Skip to main content
Springer Nature Link
Log in

The role of P-cadherin in skin biology and skin pathology: lessons from the hair follicle

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Adherens junctions (AJs) are one of the major intercellular junctions in various epithelia including the epidermis and the follicular epithelium. AJs connect the cell surface to the actin cytoskeleton and comprise classic transmembrane cadherins, such as P-cadherin, armadillo family proteins, and actin microfilaments. Loss-of-function mutations in CDH3, which encodes P-cadherin, result in two allelic autosomal recessive disorders: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM) syndromes. Both syndromes feature sparse hair heralding progressive macular dystrophy. EEM syndrome is characterized in addition by ectodermal and limb defects. Recent studies have demonstrated that, together with its involvement in cell-cell adhesion, P-cadherin plays a crucial role in regulating cell signaling, malignant transformation, and other major intercellular processes. Here, we review the roles of P-cadherin in skin and hair biology, with emphasize on human hair growth, cycling and pigmentation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  • Aksan I, Goding CR (1998) Targeting the microphthalmia basic helix-loop-helix-leucine zipper transcription factor to a subset of E-box elements in vitro and in vivo. Mol Cell Biol 18:6930–6938

    PubMed Central  CAS  PubMed  Google Scholar 

  • Angers S, Moon RT (2009) Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 10:468–477

    CAS  PubMed  Google Scholar 

  • Avitan-Hersh E, Indelman M, Khamaysi Z, Leibu R, Bergman R (2012) A novel nonsense CDH3 mutation in hypotrichosis with juvenile macular dystrophy. Int J Dermatol 51:325–327

    CAS  PubMed  Google Scholar 

  • Basel-Vanagaite L, Pasmanik-Chor M, Lurie R, Yeheskel A, Kjaer KW (2010) CDH3-related syndromes: report on a new mutation and overview of the genotype-phenotype correlations. Mol Syndromol 1:223–230

    PubMed  Google Scholar 

  • Bauer K, Dowejko A, Bosserhoff AK, Reichert TE, Bauer RJ (2009) P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation. Carcinogenesis 30:1781–1788

    CAS  PubMed  Google Scholar 

  • Becker M, Rohrschneider K, Tilgen W, Weber BH, Volcker HE (1998) Familial juvenile macular dystrophy with congenital hypotrichosis capitis. Ophthalmologe 95:233–240

    CAS  PubMed  Google Scholar 

  • Behrendt K, Klatte J, Pofahl R, Bloch W, Smyth N, Tscharntke M, Krieg T, Paus R, Niessen C, Niemann C, Brakebusch C, Haase I (2012) A function for Rac1 in the terminal differentiation and pigmentation of hair. J Cell Sci 125:896–905

    CAS  PubMed  Google Scholar 

  • Bellei B, Pitisci A, Catricala C, Larue L, Picardo M (2010) Wnt/beta-catenin signaling is stimulated by alpha-melanocyte-stimulating hormone in melanoma and melanocyte cells: implication in cell differentiation. Pigment Cell Melanoma Res 24:309–325

    Google Scholar 

  • Benitah SA, Frye M, Glogauer M, Watt FM (2005) Stem cell depletion through epidermal deletion of Rac1. Science 309:933–935

    PubMed  Google Scholar 

  • Bergman R, Sapir M, Sprecher E (2004) Histopathology of hypotrichosis with juvenile macular dystrophy. Am J Dermatopathol 26:205–209

    PubMed  Google Scholar 

  • Bertolotto C, Abbe P, Hemesath TJ, Bille K, Fisher DE, Ortonne JP, Ballotti R (1998a) Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. J Cell Biol 142:827–835

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bertolotto C, Busca R, Abbe P, Bille K, Aberdam E, Ortonne JP, Ballotti R (1998b) Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Mol Cell Biol 18:694–702

    PubMed Central  CAS  PubMed  Google Scholar 

  • Birchmeier W, Weidner KM, Hulsken J, Behrens J (1993) Molecular mechanisms leading to cell junction (cadherin) deficiency in invasive carcinomas. Semin Cancer Biol 4:231–239

    CAS  PubMed  Google Scholar 

  • Breier G, Grosser M, Rezaei M (2014) Endothelial cadherins in cancer. Cell Tissue Res 355:523–527

