JNK inhibition enhances cell–cell adhesion impaired by desmoglein 3 gene disruption in keratinocytes

c-Jun NH 2 -terminal protein kinase (JNK) and p38 are stress-activated mitogen-activated protein kinases (MAPK) that are phosphorylated by various stimuli. It has been reported that the loss of desmoglein (DSG) 3, a desmosomal transmembrane core molecule, in keratinocytes impairs cell–cell adhesion accompanied by p38 MAPK activation. To understand the biological role of DSG3 in desmosomes and its relationship with stress-activated MAPKs, we established DSG3 knockout keratinocytes (KO cells). Wild-type cells showed a linear localization of DSG1 to cell–cell contacts, whereas KO cells showed a remarkable reduction despite the increased protein levels of DSG1. Cell–cell adhesion in KO cells was impaired over time, as demonstrated by dispase-based dissociation assays. The linear localization of DSG1 to cell–cell contacts and the strength of cell–cell adhesion were promoted by the pharmacological inhibition of JNK. Conversely, pharmacological activation of JNK, but not p38 MAPK, in wild-type cells reduced the linear localization of DSG1 in cell–cell contacts. Our data indicate that DSG1 and DSG2 in KO cells cannot compensate for the attenuation of cell–cell adhesion strength caused by DSG3 deficiency and that JNK inhibition restores the strength of cell–cell adhesion by increasing the linear localization of DSG1 in cell–cell contacts in KO cells. Inhibition of JNK signaling may improve cell–cell adhesion in diseases in which DSG3 expression is impaired.