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Semin Liver Dis 2002; 22(3): 263-276
DOI: 10.1055/s-2002-34504
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Emerging Roles of the Actin Cytoskeleton in Cholangiocyte Function and Disease

R. Brian Doctor1 , Laura Fouassier2
  • 1Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Denver, Colorado
  • 2U402, Faculté de Médecine Saint-Antoine, INSERM, Paris, France
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Publication History

Publication Date:
02 October 2002 (online)

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ABSTRACT

Actin is a ubiquitous, abundant protein whose monomers polymerize into polarized actin filaments. Within epithelial cells, filamentous actin is concentrated at the plasma membrane where a wide variety of actin-associated proteins harness the potential and structure of actin filaments to moderate functions at the plasma membrane. These functions include structural support of the plasma membrane, establishing and maintaining cell polarity, regulation of membrane protein distribution and activity and enhancing membrane vesicle trafficking. Consequently, the actin cytoskeleton contributes significantly to the cellular pathogenesis in a number of disease states. In recent years, the actin cytoskeleton has been found to contribute significantly to cholangiocyte function and disease. This includes directing cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion, modulating vesicular trafficking at the apical membrane and initiating structural and functional alterations in ischemic bile ducts. Although much remains to be discovered, this article will highlight observations that indicate that the actin cytoskeleton plays a central role in the physiology and diseases of the intrahepatic bile duct.

KEYWORDS

Intrahepatic bile duct - CFTR - ischemia - ATP depletion - vesicle trafficking - Cl- secretion

REFERENCES

  • 1 Alberts B, Bray D, Lewis J. The cytoskeleton. In: Alberts B, Bray D, Lewis J, et al., eds. Molecular Biology of the Cell New York: Garland Publishing 1994: 787-863
    Google Scholar
  • 2 De La Cruz E, Pollard T. Actin' up.  Science . 2001;  293 616-618
    PubMedGoogle Scholar
  • 3 Chen H, Bernstein B, Bamburg J. Regulating actin-filament dynamics in vivo.  Trends Biochem Sci . 2000;  25 19-23
    CrossrefPubMedGoogle Scholar
  • 4 Higgs H, Pollard T. Regulation of actin filament network formation through Arp2/3 complex: Activation by a diverse array of proteins.  Annu Rev Biochem . 2001;  70 649-676
    CrossrefPubMedGoogle Scholar
  • 5 Bamburg J. Proteins of the ADF/cofilin family: essential regulators of actin dynamics.  Ann Rev Cell Dev Biol . 1999;  15 185-230
    PubMedGoogle Scholar
  • 6 van der Flier A, Sonnenberg A. Structural and functional aspects of filamins.  Biochim Biophys Acta . 2001;  1538 99-117
    CrossrefPubMedGoogle Scholar
  • 7 Bartles J, Zheng L, Li A, Wierda A, Chen B. Small espin: a third actin-bundling protein and potential forked protein ortholog in brush border microvilli.  J Cell Biol . 1998;  143 107-119
    CrossrefPubMedGoogle Scholar
  • 8 Fath K, Burgess D. Microvillus assembly. Not actin alone.  Curr Biol . 1995;  5 591-593
    CrossrefPubMedGoogle Scholar
  • 9 Zhai L, Zhao P, Panebra A, Guerrerio A, Khurana S. Tyrosine phosphorylation of villin regulates the organization of the actin cytoskeleton.  J Biol Chem . 2001;  276 36163-36167
    CrossrefPubMedGoogle Scholar
  • 10 Friederich E, Pringault E, Arpin M, Louvard D. From the structure to the function of villin, an actin-binding protein of the brush border.  Bioessays . 1990;  12 403-408
    CrossrefPubMedGoogle Scholar
  • 11 Ferrary E, Cohen-Tannoudji M, Pehau-Arnaudet G. In vivo, villin is required for Ca(2+)-dependent F-actin disruption in intestinal brush borders.  J Cell Biol . 1999;  146 819-830
    CrossrefPubMedGoogle Scholar
  • 12 Pinson K, Dunbar L, Samuelson L, Gumucio D. Targeted disruption of the mouse villin gene does not impair the morphogenesis of microvilli.  Dev Dyn . 1998;  211 109-121
    CrossrefPubMedGoogle Scholar
  • 13 Costa de Beauregard M, Pringault E, Robine S, Louvard D. Suppression of villin expression by antisense RNA impairs brush border assembly in polarized epithelial intestinal cells.  EMBO J . 1995;  14 409-421
    PubMedGoogle Scholar
  • 14 Millington P, Finean J. Electron microscope studies of the structure of the microvilli on principal epithelial cells of rat jejunem after treatment in hypo- and hypertonic solutions.  J Cell Biol . 1962;  14 125-139
    CrossrefPubMedGoogle Scholar
  • 15 Mukherjee T, Staehelin L. The fine structural organization of the brush border of intestinal epithelial cells.  J Cell Sci . 1971;  8 573-599
    PubMedGoogle Scholar
  • 16 Mooseker M, Tilney L. The organization of an actin filament-membrane complex: Filament polarity and membrane attachment in the microvilli of intestinal epithelial cells.  J Cell Biol . 1975;  67 725-743
    CrossrefPubMedGoogle Scholar
  • 17 Matsudaira P, Burgess D. Identification and organization of the components in the isolated microvillus cytoskeleton.  J Cell Biol . 1979;  83 667-673
    CrossrefPubMedGoogle Scholar
  • 18 Howe C, Mooseker M. Characterization of the 110-kdalton actin-calmodulin-, and membrane-binding protein from microvilli of intestinal epithelial cells.  J Cell Biol . 1983;  97 974-985
    CrossrefPubMedGoogle Scholar
  • 19 Heintzelman M, Hasson T, Mooseker M. Multiple unconventional myosin domains of the intestinal brush border cytoskeleton.  J Cell Sci . 1994;  107 3535-3543
    PubMedGoogle Scholar
  • 20 Chen J, Wagner M. Altered membrane-cytoskeleton linkage and membrane blebbing in energy-depleted renal proximal tubular cells.  Am J Physiol . 2001;  280 F619-F627
    PubMedGoogle Scholar
  • 21 Doctor R, Dahl R, Salter K, Fitz J. Reorganization of cholangiocyte membrane domains represents an early event in rat liver ischemia.  Hepatology . 1999;  29 1364-1374
    CrossrefPubMedGoogle Scholar
  • 22 Yonemura S, Hirao M, Doi Y. Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2.  J Cell Biol . 1998;  140 885-895
    CrossrefPubMedGoogle Scholar
  • 23 Tsukita S, Oishi K, Sato N. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons.  J Cell Biol . 1994;  126 391-401
    CrossrefPubMedGoogle Scholar
  • 24 Weinman E J, Steplock D, Wang Y, Shenolikar S. Characterization of a protein cofactor that mediates protein kinase A regulation of the renal brush border membrane Na(+)-H+ exchanger.  J Clin Invest . 1995;  95 2143-2149
    PubMedGoogle Scholar
  • 25 Reczek D, Berryman M, Bretscher A. Identification of EBP50: a PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family.  J Cell Biol . 1997;  139 169-176
    CrossrefPubMedGoogle Scholar
  • 26 Yun C H, Lamprecht G, Forster D V, Sidor A. NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin.  J Biol Chem . 1998;  273 25856-25863
    CrossrefPubMedGoogle Scholar
  • 27 Fouassier L, Duan C, Sutherland E. ERM binding phosphoprotein 50 is expressed at the apical membrane of rat liver epithelia.  Hepatology . 2001;  33 166-176
    CrossrefPubMedGoogle Scholar
  • 28 Chen J, Doctor R B, Mandel L J. Cytoskeletal dissociation of ezrin during renal anoxia: role in microvillar injury.  Am J Physiol . 1994;  267 C784-C795
    PubMedGoogle Scholar
  • 29 Chen J, Cohn J, Mandel L J. Dephosphorylation of ezrin as an early event in renal microvillar breakdown and anoxic injury.  Proc Natl Acad Sci U S A . 1995;  92 7495-7499
    PubMedGoogle Scholar
  • 30 Chen J, Mandel L J. Unopposed phosphatase action initiates ezrin dysfunction: a potential mechanism for anoxic injury.  Am J Physiol . 1997;  273 C710-C716