    CAS  PubMed  Google Scholar 

  • Buckley CD, Tan J, Anderson KL, Hanein D, Volkmann N, Weis WI, Nelson WJ, Dunn AR (2014) Cell adhesion. The minimal cadherin-catenin complex binds to actin filaments under force. Science 346:1254211

    PubMed Central  PubMed  Google Scholar 

  • Burke JM, Cao F, Irving PE, Skumatz CM (1999) Expression of E-cadherin by human retinal pigment epithelium: delayed expression in vitro. Invest Ophthalmol Vis Sci 40:2963–2970

    CAS  PubMed  Google Scholar 

  • Bussemakers MJ, Bokhoven A van, Voller M, Smit FP, Schalken JA (1994) The genes for the calcium-dependent cell adhesion molecules P- and E-cadherin are tandemly arranged in the human genome. Biochem Biophys Res Commun 203:1291–1294

  • Buxton RS, Cowin P, Franke WW, Garrod DR, Green KJ, King IA, Koch PJ, Magee AI, Rees DA, Stanley JR, Steinberg MS (1993) Nomenclature of the desmosomal cadherins. J Cell Biol 121:481–483

    CAS  PubMed  Google Scholar 

  • Castilho RM, Squarize CH, Patel V, Millar SE, Zheng Y, Molinolo A, Gutkind JS (2007) Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells. Oncogene 26:5078–5085

    CAS  PubMed  Google Scholar 

  • Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, Haeringen A van, Woods CG, Essen AJ van, Waal R de, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, Bokhoven H van (1999) Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99:143–153

  • Cheung LW, Leung PC, Wong AS (2010) Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. Oncogene 29:2427–2440

    CAS  PubMed  Google Scholar 

  • Cheung LW, Mak AS, Cheung AN, Ngan HY, Leung PC, Wong AS (2011) P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin. Oncogene 30:2964–2974

    CAS  PubMed  Google Scholar 

  • Chrostek A, Wu X, Quondamatteo F, Hu R, Sanecka A, Niemann C, Langbein L, Haase I, Brakebusch C (2006) Rac1 is crucial for hair follicle integrity but is not essential for maintenance of the epidermis. Mol Cell Biol 26:6957–6970

    PubMed Central  CAS  PubMed  Google Scholar 

  • Collinet C, Lecuit T (2013) Stability and dynamics of cell-cell junctions. Prog Mol Biol Transl Sci 116:25–47

    CAS  PubMed  Google Scholar 

  • Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163:525–534

    PubMed Central  CAS  PubMed  Google Scholar 

  • Du J, Miller AJ, Widlund HR, Horstmann MA, Ramaswamy S, Fisher DE (2003) MLANA/MART1 and SILV/PMEL17/GP100 are transcriptionally regulated by MITF in melanocytes and melanoma. Am J Pathol 163:333–343

    PubMed Central  CAS  PubMed  Google Scholar 

  • Duguay D, Foty RA, Steinberg MS (2003) Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants. Dev Biol 253:309–323

    CAS  PubMed  Google Scholar 

  • Epifano C, Megias D, Perez-Moreno M (2014) p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals. EMBO Rep 15:592–600

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fanelli MA, Montt-Guevara M, Diblasi AM, Gago FE, Tello O, Cuello-Carrion FD, Callegari E, Bausero MA, Ciocca DR (2008) P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27. Cell Stress Chaperones 13:207–220

    PubMed Central  CAS  PubMed  Google Scholar 

  • Faraldo ML, Cano A (1993) The 5′ flanking sequences of the mouse P-cadherin gene. Homologies to 5′ sequences of the E-cadherin gene and identification of a first 215 base-pair intron. J Mol Biol 231:935–941

    CAS  PubMed  Google Scholar 

  • Faraldo MM, Teuliere J, Deugnier MA, Birchmeier W, Huelsken J, Thiery JP, Cano A, Glukhova MA (2007) Beta-catenin regulates P-cadherin expression in mammary basal epithelial cells. FEBS Lett 581:831–836

    CAS  PubMed  Google Scholar 

  • Fischer B, Metzger M, Richardson R, Knyphausen P, Ramezani T, Franzen R, Schmelzer E, Bloch W, Carney TJ, Hammerschmidt M (2014) p53 and TAp63 promote keratinocyte proliferation and differentiation in breeding tubercles of the zebrafish. PLoS Genet 10:e1004048

    PubMed Central  PubMed  Google Scholar 

  • Foty RA, Steinberg MS (2005) The differential adhesion hypothesis: a direct evaluation. Dev Biol 278:255–263

    CAS  PubMed  Google Scholar 

  • Fuchs E, Raghavan S (2002) Getting under the skin of epidermal morphogenesis. Nat Rev Genet 3:199–209

    CAS  PubMed  Google Scholar 

  • Fujita M, Furukawa F, Fujii K, Horiguchi Y, Takeichi M, Imamura S (1992) Expression of cadherin cell adhesion molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts. Arch Dermatol Res 284:159–166

    CAS  PubMed  Google Scholar 

  • Furukawa F, Fujii K, Horiguchi Y, Matsuyoshi N, Fujita M, Toda K, Imamura S, Wakita H, Shirahama S, Takigawa M (1997) Roles of E- and P-cadherin in the human skin. Microsc Res Tech 38:343–352

    CAS  PubMed  Google Scholar 

  • Geletu M, Arulanandam R, Chevalier S, Saez B, Larue L, Feracci H, Raptis L (2013) Classical cadherins control survival through the gp130/Stat3 axis. Biochim Biophys Acta 1833:1947–1959

    CAS  PubMed  Google Scholar 

  • Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26:441–454

    CAS  PubMed  Google Scholar 

  • Gumbiner BM (2000) Regulation of cadherin adhesive activity. J Cell Biol 148:399–404

    PubMed Central  CAS  PubMed  Google Scholar 

  • Halford S, Holt R, Nemeth AH, Downes SM (2012) Homozygous deletion in CDH3 and hypotrichosis with juvenile macular dystrophy. Arch Ophthalmol 130:1490–1492

    PubMed  Google Scholar 

  • Hatakeyama J, Wakamatsu Y, Nagafuchi A, Kageyama R, Shigemoto R, Shimamura K (2014) Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates. Development 141:1671–1682

    CAS  PubMed  Google Scholar 

  • Hatta M, Miyatani S, Copeland NG, Gilbert DJ, Jenkins NA, Takeichi M (1991) Genomic organization and chromosomal mapping of the mouse P-cadherin gene. Nucleic Acids Res 19:4437–4441

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hay E, Dieudonne FX, Saidak Z, Marty C, Brun J, Da Nascimento S, Sonnet P, Marie PJ (2014) N-cadherin/wnt interaction controls bone marrow mesenchymal cell fate and bone mass during aging. J Cell Physiol 229:1765–1775

    CAS  PubMed  Google Scholar 

  • Hayakawa M, Yanashima K, Kato K, Nakajima A, Yamauchi H (1989) Association of ectodermal dysplasia, ectrodactyly and macular dystrophy: EEM syndrome (case report). Ophthalmic Paediatr Genet 10:287–292

    CAS  PubMed  Google Scholar 

  • Hibino T, Nishiyama T (2004) Role of TGF-beta2 in the human hair cycle. J Dermatol Sci 35:9–18

    CAS  PubMed  Google Scholar 

  • Hines MD, Jin HC, Wheelock MJ, Jensen PJ (1999) Inhibition of cadherin function differentially affects markers of terminal differentiation in cultured human keratinocytes. J Cell Sci 112:4569–4579

    CAS  PubMed  Google Scholar 

  • Hirai Y, Nose A, Kobayashi S, Takeichi M (1989) Expression and role of E- and P-cadherin adhesion molecules in embryonic histogenesis. II. Skin morphogenesis. Development 105:271–277

    CAS  PubMed  Google Scholar 

  • Horiguchi Y, Furukawa F, Fujita M, Imamura S (1994) Ultrastructural localization of E-cadherin cell adhesion molecule on the cytoplasmic membrane of keratinocytes in vivo and in vitro. J Histochem Cytochem 42:1333–1340

    CAS  PubMed  Google Scholar 

  • Ikeya M, Lee SM, Johnson JE, McMahon AP, Takada S (1997) Wnt signalling required for expansion of neural crest and CNS progenitors. Nature 389:966–970

