, Huber O* (*shared first authorship), Kemler R (1998) Pontin52, a new interaction partner of beta-catenin, binds to the TATA-box-binding protein. Proc. Natl. Acad. Sci. USA 95: 14787-14792.
Bauer A*, Chauvet S*, Huber O*, Usseglio F* (<*shared first authorship), Rothbacher U, Aragnol D, Kemler R, Pradel J (2000) Pontin52 and Reptin52 function as antagonistic regulators of b-catenin signalling activity. EMBO J. 19: 6121-6130.
Bierkamp C, Schwarz H, Huber O, Kemler R (1999) Desmosomal localization of b-catenin in plakoglobin null-mutant mice. Development 126: 371-381.
Bojarski C, Weiske J, Schöneberg T, Schröder W, Mankertz J, Schulzke JD, Florian P, Fromm M, Tauber R, Huber O (2004) The specific fate of tight junction proteins in apoptotic epithelial cells. J. Cell Sci. 117: 2097-2107.
Gessner R, Tauber R (2000) Intestinal cell adhesion molecules: liver-intestine cadherin. Ann. N.Y. Acad. Sci. 915: 136-143.
Grötzinger C, Kneifel J, Patschan D, Schnoy N, Anagnostopoulos I, Faiss S, Tauber R, Wiedenmann B, Gessner R (2001) LI-cadherin: a marker of gastric metaplasia and neoplasia. Gut 49: 73-81.
Hämmerlein A, Weiske J, Huber O (2005) A second CK1-mediated step negatively regulates Wnt signalling by disrupting the LEF-1/b-catenin complex. Cell. Mol. Life Sci. 62: 606-618.
Huber O, Kemler R, Langosch D (1999) Mutations affecting transmembrane segment interactions impair adhesiveness of E-cadherin. J. Cell Sci. 112: 4415-4423.
Kilian K, Dernedde J, Mueller EC, Bahr I, Tauber R (2004) The interaction of protein kinase C isozymes a, i. and t with the cytoplasmic domain of L-selectin is modulated by phophorylation of the receptor. J. Biol. Chem. 279: 334472-34480.
Kim JH, Kim B, Ling C, Choi HJ, Ohgi KA, Tran C, Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG, Baek SH (2005) Transcriptional regulation of a metastasis suppressor gene by Tip60 and b-catenin complexes. Nature 434: 921-926.
Kreft B, Berndorff D, Bottinger A, Finnemann S, Wedlich D, Hortsch M, Tauber R, Gessner R (1997) LI-cadherin-mediated cell-cell adhesion does not require cytoplasmic interactions. J. Cell Biol. 136: 1109-1121.
Mankertz J, Hillenbrand B, Tavalali S, Huber O, Fromm M, Schulzke JD (2004) Functional crosstalk between Wnt signaling and Cdx-related transcriptional activation in the regulation of the claudin-2 promoter activity. Biochem. Biophys. Res. Commun. 314: 1001-1007.
Meyer zum Büschenfelde D, Hoschützky H, Tauber R, Huber O (2004) Molecular mechanisms involved in the TFF3 peptide-mediated modulation of the E-cadherin/catenin cell adhesion complex. Peptides 25: 873-883.
Meyer zum Büschenfelde D, Tauber R, Huber O (2006) TFF3-peptide increases transepithelial resistance in epithelial cells by modulating claudin-1 and -2 expression. Peptides 27(12): 3383-3390 [PubMed] [WebPage] [PDF]
Müller SL, Portwich M, Schmidt A, Utepbergenov DI, Huber O, Blasig IE, Krause G (2005) The tight junction protein occludin and the adherens junction protein a-catenin share a common interaction mechanism with ZO-1. J. Biol. Chem. 280: 3747-3756.
Steinhusen U, Weiske J, Badock V, Tauber R, Bommert K, Huber O (2001) Cleavage and shedding of E-cadherin after induction of apoptosis. J. Biol. Chem. 276: 4972-4980.
Weiske J, Schöneberg T, Schröder W, Hatzfeld M, Tauber R, Huber O (2001) The fate of desmosomal proteins in apoptotic cells. J. Biol. Chem. 276: 41175-41181.