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.

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

“…In some cases, a specifi c signaling molecule associates with the Dsg3 complex. This has been shown for Rho GTPases and Src (Tsang et al, 2012a(Tsang et al, , 2012b. PKC has been located at the desmosomal plaque via electron microscopy (Garrod et al, 2005), and may directly bind to desmosomal proteins.…”

“…Rho GTPases act as molecular switches in actin dynamics (Gliem et al, 2010;Waschke et al, 2006). The involvement of p38MAPK is well established, which may require its downstream kinase MAPKAP kinase 2 (MK2) (Berkowitz et al, 2005(Berkowitz et al, , 2006Mao et al, 2013) and epidermal growth factor receptor (EGF-R) and/or Src signaling (Bektas et al, 2013;Chernyavsky et al, 2007;Frusic-Zlotkin et al, 2006;Tsang et al, 2012b). Other molecules implicated in pemphigus are Akt/mTOR and FAK (Gil et al, 2012;Pretel et al, 2009) as well as JNK (Marchenko et al, 2010), CDK-2 (Lanza et al, 2008), PERP (Nguyen et al, 2009) and factors associated with apoptotic signaling such as caspases 3, 6, 8, and 9 as well as Bcl/Bax and others (Li et al, 2009;Marchenko et al, 2010).…”

Desmosome assembly, homeostasis, and desmosomal disease

“…164 A recent study suggested that Pkp2 is also involved in the regulation of apoptosis. 165 Furthermore, reexpression of Dsp in cells with an epigenetic inactivation of the Dsp gene exhibited an increased sensitivity to apoptosis by the upregulation of Pg and the concomitant inhibition of β-catenin -TCF/ LEF-dependent transcription.…”

Desmoglein 2 Compensates for Desmoglein 3 but Does Not Control Cell Adhesion via Regulation of p38 Mitogen-activated Protein Kinase in Keratinocytes

“…All desmosomal cadherin isoforms are expressed in the human epidermis in a layer-and differentiation-dependent manner. In the human epidermis, beside building the core of desmosomes, the desmosomal cadherins are also supposed to be present in the cell membrane outside of desmosomes (3,4), whereas the expression of the anchoring protein DP is restricted to desmosomes. The relevance of adhesion mediated by desmosomal cadherins is illustrated by the autoimmune blistering skin disease pemphigus vulgaris.…”

“…phosphorylated, p38 MAPK (p-p38 MAPK), which established a link between p38 MAPK activation and loss of Dsg3 interaction in pemphigus vulgaris (20). Furthermore, Dsg3, via interaction with E-cadherin, has been demonstrated to be involved in Src signaling (3,21).…”