title: Non-junctional human desmoglein 3 acts as an upstream regulator of Src in E-cadherin adhesion, a pathway possibly involved in the pathogenesis of pemphigus vulgaris.
abstract: E-cadherin, a classical cadherin, is an adhesion receptor in adherens junctions and has important functions in cell-cell adhesion and cell signalling. Recently we reported that a desmosomal cadherin, desmoglein 3 (Dsg3), an autoantigen in pemphigus vulgaris (PV), associates with E-cadherin and activates Src, which results in tyrosine phosphorylation of adherens junction proteins. However, the nature of such an interaction and its role in cell-cell adhesion remain unclear. In this report, we provide direct evidence that it is the detergent-soluble, non-desmosomal Dsg3 that regulates the activity of Src and its association with E-cadherin in adherens junction formation. Modulation of Dsg3 levels, either by Dsg3 silencing or over-expression, alters Src activity and its association with E-cadherin. Dsg3 silencing caused retardation of calcium-induced E-cadherin junction assembly and a reduction of desmosomal protein expression. Furthermore, we provide evidence that this signalling pathway is involved, at least in part, in the pathophysiology of pemphigus. Along with the reduced expression of Dsg3, loss and disruption of E-cadherin and a concomitant decreased pSrc signalling was identified in the basal keratinocytes surrounding the blisters in PV. These findings suggest a novel function for Dsg3 in the control of E-cadherin-Src signalling and cell-cell adhesion.
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: Siu Man
authors.initials: SM
authors.lastname: Tsang
authors.forename: Louise
authors.initials: L
authors.lastname: Brown
authors.forename: Kuang
authors.initials: K
authors.lastname: Lin
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Kim
authors.initials: K
authors.lastname: Piper
authors.forename: Edel A
authors.initials: EA
authors.lastname: O'Toole
authors.forename: Richard
authors.initials: R
authors.lastname: Grose
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: David R
authors.initials: DR
authors.lastname: Garrod
authors.forename: Farida
authors.initials: F
authors.lastname: Fortune
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D051184:Desmoglein 3 / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D009061:Mouth Mucosa / Q000378:metabolism / Q000473:pathology; D010392:Pemphigus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases
chemical_list: D015820:Cadherins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human