Abstract
Cadherins are homophilic cell adhesion molecules that determine tissue architecture and control cell contact formation and dissociation in development and tissue homeostasis of all metazoans. These adhesion molecules mediate homophilic interactions between cells and are linked inside the cell via a complex set of cytosolic factors to the actin cytoskeleton. These interactions are key to the plasticity of intercellular junctions and to the various signaling functions of the cadherins. This forms the basis for cadherin-driven cell behavior, cell differentiation, and regeneration of tissue structures. Consequently, mutations in cadherins are the cause of various human pathologies, with cancer representing one of the most prominent examples.
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References
Townes PL, Holtfreter J (1955) Directed movements and selective adhesion of embryonic amphibian cells. J Exp Zool 128:53–120
Curtis ASG (1967) The cell surface: its molecular role in morphogenesis. Academic Press, New York
Sperry RW (1963) Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci U S A 50:703
Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7:619–627
Huber O, Bierkamp C, Kemler R (1996) Cadherins and catenins in development. Curr Opin Cell Biol 8:685–691
Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25
Brümmendorf T, Rathjen FG (1994) Cell adhesion molecules. 1: immunoglobulin superfamily. Protein Profile 1:951–1058
McEver RP (1994) Selectins. Curr Opin Immunol 6:75–84
Yoshida-Noro C, Suzuki N, Takeichi M (1984) Molecular nature of the calcium-dependent cell-cell adhesion system in mouse teratocarcinoma and embryonic cells studied with a monoclonal antibody. Dev Biol 101:19–27
Nagafuchi A, Shirayoshi Y, Okazaki K, Yasuda K, Takeichi M (1987) Transformation of cell adhesion properties by exogenously introduced E-cadherin cDNA. Nature 329:341–343
Takeichi M (1977) Functional correlation between cell adhesive properties and some cell surface proteins. J Cell Biol 75:464–474
Kemler R, Babinet C, Eisen H, Jacob F (1977) Surface antigen in early differentiation. Proc Natl Acad Sci U S A 74:4449–4452
Hyafil F, Morello D, Babinet C, Jacob F (1980) A cell surface glycoprotein involved in the compaction of embryonal carcinoma cells and cleavage stage embryos. Cell 21:927–934
Hyafil F, Babinet C, Jacob F (1981) Cell-cell intercations in early embryogenesis: a molecular approach to the role of calcium. Cell 26:447–454
Yoshida C, Takeichi M (1982) Teratocarcinoma cell adhesion: identification of a cell-surface protein involved in calcium-dependent cell aggregation. Cell 28:217–224
Hatta K, Okada TS, Takeichi M (1985) A monoclonal antibody disrupting calcium-dependent cell-cell adhesion of brain tissues: possible role of its target antigen in animal pattern formation. Proc Natl Acad Sci U S A 82:2789–2793
Nose A, Takeichi M (1986) A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos. J Cell Biol 103:2649–2658
Vestweber D, Kemler R (1984) Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues. Exp Cell Res 152:169–178
Boller K, Vestweber D, Kemler R (1985) Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells. J Cell Biol 100:327–332
Gallin WJ, Sorkin BC, Edelman GM, Cunningham BA (1987) Sequence analysis of a cDNA clone encoding the liver cell adhesion molecule, L-CAM. Proc Natl Acad Sci U S A 84:2808–2812
Imhof BA, Vollmers HP, Goodman SL, Birchmeier W (1983) Cell-cell interaction and polarity of epithelial cells: specific perturbation using a monoclonal antibody. Cell 35:667–675
Gumbiner BM, Simons K (1986) A functional assay for proteins involved in establishing an epithelial occluding barrier: identification of a uvomorulin-like polypeptide. J Cell Biol 102:457–468
Damsky CH, Richa J, Solter D, Knudsen K, Buck CA (1983) Identification and purification of a cell surface glycoprotein mediating intercellular adhesion in embryonic and adult tissue. Cell 34:455–466
Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grubel G, Legrand JF, Als Nielsen J, Colman DR, Hendrickson WA (1995) Structural basis of cell-cell adhesion by cadherins. Nature 374:327–337
Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L (2002) C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296:1308–1313
Leckband DE, de Rooij J (2014) Cadherin adhesion and mechanotransduction. Annu Rev Cell Dev Biol 30:291–315
Sivasankar S (2013) Tuning the kinetics of cadherin adhesion. J Investig Dermatol 133:2318–2323
Niessen CM, Gumbiner BM (2002) Cadherin-mediated cell sorting not determined by binding or adhesion specificity. J Cell Biol 156:389–399
Prakasam AK, Maruthamuthu V, Leckband DE (2006) Similarities between heterophilic and homophilic cadherin adhesion. Proc Natl Acad Sci U S A 103:15434–15439
Dejana E, Vestweber D (2013) The role of VE-cadherin in vascular morphogenesis and permeability control. In: van Roy F (ed) The molecular biology of cadherins. Elsevier, pp. 119–144
Brasch J, Harrison OJ, Ahlsen G, Carnally SM, Henderson RM, Honig B, Shapiro L (2011) Structure and binding mechanism of vascular endothelial cadherin, a divergent classical cadherin. J Mol Biol 408:57–73
Hulpiau P, van Roy F (2009) Molecular evolution of the cadherin superfamily. Int J Biochem Cell Biol 41:349–369
Nekrasova O, Green KJ (2013) Desmosome assembly and dynamics. Trends Cell Biol 23:537–546
Ozawa M, Baribault H, Kemler R (1989) The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J 8:1711–1717
Hirano S, Kimoto N, Shimoyama Y, Hirohashi S, Takeichi M (1992) Identification of a neural alpha-catenin as a key regulator of cadherin function and multicellular organization. Cell 70:293–301
Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ (2005) Deconstructing the cadherin-catenin-actin complex. Cell 123:889–901
Abe K, Takeichi M (2008) EPLIN mediates linkage of the cadherin catenin complex to F-actin and stabilizes the circumferential actin belt. Proc Natl Acad Sci U S A 105:13–19
Yonemura S, Wada Y, Watanabe T, Nagafuchi A, Shibata M (2010) Alpha-catenin as a tension transducer that induces adherens junction development. Nat Cell Biol 12:533–542
Huveneers S, Oldenburg J, Spanjaard E, van der Krogt G, Grigoriev I, Akhmanova A, Rehmann H, de Rooij J (2012) Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. J Cell Biol 196:641–652
Taguchi K, Ishiuchi T, Takeichi M (2011) Mechanosensitive EPLIN-dependent remodeling of adherens junctions regulates epithelial reshaping. J Cell Biol 194:643–656
Chervin-Pétinot A, Courçon M, Almagro S, Nicolas A, Grichine A, Grunwald D, Prandini MH, Huber P, Gulino-Debrac D (2012) Epithelial protein lost in neoplasm (EPLIN) interacts with α-catenin and actin filaments in endothelial cells and stabilizes vascular capillary network in vitro. J Biol Chem 287:7556–7572
Lecuit T, Lenne PF, Munro E (2011) Force generation, transmission, and integration during cell and tissue morphogenesis. Annu Rev Cell Dev Biol 27:157–184
Smutny M, Cox HL, Leerberg JM, Kovacs EM, Conti MA, Ferguson C, Hamilton NA, Parton RG, Adelstein RS, Yap AS (2010) Myosin II isoforms identify distinct functional modules that support integrity of the epithelial zonula adherens. Nat Cell Biol 12:696–702
Engl W, Arasi B, Yap LL, Thiery JP, Viasnoff V (2014) Actin dynamics modulate mechanosensitive immobilization of E-cadherin at adherens junctions. Nat Cell Biol 16:587–594
Xiao K, Allison DF, Buckley KM, Kottke MD, Vincent PA, Faundez V, Kowalczyk AP (2003) Cellular levels of p120 catenin function as a set point for cadherin expression levels in microvascular endothelial cells. J Cell Biol 163:535–545
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890
Vestweber D, Kemler R, Ekblom P (1985) Cell-adhesion molecule uvomorulin during kidney development. Dev Biol 112:213–221
Nakagawa S, Takeichi M (1998) Neural crest emigration from the neural tube depends on regulated cadherin expression. Development 125:2963–2971