    PubMedGoogle Scholar
  • 31 Cunningham C C, Gorlin J B, Kwiatkowski D J. Actin-binding protein requirement for cortical stability and efficient locomotion.  Science . 1992;  255 325-327
    PubMedGoogle Scholar
  • 32 Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions.  Nature Rev Mol Cell Biol . 2001;  2 285-293
    PubMedGoogle Scholar
  • 33 Madara J, Stafford J, Barenberg D, Carlson S. Functional coupling of tight junctions and microfilaments in T84 cells.  Am J Physiol . 1988;  254 G416-G423
    PubMedGoogle Scholar
  • 34 Mandel L J, Bacallao R, Zampighi G. Uncoupling of the molecular `fence' and paracellular `gate' functions in epithelial tight junctions.  Nature . 1993;  361 552-555
    CrossrefPubMedGoogle Scholar
  • 35 Mandel L J, Doctor R B, Bacallao R. ATP depletion: a novel method to study junctional properties in epithelial tissues. II. Internalization of Na+,K(+)-ATPase and E-cadherin.  J Cell Sci . 1994;  107 3315-3324
    PubMedGoogle Scholar
  • 36 Takakuwa R, Kokai Y, Kojima T. Uncoupling of gate and fence functions of MDCK cells by the actin-depolymerizing reagent mycalolide B.  Exp Cell Res . 2000;  257 238-244
    CrossrefPubMedGoogle Scholar
  • 37 Edidin M, Kuo S C, Sheetz M P. Lateral movements of membrane glycoproteins restricted by dynamic cytoplasmic barriers.  Science . 1991;  254 1379-1382
    PubMedGoogle Scholar
  • 38 Nelson W J, Veshnock P J. Dynamics of membrane-skeleton (fodrin) organization during development of polarity in Madin-Darby canine kidney epithelial cells.  J Cell Biol . 1986;  103 1751-1765
    CrossrefPubMedGoogle Scholar
  • 39 Nelson W J, Veshnock P J. Modulation of fodrin (membrane skeleton) stability by cell-cell contact in Madin-Darby canine kidney epithelial cells.  J Cell Biol . 1987;  104 1527-1537
    CrossrefPubMedGoogle Scholar
  • 40 Nelson W J, Veshnock P J. Ankyrin binding to (Na+ + K+)ATPase and implications for the organization of membrane domains in polarized cells.  Nature . 1987;  328 533-536
    CrossrefPubMedGoogle Scholar
  • 41 Nelson W J, Hammerton R W. A membrane-cytoskeletal complex containing Na+,K+-ATPase, ankyrin, and fodrin in Madin-Darby canine kidney (MDCK) cells: implications for the biogenesis of epithelial cell polarity.  J Cell Biol . 1989;  108 893-902
    CrossrefPubMedGoogle Scholar
  • 42 Hu R-J, Moorthy S, Bennett V. Expression of functional domains of beta-spectrin disrupts epithelial morphology in cultured cells.  J Cell Biol . 1995;  128 1069-1080
    CrossrefPubMedGoogle Scholar
  • 43 Moyer B D, Denton J, Karlson K H. A PDZ-interacting domain in CFTR is an apical membrane polarization signal.  J Clin Invest . 1999;  104 1353-1361
    PubMedGoogle Scholar
  • 44 Sheng M, Sala C. PDZ domains and the organization of supramolecular complexes.  Annu Rev Neurosci . 2001;  24 1-29
    CrossrefPubMedGoogle Scholar
  • 45 Karthikeyan S, Leung T, Birrane G, Webster G, Ladias J. Crystal structure of the PDZ1 domain of human NHERF provides insights into the mechanism of carboxyl-terminal leucine recognition by class I PDZ domains.  J Mol Biol . 2001;  308 963-973
    CrossrefPubMedGoogle Scholar
  • 46 Doyle D. Crystal structure of a complexed and peptide-free membrane protein-binding domain: Molecular basis of peptide recognition by PDZ.  Cell . 1996;  85 1067-1076
    CrossrefPubMedGoogle Scholar
  • 47 Fouassier L, Yun C C, Fitz J G, Doctor R B. Evidence for ERM binding phosphoprotein 50 self-association through PDZ-PDZ interactions.  J Biol Chem . 2000;  275 25039-25045
    CrossrefPubMedGoogle Scholar
  • 48 Lau A, Hall R. Oligomerization of NHERF-1 and NHERF-2 PDZ domains: differential regulation by association with receptor carboxyl-termini and by phosphorylation.  Biochemistry . 2001;  40 8572-8580
