Desmoglein 2 compensates for desmoglein 3 but does not control cell adhesion via regulation of p38-mitogen-activated protein-kinase in keratinocytes [Molecular Bases of Disease]

May 2nd, 2014 by Hartlieb, E., Rotzer, V., Radeva, M., Spindler, V., Waschke, J.

Desmosomal cadherins are transmembrane adhesion molecules that provide cell adhesion by interacting in the intercellular space of adjacent cells. In keratinocytes, several desmoglein (Dsg1-4) and desmocollin (Dsc1-3) isoforms are co-expressed. We have previously shown that Dsg2 is less important for keratinocyte cohesion compared to Dsg3 and that the latter forms a complex with p38 mitogen-activated protein kinase (p38MAPK). In the present study, we compared the involvement of Dsg2 and Dsg3 in p38MAPK-dependent regulation of keratinocyte cohesion. We show that loss of cell adhesion and keratin filament retraction induced by Dsg3-depletion is ameliorated by specific p38MAPK inhibition. Furthermore, in contrast to depletion of Dsg2, siRNA-mediated silencing of Dsg3 induced p38MAPK activation, which is in line with immunoprecipitation experiments demonstrating interaction of activated p38MAPK with Dsg3 but not with Dsg2. Cell fractionation into a cytoskeleton-unbound and a cytoskeleton-anchored desmosome-containing pool revealed that Dsg3 in contrast to Dsg2 is present in relevant amounts in the unbound pool in which activated p38MAPK is predominantly detectable. Moreover, because loss of cell adhesion by Dsg3 depletion was partially rescued by p38MAPK inhibition, we conclude that, besides its function as an adhesion molecule, Dsg3 is strengthening cell cohesion via modulation of p38MAPK-dependent keratin filament reorganization. Nevertheless, because subsequent targeting of Dsg3 in Dsg2-depleted cells led to drastically enhanced keratinocyte dissociation and Dsg2 was enhanced at the membrane in Dsg3 knockout cells, we conclude that Dsg2 compensates for Dsg3 loss of function.
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