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

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.

Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma.

Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.