A manuscript published online November 23, 2012, in the Journal of Cell Science presents new insights into the mechanisms that control epithelial cell behavior as discovered by Dr. Maria Kukuruzinska’s laboratory in the GSDM Department of Molecular & Cell Biology. The research identifies the DPAGT1 gene as a regulator of canonical Wnt signaling and E-cadherin adhesion through positive and negative feedback loops and suggests that DPAGT1 may—at least in vitro—function as an oncogene (a gene that has the potential to cause cancer).
Dr. Kukuruzinska’s laboratory previously showed that the DPAGT1/canonical Wnt signaling loop is unusually amplified in oral cancer. This new research suggests that even a modest increase in DPAGT1 expression leads to a much greater amplification of canonical Wnt signaling and a substantial inhibition of E-cadherin adhesion. This is associated with a dramatic shift from an epithelial to a mesenchymal morphology.
Researchers have shown that the highly conserved metabolic pathway of protein N-glycosylation functions in an interactive network with the canonical Wnt signaling pathway and E-cadherin-mediated cell-cell adhesion. Through this network, cells adjust proliferation in response to density information and achieve functional maturity by establishing stable E-cadherin-mediated cell-cell junctions.
The N-glycosylation pathway is initiated by the DPAGT1 gene, which regulates the extent of N-glycosylation and the quality of N-glycan structures. DPAGT1 is a target of the canonical Wnt signaling pathway, which plays a prominent role in regulating cell proliferation and cell fate. DPAGT1 regulates canonical Wnt signaling by affecting the N-glycosylation status, activity, and localization of Wnt ligands and co-receptors. By controlling the N-glycosylation of E-cadherin, a major epithelial cell-cell adhesion receptor and regulator of cell polarity and survival, DPAGT1 regulates the molecular organization of E-cadherin junctional complexes, thus impacting their adhesive functions. In turn, DPAGT1 and canonical Wnt are antagonized by E-cadherin via a mechanism that involves the depletion of transcriptionally active b- and g-catenins. Moreover, N-glycosylation affects the ability of E-cadherin to antagonize canonical Wnt signaling and DPAGT1 expression.
The authors of the manuscript, “Coordinate regulation of N-glycosylation gene DPAGT1, canonical Wnt signaling and E-cadherin adhesion,” are Pritam K. Sengupta, Meghan P. Bouchie, Mihai Nita-Lazar, Hsiao-Ying Yang, and Maria A. Kukuruzinska.