Targeting Cx43 and N-cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases

PLoS ONE

Volumn 7, Issue 5, 2012, Pages

  Mendoza Naranjo, Ariadna ^a   Cormie, Peter ^a   Serrano, Antonio E ^a   Hu, Rebecca ^b   O'Neill, Shay ^b   Wang, Chiuhui Mary ^a   Thrasivoulou, Christopher ^a   Power, Kieran T ^a   White, Alexis ^b   Serena, Thomas ^c   Phillips, Anthony R J ^b   Becker, David L ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b CoDa Therapeutics ^*  (New Zealand)

^c Newbridge Medical Research Corp   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CONNEXIN 43; F ACTIN; NERVE CELL ADHESION MOLECULE; PROTEIN ZO1; RAC1 PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; CADHERIN; MEMBRANE PROTEIN; PHOSPHOPROTEIN; ZONULA OCCLUDENS-1 PROTEIN;

ADULT; AGED; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL ADHESION; CELL CONTACT; CELL MIGRATION; CELL PROLIFERATION; CELL STRAIN 3T3; CHRONIC DISEASE; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOSKELETON; DERMIS; DOWN REGULATION; ENZYME ACTIVATION; FEMALE; FIBROBLAST; GOLGI COMPLEX; HUMAN; HUMAN CELL; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; LEG ULCER; MALE; MOLECULAR DYNAMICS; MOUSE; NONHUMAN; PHENOTYPE; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN SYNTHESIS REGULATION; PROTEIN TARGETING; RAT; REGULATORY MECHANISM; SKIN BIOPSY; UPREGULATION; WOUND; WOUND HEALING; ANIMAL; CELL MOTION; DRUG EFFECT; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENETICS; LEG; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; VARICOSIS;

3T3 CELLS; ANIMALS; CADHERINS; CELL ADHESION; CELL MOVEMENT; CELL PROLIFERATION; CONNEXIN 43; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMANS; LEG; MEMBRANE PROTEINS; MICE; PHOSPHOPROTEINS; RHO GTP-BINDING PROTEINS; UP-REGULATION; VARICOSE ULCER; WOUND HEALING;

EID: 84866456559     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0037374     Document Type: Article

References (62)