    CAS  PubMed  Google Scholar 

  • Indelman M, Bergman R, Lurie R, Richard G, Miller B, Petronius D, Ciubutaro D, Leibu R, Sprecher E (2002) A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with juvenile macular dystrophy. J Invest Dermatol 119:1210–1213

    CAS  PubMed  Google Scholar 

  • Indelman M, Hamel CP, Bergman R, Nischal KK, Thompson D, Surget MO, Ramon M, Ganthos H, Miller B, Richard G, Lurie R, Leibu R, Russell-Eggitt I, Sprecher E (2003) Phenotypic diversity and mutation spectrum in hypotrichosis with juvenile macular dystrophy. J Invest Dermatol 121:1217–1220

    CAS  PubMed  Google Scholar 

  • Indelman M, Leibu R, Jammal A, Bergman R, Sprecher E (2005) Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings. Br J Dermatol 153:635–638

    CAS  PubMed  Google Scholar 

  • Indelman M, Eason J, Hummel M, Loza O, Suri M, Leys MJ, Bayne M, Schwartz FL, Sprecher E (2007) Novel CDH3 mutations in hypotrichosis with juvenile macular dystrophy. Clin Exp Dermatol 32:191–196

    CAS  PubMed  Google Scholar 

  • Ip CK, Yung S, Chan TM, Tsao SW, Wong AS (2014) p70 S6 kinase drives ovarian cancer metastasis through multicellular spheroid-peritoneum interaction and P-cadherin/b1 integrin signaling activation. Oncotarget 5:9133–9149

    PubMed  Google Scholar 

  • Ishiko A, Matsunaga Y, Masunaga T, Aiso S, Nishikawa T, Shimizu H (2003) Immunomolecular mapping of adherens junction and desmosomal components in normal human epidermis. Exp Dermatol 12:747–754

    CAS  PubMed  Google Scholar 

  • Ivanov AI, Naydenov NG (2013) Dynamics and regulation of epithelial adherens junctions: recent discoveries and controversies. Int Rev Cell Mol Biol 303:27–99

    CAS  PubMed  Google Scholar 

  • Jamora C, Fuchs E (2002) Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol 4:E101–E108

    CAS  PubMed  Google Scholar 

  • Jamora C, DasGupta R, Kocieniewski P, Fuchs E (2003) Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422:317–322

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jelani M, Salman Chishti M, Ahmad W (2009) A novel splice-site mutation in the CDH3 gene in hypotrichosis with juvenile macular dystrophy. Clin Exp Dermatol 34:68–73

    CAS  PubMed  Google Scholar 

  • Kamran-ul-Hassan Naqvi S, Azeem Z, Ali G, Ahmad W (2010) A novel splice-acceptor site mutation in CDH3 gene in a consanguineous family exhibiting hypotrichosis with juvenile macular dystrophy. Arch Dermatol Res 302:701–703

    CAS  PubMed  Google Scholar 

  • Kim S, Choi IF, Quante JR, Zhang L, Roop DR, Koster MI (2009) p63 directly induces expression of Alox12, a regulator of epidermal barrier formation. Exp Dermatol 18:1016–1021

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kjaer KW, Hansen L, Schwabe GC, Marques-de-Faria AP, Eiberg H, Mundlos S, Tommerup N, Rosenberg T (2005) Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). J Med Genet 42:292–298

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ko SY, Naora H (2014) HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin. Mol Cancer 13:170

    PubMed Central  PubMed  Google Scholar 

  • Larue L, Ohsugi M, Hirchenhain J, Kemler R (1994) E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc Natl Acad Sci U S A 91:8263–8267

    PubMed Central  CAS  PubMed  Google Scholar 

  • Leibu R, Jermans A, Hatim G, Miller B, Sprecher E, Perlman I (2006) Hypotrichosis with juvenile macular dystrophy: clinical and electrophysiological assessment of visual function. Ophthalmology 113:e843

    Google Scholar 

  • Leiros GJ, Attorresi AI, Balana ME (2012) Hair follicle stem cell differentiation is inhibited through cross-talk between Wnt/beta-catenin and androgen signalling in dermal papilla cells from patients with androgenetic alopecia. Br J Dermatol 166:1035–1042

