title: Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation.
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.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Harmon
authors.forename: Cory L
authors.initials: CL
authors.lastname: Simpson
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Koetsier
authors.forename: Adi D
authors.initials: AD
authors.lastname: Dubash
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Najor
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D051187:Desmocollins / Q000378:metabolism; D051183:Desmoglein 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation; D004817:Epidermis / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D007645:Keratoderma, Palmoplantar / Q000378:metabolism / Q000473:pathology; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D061251:Primary Cell Culture; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081560:DSC1 protein, human; C495297:DSG1 protein, human; D051187:Desmocollins; D051183:Desmoglein 1; C413364:ERBIN protein, human; D047908:Intracellular Signaling Peptides and Proteins; D034882:Lamins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C112913:SHOC2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins