Serine/threonine‐protein kinase D2‐mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression

Abstract

Desmoglein‐2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell–cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine‐protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2‐T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2‐mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

Dsg2 truncation causes a lethal barrier breakdown in mice

“…These data indicate that Dsg molecules can regulate expression of inflammatory molecules including S100A8 and S100A9, which were here found to be up-regulated in both Dsg2-truncation mice and CD patients and are known to be involved in IBD pathogenesis 29 42 . In this context it is important that both S100A8 and S100A9 were found very recently to interact with Dsg2 which provides a functional link between Dsg2 and regulation of inflammation 43 . Finally, it is interesting that the immune signature of Dsg1-deficient mice was to some extent comparable to psoriasis patients 26 .…”