    CAS  PubMed  Google Scholar 

  • Lu M, Marsters S, Ye X, Luis E, Gonzalez L, Ashkenazi A (2014) E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis. Mol Cell 54:987–998

    CAS  PubMed  Google Scholar 

  • Lysne D, Johns J, Walker A, Ecker R, Fowler C, Lawson KR (2014) P-cadherin potentiates ligand-dependent EGFR and IGF-1R signaling in dysplastic and malignant oral keratinocytes. Oncol Rep 32:2541–2548

    CAS  PubMed  Google Scholar 

  • MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26

    PubMed Central  CAS  PubMed  Google Scholar 

  • Marie PJ, Hay E, Saidak Z (2014) Integrin and cadherin signaling in bone: role and potential therapeutic targets. Trends Endocrinol Metab 25:567–575

    CAS  PubMed  Google Scholar 

  • Marren P, Wilson C, Dawber RP, Walshe MM (1992) Hereditary hypotrichosis (Marie-Unna type) and juvenile macular degeneration (Stargardt’s maculopathy). Clin Exp Dermatol 17:189–191

    CAS  PubMed  Google Scholar 

  • Matsuyoshi T, Kimura M, Tachikawa Y, Nakamura M, Iwakuma A, Morishige N, Nakamura K, Sukehiro S, Kawano Y, Anai K (1993) Early and late results with combined mitral and aortic valve replacement. Igaku Kenkyu 63:85–94

    CAS  PubMed  Google Scholar 

  • Mikkola ML, Costanzo A, Thesleff I, Roop DR, Koster MI (2010) Treasure or artifact: a decade of p63 research speaks for itself. Cell Death Differ 17:180–186

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mosimann C, Hausmann G, Basler K (2009) Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol 10:276–286

    CAS  PubMed  Google Scholar 

  • Muller-Rover S, Tokura Y, Welker P, Furukawa F, Wakita H, Takigawa M, Paus R (1999) E- and P-cadherin expression during murine hair follicle morphogenesis and cycling. Exp Dermatol 8:237–246

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Nelson WJ, Nusse R (2004) Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303:1483–1487

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nishimura EK, Granter SR, Fisher DE (2005) Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science 307:720–724

    CAS  PubMed  Google Scholar 

  • Nollet F, Kools P, Roy F van (2000) Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol 299:551–572

  • 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

    CAS  PubMed  Google Scholar 

  • Nose A, Nagafuchi A, Takeichi M (1988) Expressed recombinant cadherins mediate cell sorting in model systems. Cell 54:993–1001

    CAS  PubMed  Google Scholar 

  • Ohdo S, Hirayama K, Terawaki T (1983) Association of ectodermal dysplasia, ectrodactyly, and macular dystrophy: the EEM syndrome. J Med Genet 20:52–57

    PubMed Central  CAS  PubMed  Google Scholar 

  • Osada M, Park HL, Nagakawa Y, Yamashita K, Fomenkov A, Kim MS, Wu G, Nomoto S, Trink B, Sidransky D (2005) Differential recognition of response elements determines target gene specificity for p53 and p63. Mol Cell Biol 25:6077–6089

    PubMed Central  CAS  PubMed  Google Scholar 

  • Paredes J, Albergaria A, Oliveira JT, Jeronimo C, Milanezi F, Schmitt FC (2005) P-cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation. Clin Cancer Res 11:5869–5877

    CAS  PubMed  Google Scholar 

  • Paredes J, Correia AL, Ribeiro AS, Albergaria A, Milanezi F, Schmitt FC (2007) P-cadherin expression in breast cancer: a review. Breast Cancer Res 9:214

    PubMed Central  PubMed  Google Scholar 

  • Paredes J, Correia AL, Ribeiro AS, Milanezi F, Cameselle-Teijeiro J, Schmitt FC (2008) Breast carcinomas that co-express E- and P-cadherin are associated with p120-catenin cytoplasmic localisation and poor patient survival. J Clin Pathol 61:856–862

