Desmoglein 3 acting as an upstream regulator of Rho GTPases, Rac-1/Cdc42 in the regulation of actin organisation and dynamics

Abstract

Desmoglein 3 (Dsg3), a member of the desmoglein sub-family, serves as an adhesion molecule in desmosomes. Our previous study showed that overexpression of human Dsg3 in several epithelial lines induces formation of membrane protrusions, a phenotype suggestive of Rho GTPase activation. Here we examined the interaction between Dsg3 and actin in detail and showed that endogenous Dsg3 colocalises and interacts with actin, particularly the junctional actin in a Rac1-dependent manner. Ablation of Rac1 activity by dominant negative Rac1 mutant (N17Rac1) or the Rac1 specific inhibitor (NSC23766) directly disrupts the interaction between Dsg3 and actin. Assembly of the junctional actin at the cell borders is accompanied with enhanced levels of Dsg3, while inhibition of Dsg3 by RNAi results in profound changes in the organisation of actin cytoskeleton. In accordance, overexpression of Dsg3 results in a remarkable increase of Rac1 and Cdc42 activities and to a lesser extent, RhoA. The enhancements in Rho GTPases are accompanied by the pronounced actin-based membrane structures such as lamellipodia and filopodia, enhanced rate of actin turnover and cell polarisation. Together, our results reveal an important novel function for Dsg3 in promoting actin dynamics through regulating Rac1 and Cdc42 activation in epithelial cells.

Adducin Is Required for Desmosomal Cohesion in Keratinocytes

“…These data suggest that adducin controls keratinocyte cohesion specifically by regulating desmosomal Dsg3 levels. Previously, a direct interaction of Dsg3 and actin was demonstrated, however, in the non-cytoskeletal pool only and not in Dsg3 connected to the cytoskeleton (24). Nevertheless, a direct regulation of Dsg3 by adducin, i.e.…”

“…Moreover, for RhoA-mediated protection against autoantibody-induced loss of cell cohesion a requirement of cortical actin polymeri-zation has been demonstrated (23). Concomitantly, a recent study reported a direct association of Dsg3 with actin and its involvement in actin dynamics (24).…”

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.…”

“…RhoA is inhibited in response to pemphigus autoantibodies in p38MAPK-dependent manner and activation of this GTPase blocked blister formation and enhanced insertion of keratin 14 at cell junctions (Waschke, 2008). Recently, RhoA, Rac1, and Cdc42 were shown to directly bind to Dsg3, at least in the non-desmosomal fraction, further indicating that the desmosomal cadherins regulate Rho GTPases (Tsang et al, 2012a). Keratin retraction downstream of p38MAPK is dependent on EGF-R activation, (Figure 1) (Bektas et al, 2013).…”

“…As membranes initially separate between desmosomes in response to pemphigus autoantibodies (Schulze al., 2012;Takahashi et al, 1985), it may be concluded that extradesmosomal molecules are necessary for maintaining cell adhesion. Additionally, these molecules may be relevant for intracellular signaling, because some signaling molecules such as active Rho GTPases are specifi cally coupled to extradesmosomal Dsg3 (Tsang et al, 2012a).…”