Home LiteratureArticle Details
PMID: 23524970 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation.

The Journal of clinical investigation ·Vol. 123 ·No. 4 ·2013-04-00 ·Pages 1556-70

Harmon RM, Simpson CL, Johnson JL, Koetsier JL, Dubash AD, Najor NA, Sarig O, Sprecher E, Green KJ

Abstract

Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

MeSH Terms
Adaptor Proteins, Signal Transducing/chemistry,genetics,metabolism Adolescent Adult Cell Differentiation Cells, Cultured Desmocollins/metabolism Desmoglein 1/genetics,metabolism,physiology Enzyme Activation Epidermis/pathology Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors,metabolism Female Gene Knockdown Techniques Humans Intracellular Signaling Peptides and Proteins/metabolism Keratinocytes/metabolism,physiology Keratoderma, Palmoplantar/metabolism,pathology Lamins/genetics,metabolism MAP Kinase Signaling System Male Primary Cell Culture Protein Binding Protein Interaction Domains and Motifs Protein Kinase Inhibitors/pharmacology Protein Transport RNA, Small Interfering/genetics Young Adult ras Proteins/metabolism
Chemicals
Adaptor Proteins, Signal Transducing DSC1 protein, human DSG1 protein, human Desmocollins Desmoglein 1 ERBIN protein, human Intracellular Signaling Peptides and Proteins Lamins Protein Kinase Inhibitors RNA, Small Interfering SHOC2 protein, human Extracellular Signal-Regulated MAP Kinases ras Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Harmon Robert M
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Simpson Cory L
Johnson Jodi L
Koetsier Jennifer L
Dubash Adi D
Najor Nicole A
Sarig Ofer
Sprecher Eli
Green Kathleen J
References (96)
96 references, click to expand
  1. β2-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes.
    Int J Cardiol. 2013 Aug 20;167(4):1570-7 PMID: 22564389
  2. Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death.
    J Biol Chem. 2005 Sep 23;280(38):32856-65 PMID: 16036919
  3. Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin desmoglein 1: implications for exfoliative toxin-mediated skin blistering.
    Am J Pathol. 2010 Dec;177(6):2921-37 PMID: 21075858
  4. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.
    Nat Genet. 2009 Sep;41(9):1022-6 PMID: 19684605
  5. The scaffold protein Shoc2/SUR-8 accelerates the interaction of Ras and Raf.
    J Biol Chem. 2010 Mar 5;285(10):7818-26 PMID: 20051520
  6. Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro.
    Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6728-33 PMID: 10359780
  7. The classical nuclear localization signal receptor, importin-alpha, is required for efficient transition through the G1/S stage of the cell cycle in Saccharomyces cerevisiae.
    Genetics. 2009 Jan;181(1):105-18 PMID: 18984568
  8. A clathrin-dependent pathway leads to KRas signaling on late endosomes en route to lysosomes.
    J Cell Biol. 2009 Mar 23;184(6):863-79 PMID: 19289794
  9. Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium.
    Cell Growth Differ. 1995 Feb;6(2):149-57 PMID: 7756173
  10. Temporal smad7 transgene induction in mouse epidermis accelerates skin wound healing.
    Am J Pathol. 2011 Oct;179(4):1768-79 PMID: 21944279
  11. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway.
    Expert Rev Mol Med. 2008 Dec 09;10:e37 PMID: 19063751
  12. Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network.
    Br J Dermatol. 2004 May;150(5):878-91 PMID: 15149499
  13. The C-terminal unique region of desmoglein 2 inhibits its internalization via tail-tail interactions.
    J Cell Biol. 2012 Nov 12;199(4):699-711 PMID: 23128240
  14. The differentiation-dependent desmosomal cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in keratinocytes.
    J Biol Chem. 2006 Feb 10;281(6):3614-24 PMID: 16286477
  15. Nonconventional trafficking of Ras associated with Ras signal organization.
    Traffic. 2006 Sep;7(9):119-26 PMID: 16824054
  16. Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.
    Dev Cell. 2009 Mar;16(3):433-44 PMID: 19289088
  17. The desmoglein-specific cytoplasmic region is intrinsically disordered in solution and interacts with multiple desmosomal protein partners.
    J Mol Biol. 2009 Feb 20;386(2):531-43 PMID: 19136012
  18. EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer.
    Nat Cell Biol. 2008 Aug;10(8):902-11 PMID: 18604200
  19. An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells.
    J Proteome Res. 2009 Aug;8(8):3852-61 PMID: 19534553
  20. RNA interference in keratinocytes and an organotypic model of human epidermis.
    Methods Mol Biol. 2010;585:127-46 PMID: 19908001
  21. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.