    CAS  PubMed  Google Scholar 

  • Paredes J, Figueiredo J, Albergaria A, Oliveira P, Carvalho J, Ribeiro AS, Caldeira J, Costa AM, Simoes-Correia J, Oliveira MJ, Pinheiro H, Pinho SS, Mateus R, Reis CA, Leite M, Fernandes MS, Schmitt F, Carneiro F, Figueiredo C, Oliveira C, Seruca R (2012) Epithelial E- and P-cadherins: role and clinical significance in cancer. Biochim Biophys Acta 1826:297–311

    CAS  PubMed  Google Scholar 

  • Pece S, Gutkind JS (2000) Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J Biol Chem 275:41227–41233

    CAS  PubMed  Google Scholar 

  • Piao HL, Yuan Y, Wang M, Sun Y, Liang H, Ma L (2014) Alpha-catenin acts as a tumour suppressor in E-cadherin-negative basal-like breast cancer by inhibiting NF-kappaB signalling. Nat Cell Biol 16:245–254

    PubMed Central  CAS  PubMed  Google Scholar 

  • Radice GL, Ferreira-Cornwell MC, Robinson SD, Rayburn H, Chodosh LA, Takeichi M, Hynes RO (1997) Precocious mammary gland development in P-cadherin-deficient mice. J Cell Biol 139:1025–1032

    PubMed Central  CAS  PubMed  Google Scholar 

  • Raison-Peyron N, Duval PA, Barneon G, Durand L, Arnaud B, Meynadier J, Hamel C (2000) A syndrome combining severe hypotrichosis and macular dystrophy: absence of mutations in TIMP genes. Br J Dermatol 143:902–904

    CAS  PubMed  Google Scholar 

  • Revollo L, Kading J, Jeong SY, Li J, Salazar V, Mbalaviele G, Civitelli R (2014) N-cadherin restrains PTH activation of Lrp6/beta-catenin signaling and osteoanabolic action. J Bone Miner Res (in press)

  • Ribeiro AS, Sousa B, Carreto L, Mendes N, Nobre AR, Ricardo S, Albergaria A, Cameselle-Teijeiro JF, Gerhard R, Soderberg O, Seruca R, Santos MA, Schmitt F, Paredes J (2013) P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model. J Pathol 229:705–718

    CAS  PubMed  Google Scholar 

  • Rinne T, Spadoni E, Kjaer KW, Danesino C, Larizza D, Kock M, Huoponen K, Savontaus ML, Aaltonen M, Duijf P, Brunner HG, Penttinen M, Bokhoven H van (2006) Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene. Eur J Hum Genet 14:904–910

  • Rishikaysh P, Dev K, Diaz D, Qureshi WM, Filip S, Mokry J (2014) Signaling involved in hair follicle morphogenesis and development. Int J Mol Sci 15:1647–1670

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rosenbluh J, Wang X, Hahn WC (2014) Genomic insights into WNT/beta-catenin signaling. Trends Pharmacol Sci 35:103–109

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sakharkar KR, Chow VT (2004) PPD—Proteome Profile Database. In Silico Biol 4:219–223

    CAS  PubMed  Google Scholar 

  • Samuelov L, Sprecher E, Tsuruta D, Biro T, Kloepper JE, Paus R (2012) P-cadherin regulates human hair growth and cycling via canonical Wnt signaling and transforming growth factor-beta2. J Invest Dermatol 132:2332–2341

    CAS  PubMed  Google Scholar 

  • Samuelov L, Sprecher E, Sugawara K, Singh SK, Tobin DJ, Tsuruta D, Biro T, Kloepper JE, Paus R (2013) Topobiology of human pigmentation: P-cadherin selectively stimulates hair follicle melanogenesis. J Invest Dermatol 133:1591–1600

    CAS  PubMed  Google Scholar 

  • Schepsky A, Bruser K, Gunnarsson GJ, Goodall J, Hallsson JH, Goding CR, Steingrimsson E, Hecht A (2006) The microphthalmia-associated transcription factor Mitf interacts with beta-catenin to determine target gene expression. Mol Cell Biol 26:8914–8927

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schmidt-Ullrich R, Paus R (2005) Molecular principles of hair follicle induction and morphogenesis. Bioessays 27:247–261

    CAS  PubMed  Google Scholar 

  • Senecky Y, Halpern GJ, Inbar D, Attias J, Shohat M (2001) Ectodermal dysplasia, ectrodactyly and macular dystrophy (EEM syndrome) in siblings. Am J Med Genet 101:195–197

    CAS  PubMed  Google Scholar 

  • Shapiro L, Kwong PD, Fannon AM, Colman DR, Hendrickson WA (1995) Considerations on the folding topology and evolutionary origin of cadherin domains. Proc Natl Acad Sci U S A 92:6793–6797

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shi F, Hu L, Jacques BE, Mulvaney JF, Dabdoub A, Edge AS (2014) Beta-catenin is required for hair-cell differentiation in the cochlea. J Neurosci 34:6470–6479

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shimomura Y, Wajid M, Shapiro L, Christiano AM (2008) P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle. Development 135:743–753

    CAS  PubMed  Google Scholar 

  • Shimomura Y, Wajid M, Kurban M, Christiano AM (2010) Splice site mutations in the P-cadherin gene underlie hypotrichosis with juvenile macular dystrophy. Dermatology 220:208–212

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shimoyama Y, Hirohashi S (1991) Expression of E- and P-cadherin in gastric carcinomas. Cancer Res 51:2185–2192

    CAS  PubMed  Google Scholar 

  • Shimoyama Y, Hirohashi S, Hirano S, Noguchi M, Shimosato Y, Takeichi M, Abe O (1989a) Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res 49:2128–2133

    CAS  PubMed  Google Scholar 

  • Shimoyama Y, Yoshida T, Terada M, Shimosato Y, Abe O, Hirohashi S (1989b) Molecular cloning of a human Ca2+−dependent cell-cell adhesion molecule homologous to mouse placental cadherin: its low expression in human placental tissues. J Cell Biol 109:1787–1794

    CAS  PubMed  Google Scholar 

  • Song X, Wang S, Li L (2014) New insights into the regulation of Axin function in canonical Wnt signaling pathway. Protein Cell 5:186–193

    PubMed Central  CAS  PubMed  Google Scholar 

  • Souied E, Amalric P, Chauvet ML, Chevallier C, Le Hoang P, Munnich A, Kaplan J (1995) Unusual association of juvenile macular dystrophy with congenital hypotrichosis: occurrence in two siblings suggesting autosomal recessive inheritance. Ophthalmic Genet 16:11–15

    CAS  PubMed  Google Scholar 

  • Sprecher E, Bergman R, Richard G, Lurie R, Shalev S, Petronius D, Shalata A, Anbinder Y, Leibu R, Perlman I, Cohen N, Szargel R (2001) Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nat Genet 29:134–136

    CAS  PubMed  Google Scholar 

  • Stavropoulos I, Golla K, Moran N, Martin F, Shields DC (2014) Cadherin juxtamembrane region derived peptides inhibit TGFbeta1 induced gene expression. Bioarchitecture 4:103–110

    PubMed Central  PubMed  Google Scholar 

  • Takeda K, Yasumoto K, Takada R, Takada S, Watanabe K, Udono T, Saito H, Takahashi K, Shibahara S (2000) Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a. J Biol Chem 275:14013–14016

    CAS  PubMed  Google Scholar 

  • Takeichi M (1988) Cadherins: key molecules for selective cell-cell adhesion. IARC Sci Publ 92:76–79

    CAS  PubMed  Google Scholar 

  • Takeichi M (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455

    CAS  PubMed  Google Scholar 

  • Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7:619–627

    CAS  PubMed  Google Scholar 

  • Takeichi M (2014) Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol 15:397–410

    CAS  PubMed  Google Scholar 

  • Takeichi M, Hatta K, Nose A, Nagafuchi A (1988) Identification of a gene family of cadherin cell adhesion molecules. Cell Differ Dev 25 (Suppl):91–94

    CAS  PubMed  Google Scholar 

  • Taneyhill LA, Schiffmacher AT (2013) Cadherin dynamics during neural crest cell ontogeny. Prog Mol Biol Transl Sci 116:291–315

    CAS  PubMed  Google Scholar 

  • Taniuchi K, Nakagawa H, Hosokawa M, Nakamura T, Eguchi H, Ohigashi H, Ishikawa O, Katagiri T, Nakamura Y (2005) Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases. Cancer Res 65:3092–3099