1. Gottrup F (2004) A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg 187: 38S-43S.
2. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, et al. (2009) Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen 17: 763-771.
3. Walmsley S (2002) Advances in wound management: executive summary. London: PJB Publications, Ltd.
4. Coutinho P, Qiu C, Frank S, Tamber K, Becker D (2003) Dynamic changes in connexin expression correlate with key events in the wound healing process. Cell Biol Int 27: 525-541.
5. Guo H, Acevedo P, Parsa FD, Bertram JS (1992) Gap-junctional protein connexin 43 is expressed in dermis and epidermis of human skin: differential modulation by retinoids. J Invest Dermatol 99: 460-467.
6. Qiu C, Coutinho P, Frank S, Franke S, Law LY, et al. (2003) Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol 13: 1697-1703.
7. Mori R, Power KT, Wang CM, Martin P, Becker DL (2006) Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci 119: 5193-5203.
8. Goliger JA, Paul DL (1995) Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication. Mol Biol Cell 6: 1491-1501.
9. Saitoh M, Oyamada M, Oyamada Y, Kaku T, Mori M (1997) Changes in the expression of gap junction proteins (connexins) in hamster tongue epithelium during wound healing and carcinogenesis. Carcinogenesis 18: 1319-1328.
10. Richards TS, Dunn CA, Carter WG, Usui ML, Olerud JE, et al. (2004) Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368. J Cell Biol 167: 555-562.
11. Brandner JM, Houdek P, Husing B, Kaiser C, Moll I (2004) Connexins 26, 30, and 43: differences among spontaneous, chronic, and accelerated human wound healing. J Invest Dermatol 122: 1310-1320.
12. Coutinho P, Qiu C, Frank S, Wang CM, Brown T, et al. (2005) Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury. Br J Plast Surg 58: 658-667.
13. Kretz M, Euwens C, Hombach S, Eckardt D, Teubner B, et al. (2003) Altered connexin expression and wound healing in the epidermis of connexin-deficient mice. J Cell Sci 116: 3443-3452.
14. Kretz M, Maass K, Willecke K (2004) Expression and function of connexins in the epidermis, analyzed with transgenic mouse mutants. Eur J Cell Biol 83: 647-654.
15. Wang CM, Lincoln J, Cook JE, Becker DL (2007) Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 56: 2809-2817.
16. Nakano Y, Oyamada M, Dai P, Nakagami T, Kinoshita S, et al. (2008) Connexin43 knockdown accelerates wound healing but inhibits mesenchymal transition after corneal endothelial injury in vivo. Invest Ophthalmol Vis Sci 49: 93-104.
17. Wei CJ, Francis R, Xu X, Lo CW (2005) Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J Biol Chem 280: 19925-19936.
18. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, et al. (2007) Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell 128: 547-560.
19. Giepmans BN, Moolenaar WH (1998) The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein. Curr Biol 8: 931-934.
20. van Zeijl L, Ponsioen B, Giepmans BN, Ariaens A, Postma FR, et al. (2007) Regulation of connexin43 gap junctional communication by phosphatidylinositol 4,5-bisphosphate. J Cell Biol 177: 881-891.
21. Becker D, Ciantar D, Catsicas M, Pearson R, Mobbs P (2001) Use of pIRES vectors to express EGFP and connexin constructs in studies of the role of gap junctional communication in the early development of the chick retina and brain. Cell Commun Adhes 8: 355-359.
22. Francis R, Xu X, Park H, Wei CJ, Chang S, et al. (2011) Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. PloS one 6: e26379.
23. Hosokawa K, Arai F, Yoshihara H, Iwasaki H, Nakamura Y, et al. (2010) Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells. Blood 116: 554-563.
24. Underwood JL, Murphy CG, Chen J, Franse-Carman L, Wood I, et al. (1999) Glucocorticoids regulate transendothelial fluid flow resistance and formation of intercellular junctions. Am J Physiol 277: C330-342.
25. Alt-Holland A, Shamis Y, Riley KN, DesRochers TM, Fusenig NE, et al. (2008) E-cadherin suppression directs cytoskeletal rearrangement and intraepithelial tumor cell migration in 3D human skin equivalents. J Invest Dermatol 128: 2498-2507.
26. Elbert M, Cohen D, Musch A (2006) PAR1b promotes cell-cell adhesion and inhibits dishevelled-mediated transformation of Madin-Darby canine kidney cells. Mol Biol Cell 17: 3345-3355.
27. Redfield A, Nieman MT, Knudsen KA (1997) Cadherins promote skeletal muscle differentiation in three-dimensional cultures. J Cell Biol 138: 1323-1331.
28. Magdalena J, Millard TH, Etienne-Manneville S, Launay S, Warwick HK, et al. (2003) Involvement of the Arp2/3 complex and Scar2 in Golgi polarity in scratch wound models. Mol Biol Cell 14: 670-684.
29. Yonemura S, Itoh M, Nagafuchi A, Tsukita S (1995) Cell-to-cell adherens junction formation and actin filament organization: similarities and differences between non-polarized fibroblasts and polarized epithelial cells. J Cell Sci 108 (Pt 1): 127-142.
30. Gundersen GG, Bulinski JC (1988) Selective stabilization of microtubules oriented toward the direction of cell migration. Proc Natl Acad Sci U S A 85: 5946-5950.
31. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21: 247-269.