    CrossrefPubMedGoogle Scholar
  • 49 Papakonstanti E, Vardaki E, Stournaras C. Actin cytoskeleton: a signaling sensor in cell volume regulation.  Cell Physiol Biochem . 2000;  10 257-264
    PubMedGoogle Scholar
  • 50 Cantiello H. Role of actin filament organization in cell volume and ion channel regulation.  J Exp Zool . 1997;  279 425-435
    CrossrefPubMedGoogle Scholar
  • 51 Mills J, Schwiebert E, Stanton B, Takahashi N. The cytoskeleton and membrane transport.  Curr Opin Nephrol Hypertens . 1994;  3 529-534
    PubMedGoogle Scholar
  • 52 Weinman E, Steplock D, Wade J, Shenolikar S. Ezrin binding domain-deficient NHERF attenuates cAMP-mediated inhibition of Na+/H+ exchange in OK cells.  Am J Physiol . 2001;  281 F372-F380
    PubMedGoogle Scholar
  • 53 Wang S, Yue H, Derin R, Guggino W, Li M. Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity.  Cell . 2000;  103 169-179
    CrossrefPubMedGoogle Scholar
  • 54 Raghuram V, Mak D, Foskett J. Regulation of CFTR single-channel gating by bivalent PDZ domain-mediated interaction.  Proc Natl Acad Sci USA . 2001;  98 1300-1305
    CrossrefPubMedGoogle Scholar
  • 55 Guggino W B. Focus on ``exocytosis is not involved in activation of Cl- secretion via CFTR in Calu-3 airway epithelial cells''.  Am J Physiol . 1998;  275 C911-C912
    PubMedGoogle Scholar
  • 56 Doctor R, Dahl R, Fouassier K, Kilic G, Fitz J. Cholangiocytes exhibit dynamic, actin-dependent apical membrane turnover.  Am J Physiol . 2002;  282 C1042-C1053
    PubMedGoogle Scholar
  • 57 Kato A, Gores G, LaRusso N. Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP-mediated mechanism.  J Biol Chem . 1992;  267 15523-15529
    PubMedGoogle Scholar
  • 58 Baudin H, Stock C, Vincent D, Grenier J. Microfilamentous system and secretion of enzyme in the exocrine pancreas.  J Cell Biol . 1975;  66 165-181
    CrossrefPubMedGoogle Scholar
  • 59 Valentijn K, Gumkowski F, Jamieson J. The subapical cytoskeleton regulates secretion and membrane retrieval in pancreatic acinar cells.  J Cell Sci . 1999;  112 81-96
    PubMedGoogle Scholar
  • 60 Valentijn J, Valentijn K, Pastore L, Jamieson J. Actin coating of secretory granules during regulated exocytosis correlates with the release of rab3D.  Proc Natl Acad Sci USA . 2000;  97 1091-1095
    CrossrefPubMedGoogle Scholar
  • 61 Prat A, Cunningham C, Jackson G J. Actin filament organization is required for proper cAMP-dependent activation of CFTR.  Am J Physiol . 1999;  277 C1160-C1169
    PubMedGoogle Scholar
  • 62 Gallagher A, Cedzich A, Gretz N, Somlo S, Witzgall R. The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton.  Proc Natl Acad Sci USA . 2000;  97 4017-4022
    CrossrefPubMedGoogle Scholar
  • 63 Sanchez-Urdazpal L, Gores G J, Ward E M. Ischemic-type biliary complications after orthotopic liver transplantation.  Hepatology . 1992;  16 49-53
    CrossrefPubMedGoogle Scholar
  • 64 Molitoris B, Geerdes A, McIntosh J. Dissociation and redistribution of Na+,K(+)-ATPase from its surface membrane actin cytoskeletal complex during cellular ATP depletion.  J Clin Invest . 1991;  88 462-469
    PubMedGoogle Scholar
  • 65 White P, Doctor R B, Dahl R H, Chen J. Coincident microvillar actin bundle disruption and perinuclear actin sequestration in anoxic proximal tubules.  Am J Physiol . 2000;  278 F886-F893
    PubMedGoogle Scholar
  • 66 Bacallao R, Garfinkel A, Monke S, Zampighi G, Mandel L J. ATP depletion: a novel method to study junctional properties in epithelial tissues. I. Rearrangement of the actin cytoskeleton.  J Cell Sci . 1994;  107 3301-3313
    PubMedGoogle Scholar
  • 67 Doctor R, Zhelev D, Mandel L. Loss of plasma membrane structural support in ATP-depleted renal epithelia.  Am J Physiol . 1997;  272 C439-C449
    PubMedGoogle Scholar