    CAS  PubMed  Google Scholar 

  • Thuault S, Hayashi S, Lagirand-Cantaloube J, Plutoni C, Comunale F, Delattre O, Relaix F, Gauthier-Rouviere C (2013) P-cadherin is a direct PAX3-FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness. Oncogene 32:1876–1887

    CAS  PubMed  Google Scholar 

  • Tobin DJ (2011) The cell biology of human hair follicle pigmentation. Pigment Cell Melanoma Res 24:75–88

    PubMed  Google Scholar 

  • Vachtenheim J, Borovansky J (2010) “Transcription physiology” of pigment formation in melanocytes: central role of MITF. Exp Dermatol 19:617–627

    CAS  PubMed  Google Scholar 

  • Vendome J, Felsovalyi K, Song H, Yang Z, Jin X, Brasch J, Harrison OJ, Ahlsen G, Bahna F, Kaczynska A, Katsamba PS, Edmond D, Hubbell WL, Shapiro L, Honig B (2014) Structural and energetic determinants of adhesive binding specificity in type I cadherins. Proc Natl Acad Sci U S A 111:E4175–E4184

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vinyoles M, Del Valle-Perez B, Curto J, Vinas-Castells R, Alba-Castellon L, Garcia de Herreros A, Dunach M (2014) Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6. Mol Cell 53:444–457

    CAS  PubMed  Google Scholar 

  • Vleminckx K, Kemler R (1999) Cadherins and tissue formation: integrating adhesion and signaling. Bioessays 21:211–220

    CAS  PubMed  Google Scholar 

  • Wen J, Yang HB, Zhou B, Lou HF, Duan S (2013) Beta-catenin is critical for cerebellar foliation and lamination. PLoS One 8:e64451

    PubMed Central  CAS  PubMed  Google Scholar 

  • Xu L, Overbeek PA, Reneker LW (2002) Systematic analysis of E-, N- and P-cadherin expression in mouse eye development. Exp Eye Res 74:753–760

    CAS  PubMed  Google Scholar 

  • Yagi T, Takeichi M (2000) Cadherin superfamily genes: functions, genomic organization, and neurologic diversity. Genes Dev 14:1169–1180

    CAS  PubMed  Google Scholar 

  • Yamaguchi Y, Passeron T, Watabe H, Yasumoto K, Rouzaud F, Hoashi T, Hearing VJ (2007) The effects of dickkopf 1 on gene expression and Wnt signaling by melanocytes: mechanisms underlying its suppression of melanocyte function and proliferation. J Invest Dermatol 127:1217–1225

    CAS  PubMed  Google Scholar 

  • Yap AS, Kovacs EM (2003) Direct cadherin-activated cell signaling: a view from the plasma membrane. J Cell Biol 160:11–16

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S (1994) Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol 14:8058–8070

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ye J, Yang T, Guo H, Tang Y, Deng F, Li Y, Xing Y, Yang L, Yang K (2013) Wnt10b promotes differentiation of mouse hair follicle melanocytes. Int J Med Sci 10:691–698

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang Y, Yu J, Shi C, Huang Y, Wang Y, Yang T, Yang J (2013) Lef1 contributes to the differentiation of bulge stem cells by nuclear translocation and cross-talk with the Notch signaling pathway. Int J Med Sci 10:738–746

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao J, Harada N, Kurihara H, Nakagata N, Okajima K (2011) Dietary isoflavone increases insulin-like growth factor-I production, thereby promoting hair growth in mice. J Nutr Biochem 22:227–233

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv, 64239, Israel

    Liat Samuelov & Eli Sprecher

  2. Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Eli Sprecher

  3. Dermatology Research Centre, Institute of Inflammation and Repair, University of Manchester, Manchester, UK

    Ralf Paus

  4. Department of Dermatology, University of Münster, Münster, Germany

    Ralf Paus

Authors
  1. Liat Samuelov
    View author publications

    Search author on:PubMed Google Scholar

  2. Eli Sprecher
    View author publications

    Search author on:PubMed Google Scholar

  3. Ralf Paus
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Liat Samuelov.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Samuelov, L., Sprecher, E. & Paus, R. The role of P-cadherin in skin biology and skin pathology: lessons from the hair follicle. Cell Tissue Res 360, 761–771 (2015). https://doi.org/10.1007/s00441-015-2114-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-015-2114-y

Keywords