Bronner-Fraser M, Wolf JJ, Murray BA (1992) Effects of antibodies against N-cadherin and N-CAM on the cranial neural crest and neural tube. Dev Biol 153:291–301
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428
Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003) BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968
Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G et al (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498:492–496
Broermann A, Winderlich M, Block H, Frye M, Rossaint J, Zarbock A, Cagna G, Linnepe R, Schulte D, Nottebaum AF et al (2011) Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo. J Exp Med 208:2393–2401
Wessel F, Winderlich M, Holm M, Frye M, Rivera-Galdos R, Vockel M, Linnepe R, Ipe U, Stadtmann A, Zarbock A et al (2014) Leukocyte extravasation and vascular permeability are each controlled in vivo by a different tyrosine residue of VE-cadherin. Nat Immunol 15:223–230
Payne AS, Hanakawa Y, Amagai M, Stanley JR (2004) Desmosomes and disease: pemphigus and bullous impetigo. Curr Opin Cell Biol 16:536–543
Rickman L, Simrak D, Stevens HP, Hunt DM, King IA, Bryant SP, Eady RA, Leigh IM, Arnemann J, Magee AI et al (1999) N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet 8:971–976
Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaughnessy R, Mahoney MG, Levy M, Montagutelli X, Ahmad W, Aita VM et al (2003) Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113:249–260
Ayub M, Basit S, Jelani M, Ur Rehman F, Iqbal M, Yasinzai M, Ahmad W (2009) A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. Am J Hum Genet 85:515–520
Awad MM, Calkins H, Judge DP (2008) Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med 5:258–267
Birchmeier W, Behrens J (1994) Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim Biophys Acta 1198:11–26
Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392:190–193
Vasioukhin V, Bauer C, Degenstein L, Wise B, Fuchs E (2001) Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin. Cell 104:605–617
White BD, Chien AJ, Dawson DW (2012) Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology 142:219–232
Berx G, van Roy F (2009) Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol 1:a003129
Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, Lantz DM, Seykora JT, Vasioukhin V (2011) α-Catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1. Sci Signal 4:ra33
Gumbiner BM, Kim NG (2014) The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci 127:709–717
Fanjul-Fernández M, Quesada V, Cabanillas R, Cadiñanos J, Fontanil T, Obaya A, Ramsay AJ, Llorente JL, Astudillo A, Cal S et al (2013) Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas. Nat Commun 4:2531
Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642
Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destree O, Clevers H (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86:391–399
Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R (1996) Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev 59:3–10
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790
Schackmann RC, Tenhagen M, van de Ven RA, Derksen PW (2013) p120-Catenin in cancer—mechanisms, models and opportunities for intervention. J Cell Sci 126:3515–3525
El-Amraoui A, Petit C (2013) Cadherin defects in inherited human diseases. In: van Roy F (ed) The molecular biology of cadherins. Elsevier, pp. 361–384
Acknowledgments
I thank Stefan Butz for critically reading the manuscript and Annette Wintgens for the help with the figure. Work in the author’s laboratory was supported by the Max Planck Society and the Deutsche Forschungsgemeinschaft (SFB629, SFB 1009, SFB/TR128, Excellence Cluster CiM).
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Vestweber, D. Cadherins in tissue architecture and disease. J Mol Med 93, 5–11 (2015). https://doi.org/10.1007/s00109-014-1231-5
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DOI: https://doi.org/10.1007/s00109-014-1231-5