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

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Abstract

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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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