    J Clin Invest. 2001 Aug;108(4):527-36 PMID: 11518726
  22. Fusion of docked membranes requires the armadillo repeat protein Vac8p.
    J Biol Chem. 2001 Sep 14;276(37):35133-40 PMID: 11441010
  23. Molecular organization of the desmoglein-plakoglobin complex.
    J Cell Sci. 1998 Jul 30;111 ( Pt 14):1941-9 PMID: 9645942
  24. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.
    J Hum Genet. 2010 Dec;55(12):801-9 PMID: 20882035
  25. Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry.
    Curr Opin Cell Biol. 2007 Oct;19(5):515-20 PMID: 17951043
  26. ERBIN associates with p0071, an armadillo protein, at cell-cell junctions of epithelial cells.
    Genes Cells. 2002 May;7(5):475-85 PMID: 12047349
  27. Compartmentalized signalling: Ras proteins and signalling nanoclusters.
    FEBS J. 2009 Apr;276(7):1817-25 PMID: 19243428
  28. Visualisation by electron microscopy of the unique part of the cytoplasmic domain of a desmoglein, a cadherin-like protein of the desmosome type of cell junction.
    FEBS Lett. 1994 Oct 17;353(2):194-6 PMID: 7926050
  29. Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra.
    J Proteome Res. 2007 Nov;6(11):4150-62 PMID: 17924679
  30. Outside-in signaling through integrins and cadherins: a central mechanism to control epidermal growth and differentiation?
    J Invest Dermatol. 2008 Mar;128(3):501-16 PMID: 18268536
  31. Mutations in the desmoglein 1 gene in five Pakistani families with striate palmoplantar keratoderma.
    J Dermatol Sci. 2009 Mar;53(3):192-7 PMID: 19157795
  32. Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1.
    J Cell Sci. 2007 Apr 15;120(Pt 8):1480-90 PMID: 17389689
  33. Disruption of desmosome assembly by monovalent human pemphigus vulgaris monoclonal antibodies.
    J Invest Dermatol. 2009 Apr;129(4):908-18 PMID: 19037235
  34. Disruption of ERBB2IP is not associated with dystrophic epidermolysis bullosa in both father and son carrying a balanced 5;13 translocation.
    J Invest Dermatol. 2005 Oct;125(4):700-4 PMID: 16185268
  35. Ras signalling on the endoplasmic reticulum and the Golgi.
    Nat Cell Biol. 2002 May;4(5):343-50 PMID: 11988737
  36. Coordinated expression of desmoglein 1 and desmocollin 1 regulates intercellular adhesion.
    Differentiation. 2004 Oct;72(8):419-33 PMID: 15606501
  37. ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor.
    Nat Cell Biol. 2000 Jul;2(7):407-14 PMID: 10878805
  38. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2.
    J Cell Sci. 2002 Nov 15;115(Pt 22):4251-62 PMID: 12376557
  39. Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3.
    J Invest Dermatol. 2011 Mar;131(3):706-18 PMID: 21160493
  40. The PDZ protein erbin modulates beta-catenin-dependent transcription.
    Eur Surg Res. 2008;41(3):284-9 PMID: 18667832
  41. Molecular markers in patients with chronic wounds to guide surgical debridement.
    Mol Med. 2007 Jan-Feb;13(1-2):30-9 PMID: 17515955
  42. Ras/Erk MAPK signaling in epidermal homeostasis and neoplasia.
    Cell Cycle. 2007 Dec 1;6(23):2928-31 PMID: 18000402
  43. Chronic wound state exacerbated by oxidative stress in Pax6+/- aniridia-related keratopathy.
    J Pathol. 2008 Aug;215(4):421-30 PMID: 18491289
  44. Differential expression of phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated p38 mitogen-activated protein kinase and nuclear factor-kappaB p105/p50 in chronic inflammatory skin diseases.
    J Dermatol. 2009 Oct;36(10):534-40 PMID: 19785707
  45. Novel mutations in DSG1 causing striate palmoplantar keratoderma.
    Clin Exp Dermatol. 2009 Mar;34(2):224-8 PMID: 19018793
  46. Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks.
    Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5860-5 PMID: 17389395
  47. Palmitoylation of ERBIN is required for its plasma membrane localization.
    Genes Cells. 2008 Jul;13(7):691-701 PMID: 18498353
  48. Internalization of EGF receptor following lipid rafts disruption in keratinocytes is delayed and dependent on p38 MAPK activation.
    J Cell Physiol. 2008 Dec;217(3):834-45 PMID: 18727093
  49. Erbin regulates mitogen-activated protein (MAP) kinase activation and MAP kinase-dependent interactions between Merlin and adherens junction protein complexes in Schwann cells.
    J Biol Chem. 2005 Mar 25;280(12):11790-7 PMID: 15659388
  50. ERBIN is a new SARA-interacting protein: competition between SARA and SMAD2 and SMAD3 for binding to ERBIN.
    J Cell Sci. 2011 Oct 1;124(Pt 19):3209-22 PMID: 21878490
  51. The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf.
    Genes Dev. 2000 Apr 15;14(8):895-900 PMID: 10783161
  52. Proceedings from the 2009 genetic syndromes of the Ras/MAPK pathway: From bedside to bench and back.
    Am J Med Genet A. 2010 Jan;152A(1):4-24 PMID: 20014119
  53. Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain.
    Mol Cell Biol. 2007 Sep;27(17):6183-94 PMID: 17591701
  54. Identification of the plakoglobin-binding domain in desmoglein and its role in plaque assembly and intermediate filament anchorage.
    J Cell Biol. 1994 Oct;127(1):151-60 PMID: 7929560
  55. Desmoglein 1-dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis.
    J Cell Biol. 2009 Jun 29;185(7):1243-58 PMID: 19546243
  56. Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1.
    Arch Dermatol. 2005 May;141(5):625-8 PMID: 15897387
  57. Clinical manifestations of mutations in RAS and related intracellular signal transduction factors.
    Curr Opin Pediatr. 2011 Aug;23(4):443-51 PMID: 21750428
  58. Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.
    Nat Biotechnol. 2005 Jan;23(1):94-101 PMID: 15592455
  59. Noonan syndrome: clinical aspects and molecular pathogenesis.
    Mol Syndromol. 2010 Feb;1(1):2-26 PMID: 20648242
  60. The hemidesmosomal protein bullous pemphigoid antigen 1 and the integrin beta 4 subunit bind to ERBIN. Molecular cloning of multiple alternative splice variants of ERBIN and analysis of their tissue expression.
    J Biol Chem. 2001 Aug 31;276(35):32427-36 PMID: 11375975
  61. The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF.
    J Biol Chem. 2002 Apr 12;277(15):12906-14 PMID: 11821434
  62. Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing.
    Am J Pathol. 2005 Jul;167(1):59-69 PMID: 15972952
  63. Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry.
    Anal Chem. 2004 May 15;76(10):2763-72 PMID: 15144186
  64. Extracellular regulated kinase and c-Jun N-terminal kinase are activated in psoriatic involved epidermis.
    J Dermatol Sci. 2002 Nov;30(2):94-9 PMID: 12413764
  65. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.
    Cell. 2006 Nov 3;127(3):635-48 PMID: 17081983
  66. The NF2 tumor suppressor, Merlin, regulates epidermal development through the establishment of a junctional polarity complex.
    Dev Cell. 2010 Nov 16;19(5):727-39 PMID: 21074722
  67. Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex.
    J Biol Chem. 2006 Jan 13;281(2):927-33 PMID: 16301319
  68. Screening for EphB signaling effectors using SILAC with a linear ion trap-orbitrap mass spectrometer.
    J Proteome Res. 2008 Nov;7(11):4715-26 PMID: 18816084
  69. Erbin regulates NRG1 signaling and myelination.
    Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9477-82 PMID: 19458253
  70. Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo.
    Oncogene. 2010 Jun 10;29(23):3362-73 PMID: 20383193
  71. Cardio-facio-cutaneous syndrome: does genotype predict phenotype?
    Am J Med Genet C Semin Med Genet. 2011 May 15;157C(2):129-35 PMID: 21495173
  72. Striate palmoplantar keratoderma resulting from a frameshift mutation in the desmoglein 1 gene.
    J Dermatol Sci. 2007 Mar;45(3):161-6 PMID: 17194569
  73. Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions.
    Sci Signal. 2009 Aug 18;2(84):ra46 PMID: 19690332
  74. Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.
