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

• Published in: The Journal of biological chemistry 2014-06, Vol.289 (24), p.17043-17053
• Main Authors: Hartlieb, Eva, Rötzer, Vera, Radeva, Mariya, Spindler, Volker, Waschke, Jens
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion; Cell Biology; Cell Line; Cytoskeleton - metabolism; Desmoglein 2 - genetics; Desmoglein 2 - metabolism; Desmoglein 3 - genetics; Desmoglein 3 - metabolism; Desmosome; Desmosomes - metabolism; Humans; Keratinocyte; Keratinocytes - metabolism; Keratinocytes - physiology; Mice; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Pemphigus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.489336

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 coexpressed. We have shown previously that Dsg2 is less important for keratinocyte cohesion compared with Dsg3 and that the latter forms a complex with p38 MAPK. In this study, we compared the involvement of Dsg2 and Dsg3 in the p38 MAPK-dependent regulation of keratinocyte cohesion. We show that loss of cell adhesion and keratin filament retraction induced by Dsg3 depletion is ameliorated by specific p38 MAPK inhibition. Furthermore, in contrast to depletion of Dsg2, siRNA-mediated silencing of Dsg3 induced p38 MAPK activation, which is in line with immunoprecipitation experiments demonstrating the interaction of activated p38 MAPK 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 p38 MAPK is predominantly detectable. Moreover, because loss of cell adhesion by Dsg3 depletion was partially rescued by p38 MAPK inhibition, we conclude that, besides its function as an adhesion molecule, Dsg3 is strengthening cell cohesion via modulation of p38 MAPK-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. Background: The roles of the adhesion molecules desmoglein (Dsg) 2 and Dsg3 for keratinocyte adhesion and signaling are poorly understood. Results: Dsg2 compensates for Dsg3 depletion with regard to cell cohesion, but, in contrast to Dsg3, does not regulate p38 MAPK signaling. Conclusion: Dsg2 and Dsg3 contribute differently to cell adhesion and signaling pathways. Significance: The results demonstrate unique functions of different Dsgs expressed in the same cells.