Desmoglein 3-Dependent Signaling Regulates Keratinocyte Migration and Wound Healing

Abstract

The desmosomal transmembrane adhesion molecules desmoglein 3 (Dsg3) and desmocollin 3 (Dsc3) are required for strong keratinocyte cohesion. Recently, we have shown that Dsg3 associates with p38MAPK and suppresses its activity. Here, we further investigated the role of Dsg3-dependent control of p38MAPK function. Dsg3-deficient mice display recurrent spontaneously healing skin erosions. In lesional and perilesional biopsies, p38MAPK activation was detectable compared to control animals. This led us to speculate that Dsg3 regulates wound repair in a p38MAPK-dependent manner. Indeed, scratch wounded keratinocyte monolayers exhibited p38MAPK activation and loss of Dsg3 in cells lining the wound edge. Human keratinocytes after silencing of Dsg3 as well as primary cells isolated from Dsg3 knockout animals exhibited accelerated migration, which was further corroborated in an ex vivo skin outgrowth assay. Importantly, migration was efficiently blocked by inhibition of p38MAPK, indicating that p38MAPK mediates the effects observed upon loss of Dsg3. In line with this, we show that levels of active p38MAPK associated with Dsc3 are increased in Dsg3-deficient cells. These data indicate that Dsg3 controls a switch from an adhesive to a migratory keratinocyte phenotype via p38MAPK inhibition. Thus, loss of Dsg3 adhesion may foster wound closure by allowing p38MAPK-dependent migration.Journal of Investigative Dermatology accepted article preview online, 30 September 2015. doi:10.1038/jid.2015.380.

Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells

“…Thus, we suggest a novel pathway in which loss of Dsg2 triggers canonical MAPK signaling which in turn promotes migration due to reduced levels of PG. Because loss of cell‐cell cohesion by inducing a scratch wound is sufficient to activate pERK, it is conceivable that Dsg2 acts as a sensor for loss of adhesion in pancreatic cancer cells as it was proposed for Dsg3 in keratinocytes . In this model, Dsg2 by suppressing ERK activity keeps pancreatic cancer cells in an adhesive, quiescent state.…”

“…Because loss of cell-cell cohesion by inducing a scratch wound is sufficient to activate pERK, it is conceivable that Dsg2 acts as a sensor for loss of adhesion in pancreatic cancer cells as it was proposed for Dsg3 in keratinocytes. 54 In this model, Dsg2 by suppressing ERK activity keeps pancreatic cancer cells in an adhesive, quiescent state. To our knowledge, no Dsg2 and only few PG variants were associated with epithelial cancers so far.…”

Microwave‐Assisted Syntheses of Benzimidazole‐Containing Selenadiazole Derivatives That Induce Cell‐Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway

“…Wound‐healing migration assay : According to a published method with minor modification, 1×10 5 MDA‐MB‐231 cells were plated into 60 mm dishes for 48 h to achieve 80 % confluency. A wound on the confluent monolayer was created by scratching the monolayer with a yellow Gilson d200 pipette tip.…”

Pemphigus Autoantibodies Induce Blistering in Human Conjunctiva

“…14,24 Further, some of the mice have an eye involvement, 14 which to our knowledge has not been characterized before. In our study, approximately half (43%) of Dsg3 KO mice showed eye symptoms during the observation period, such as reddened conjunctiva, small bleedings at the inner corner of the eye, and clotted eyelids ( Fig.…”

“…4A, 4B; arrows). We previously observed p38MAPK activation in the skin of Dsg3 KO animals 24 and, thus, investigated the activation of p38MAPK and MK2 in eyes of Dsg3 WT and KO mice. Activation of p38MAPK and less pronounced of MK2 was observed in Dsg3 KO animals, whereas no change of the total protein expression was detectable (Fig.…”