32. Itoh RE, Kurokawa K, Ohba Y, Yoshizaki H, Mochizuki N, et al. (2002) Activation of rac and cdc42 video imaged by fluorescent resonance energy transfer-based single-molecule probes in the membrane of living cells. Mol Cell Biol 22: 6582-6591.
33. Pertz O, Hodgson L, Klemke RL, Hahn KM (2006) Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440: 1069-1072.
34. Wei CJ, Xu X, Lo CW (2004) Connexins and cell signaling in development and disease. Annu Rev Cell Dev Biol 20: 811-838.
35. Wright CS, van Steensel MA, Hodgins MB, Martin PE (2009) Connexin mimetic peptides improve cell migration rates of human epidermal keratinocytes and dermal fibroblasts in vitro. Wound Repair Regen 17: 240-249.
36. Pollok S, Pfeiffer AC, Lobmann R, Wright CS, Moll I, et al. (2010) Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells. J Cell Mol Med.
37. Taliana L, Benezra M, Greenberg RS, Masur SK, Bernstein AM (2005) ZO-1: lamellipodial localization in a corneal fibroblast wound model. Invest Ophthalmol Vis Sci 46: 96-103.
38. Hunter AW, Barker RJ, Zhu C, Gourdie RG (2005) Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 16: 5686-5698.
39. Gourdie RG, Ghatnekar GS, O'Quinn M, Rhett MJ, Barker RJ, et al. (2006) The unstoppable connexin43 carboxyl-terminus: new roles in gap junction organization and wound healing. Annals of the New York Academy of Sciences 1080: 49-62.
40. Ghatnekar GS, O'Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL, et al. (2009) Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regenerative medicine 4: 205-223.
41. Rhett JM, Ghatnekar GS, Palatinus JA, O'Quinn M, Yost MJ, et al. (2008) Novel therapies for scar reduction and regenerative healing of skin wounds. Trends in biotechnology 26: 173-180.
42. McDonough WS, Johansson A, Joffee H, Giese A, Berens ME (1999) Gap junction intercellular communication in gliomas is inversely related to cell motility. Int J Dev Neurosci 17: 601-611.
43. Batten BE, Haar JL (1979) Fine structural differentiation of germ layers in the mouse at the time of mesoderm formation. Anat Rec 194: 125-141.
44. Xu X, Francis R, Wei CJ, Linask KL, Lo CW (2006) Connexin 43-mediated modulation of polarized cell movement and the directional migration of cardiac neural crest cells. Development 133: 3629-3639.
45. Huang GY, Cooper ES, Waldo K, Kirby ML, Gilula NB, et al. (1998) Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol 143: 1725-1734.
46. Pokutta S, Weis WI (2002) The cytoplasmic face of cell contact sites. Curr Opin Struct Biol 12: 255-262.
47. Wilby MJ, Muir EM, Fok-Seang J, Gour BJ, Blaschuk OW, et al. (1999) N-Cadherin inhibits Schwann cell migration on astrocytes. Mol Cell Neurosci 14: 66-84.
48. Chakraborty S, Mitra S, Falk MM, Caplan SH, Wheelock MJ, et al. (2010) Ecadherin differentially regulates the assembly of Connexin43 and Connexin32 into gap junctions in human squamous carcinoma cells. J Biol Chem 285: 10761-10776.
49. Lin JH, Takano T, Cotrina ML, Arcuino G, Kang J, et al. (2002) Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J Neurosci 22: 4302-4311.
50. Cotrina ML, Lin JH, Nedergaard M (2008) Adhesive properties of connexin hemichannels. Glia 56: 1791-1798.
51. Becker DL, Davies CS (1995) Role of gap junctions in the development of the preimplantation mouse embryo. Microsc Res Tech 31: 364-374.
52. Wang H, Ding T, Brown N, Yamamoto Y, Prince LS, et al. (2008) Zonula occludens-1 (ZO-1) is involved in morula to blastocyst transformation in the mouse. Dev Biol 318: 112-125.
53. Li W, Hertzberg EL, Spray DC (2005) Regulation of connexin43-protein binding in astrocytes in response to chemical ischemia/hypoxia. J Biol Chem 280: 7941-7948.
54. Butkevich E, Hulsmann S, Wenzel D, Shirao T, Duden R, et al. (2004) Drebrin is a novel connexin-43 binding partner that links gap junctions to the submembrane cytoskeleton. Curr Biol 14: 650-658.
55. Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, et al. (2001) Gap junction protein connexin-43 interacts directly with microtubules. Curr Biol 11: 1364-1368.
56. Theiss C, Meller K (2002) Microinjected anti-actin antibodies decrease gap junctional intercellular commmunication in cultured astrocytes. Exp Cell Res 281: 197-204.
57. Machacek M, Hodgson L, Welch C, Elliott H, Pertz O, et al. (2009) Coordination of Rho GTPase activities during cell protrusion. Nature 461: 99-103.
58. Carr AJ, Whitmore D (2005) Imaging of single light-responsive clock cells reveals fluctuating free-running periods. Nat Cell Biol 7: 319-321.
59. Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, et al. (2002) High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum Gene Ther 13: 803-813.
60. Magdalena J, Millard TH, Machesky LM (2003) Microtubule involvement in NIH 3T3 Golgi and MTOC polarity establishment. J Cell Sci 116: 743-756.
61. Becker DL, Evans WH, Green CR, Warner A (1995) Functional analysis of amino acid sequences in connexin43 involved in intercellular communication through gap junctions. J Cell Sci 108 (Pt 4): 1455-1467.
62. Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni RB (2007) Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120: 279-288.