  • 68 Wagner M, Molitoris B. ATP depletion alters myosin I beta cellular location in LLC-PK1 cells.  Am J Physiol . 1997;  272 C1680-C1690
    PubMedGoogle Scholar
  • 69 Boyd-White J, Srirangam A, Goheen M, Wagner M. Ischemia disrupts myosin I beta in renal tubules.  Am J Physiol . 2001;  281 C1326-C1335
    PubMedGoogle Scholar
  • 70 Spencer A J, LeFurgey A, Ingram P, Mandel L J. Elemental microanalysis of organelles in proximal tubules. II. Effects of oxygen deprivation.  J Am Soc Nephrol . 1991;  1 1321-1333
    PubMedGoogle Scholar
  • 71 Golenhofen N, Doctor R B, Bacallao R, Mandel L J. Actin and villin compartmentation during ATP depletion and recovery in renal cultured cells.  Kidney Int . 1995;  48 1837-1845
    PubMedGoogle Scholar
  • 72 Schwartz N, Hosford M, Sandoval R. Ischemia activates actin depolymerizing factor: role in proximal tubule microvillar actin alterations.  Am J Physiol . 1999;  276 F544-F51
    PubMedGoogle Scholar
  • 73 Ashworth S, Sandoval R, Hosford M, Bamburg J, Molitoris B. Ischemic injury induces ADF relocalization to the apical domain of rat proximal tubule cells.  Am J Physiol . 2001;  280 F886-F894
    PubMedGoogle Scholar
  • 74 Glaumann B, Glaumann H, Berezesky I K, Trump B F. Studies on the pathogenesis of ischemic cell injury. II. Morphological changes of the P1 and P2 of the proximal tubule of the rat kidney made ischemic in vivo.  Virchows Arch . 1975;  19 281-302
    PubMedGoogle Scholar
  • 75 Venkatachalam M A, Bernard D B, Donohoe J G, Levinsky N G. Ischemic damage and repair in the rat proximal tubule: differences among the S1, S2, and S3 segments.  Kidney Int . 1978;  14 31-49
    PubMedGoogle Scholar
  • 76 Molitoris B, Dahl R, Geerdes A. Cytoskeleton disruption and apical redistribution of proximal tubule Na(+)-K(+)-ATPase during ischemia.  Am J Physiol . 1992;  263 F488-F495
    PubMedGoogle Scholar
  • 77 Molitoris B A, Falk S A, Dahl R H. Ischemia-induced loss of epithelial polarity. Role of the tight junction.  J Clin Invest . 1989;  84 1334-1339
    PubMedGoogle Scholar
  • 78 Tsukamoto T, Nigam S. Tight junction proteins form large complexes and associate with the cytoskeleton in an ATP depletion model for reversible junction assembly.  J Biol Chem . 1997;  272 16133-16139
    CrossrefPubMedGoogle Scholar
  • 79 Alejandro V S, Nelson W J, Huie P. Postischemic injury, delayed function and Na+/K(+)-ATPase distribution in the transplanted kidney.  Kidney Int . 1995;  48 1308-1315
    PubMedGoogle Scholar
  • 80 Doctor R, Bennett V, Mandel L. Degradation of spectrin and ankyrin in the ischemic rat kidney.  Am J Physiol . 1993;  264 C1003-C1013
    PubMedGoogle Scholar
  • 81 Doctor R, Chen J, Peters L, Lux S, Mandel L. Expression of Ank3 spliceoforms in the mouse renal proximal tubules.  Am J Physiol . 1997;  274 F129-F138
    PubMedGoogle Scholar
  • 82 Doctor R, Dahl R, Salter K. ATP depletion in cholangiocytes leads to marked internalization of membrane proteins.  Hepatology . 2000;  31 1045-1054
    CrossrefPubMedGoogle Scholar
  • 83 Spiegel D M, Wilson P D, Molitoris B A. Epithelial polarity following ischemia: a requirement for normal cell function.  Am J Physiol . 1989;  256 F430-F436
    PubMedGoogle Scholar
  • 84 Kwon O, Nelson W, Sibley R. Backleak, tight junctions, and cell-cell adhesion in postischemic injury to the renal allograft.  J Clin Invest . 1998;  101 2045-2064
    PubMedGoogle Scholar
  • 85 Kwon O, Corrigan G, Myers B. Sodium reabsorption and distribution of Na+/K+-ATPase during postischemic injury to the renal allograft.  Kidney Int . 1999;  55 963-975
    CrossrefPubMedGoogle Scholar
  • 86 Gopalakrishnan S, Raman N, Atkinson S, Marrs J. Rho GTPase signaling regulates tight junction assembly and protects tight junctions during ATP depletion.  Am J Physiol . 275 C798-C809
    PubMedGoogle Scholar
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