    Eur J Hum Genet. 2001 Mar;9(3):197-203 PMID: 11313759
  75. Sur8/Shoc2 involves both inhibition of differentiation and maintenance of self-renewal of neural progenitor cells via modulation of extracellular signal-regulated kinase signaling.
    Stem Cells. 2011 Feb;29(2):320-31 PMID: 21732489
  76. Deregulation of keratinocyte differentiation and activation: a hallmark of venous ulcers.
    J Cell Mol Med. 2008 Dec;12(6B):2675-90 PMID: 18373736
  77. Terminal differentiation and mitogen-activated protein kinase signaling in human cholesteatoma epithelium.
    Otol Neurotol. 2006 Apr;27(3):422-6 PMID: 16639284
  78. Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development.
    Br J Dermatol. 2012 Mar;166(3):601-7 PMID: 22098123
  79. A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity.
    Mol Cell. 2006 Apr 21;22(2):217-30 PMID: 16630891
  80. SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor.
    J Biol Chem. 2012 Dec 7;287(50):41797-807 PMID: 23076151
  81. Erbin suppresses the MAP kinase pathway.
    J Biol Chem. 2003 Jan 10;278(2):1108-14 PMID: 12379659
  82. A quantitative atlas of mitotic phosphorylation.
    Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7 PMID: 18669648
  83. Transcriptional profiling defines the roles of ERK and p38 kinases in epidermal keratinocytes.
    J Cell Physiol. 2008 May;215(2):292-308 PMID: 18247374
  84. Comparative analysis of the expression of ERBIN and Erb-B2 in normal human skin and cutaneous carcinomas.
    Br J Dermatol. 2005 Jun;152(6):1248-55 PMID: 15948989
  85. A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma.
    Exp Dermatol. 2003 Aug;12(4):523-7 PMID: 12930313
  86. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome.
    J Clin Invest. 2002 Jul;110(1):53-60 PMID: 12093888
  87. Compartmentalized signaling of Ras in fission yeast.
    Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9045-50 PMID: 16754851
  88. Ras and calcium signaling pathways converge at Raf1 via the Shoc2 scaffold protein.
    Mol Biol Cell. 2010 Mar 15;21(6):1088-96 PMID: 20071468
  89. Mutation in DSG1 causing autosomal dominant striate palmoplantar keratoderma.
    Br J Dermatol. 2009 Sep;161(3):692-4 PMID: 19558595
  90. Shoc2 is targeted to late endosomes and required for Erk1/2 activation in EGF-stimulated cells.
    PLoS One. 2012;7(5):e36469 PMID: 22606262
  91. ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis.
    J Invest Dermatol. 2008 Jul;128(7):1737-46 PMID: 18200054
  92. Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry.
    Nat Methods. 2005 Aug;2(8):591-8 PMID: 16094384
  93. Proximity ligation assays: a recent addition to the proteomics toolbox.
    Expert Rev Proteomics. 2010 Jun;7(3):401-9 PMID: 20536310
  94. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1.
    Mol Biol Cell. 2010 Nov 15;21(22):3902-14 PMID: 20861311
  95. Desmosomes: adhesive strength and signalling in health and disease.
    Biochem J. 2010 Aug 1;429(3):419-33 PMID: 20626351
  96. Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion.
    J Dermatol Sci. 2007 Jan;45(1):7-21 PMID: 17141479
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI65220
Published
2013-04-00
Epub
2013-00-25
Pages
1556-70
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC3613912
Subset
IM
Grants
NIAMS NIH HHS · P30AR057216 · United States
NIEHS NIH HHS · F30 ES14990 · United States
NIAMS NIH HHS · R01 AR043380 · United States
NIGMS NIH HHS · T32 GM08061 · United States
NIGMS NIH HHS · T32 GM008061 · United States
NIEHS NIH HHS · F30 ES014990 · United States
NCI NIH HHS · P30 CA060553 · United States
NCI NIH HHS · P30 CA060553-159026 · United States
NCI NIH HHS · T32 CA070085-14 · United States
NIAMS NIH HHS · R01 AR041836 · United States
NCI NIH HHS · T32 CA070085 · United States
NCI NIH HHS · CA122151 · United States
NIAMS NIH HHS · P30 AR057216 · United States
NIAMS NIH HHS · R37 AR043380 · United States
NIAMS NIH HHS · AR43380 · United States
NCI NIH HHS · R01 CA122151 · United States
Corrections
CommentIn
PMID: 23524961
External Links
PubMed source DOI: 10.1172/JCI65220 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2