GSDM Research Highlighted in Nature Chemical Biology
Work from Associate Dean for Research Dr. Maria Kukuruzinska’s laboratory has unveiled a link between the canonical Wnt/beta-catenin signaling pathway and protein N-glycosylation by showing that the first N-glycosylation gene, DPAGT1, is a target of the Wnt/beta-catenin signaling pathway. Under conditions of Wnt activation, DPAGT1 transcription is upregulated though the binding of beta-catenin to Tcf at the TCF/LEF binding site in the DPAGT1promoter. The Wnt-dependent upregulation of DPAGT1 expression, in turn, leads to more extensive modification of E-cadherin, a major epithelial cell-cell adhesion receptor, with complex N-glycans, previously shown to be inhibitory to cell-cell adhesion. Thus, DPAGT1 coordinates pro-proliferative effects of Wnt/beta-catenin signaling with suppression of intercellular adhesion. Moreover, since Wnt ligands require N-glycosylation for activity and since DPAGT1 determines the N-glycosylation status of proteins, the Wnt/beta-catenin pathway is also DPAGT1-dependent, indicating that there is a positive feedback loop between Wnt signaling and the metabolic pathway of protein N-glycosylation. Although to date, at least 80 target genes of Wnt/beta-catenin signaling have been identified, this is the first demonstration that a gene involved in cellular metabolism is a downstream target of Wnt/β-catenin signaling.
“Our findings are particularly significant,” said Dr. Kukuruzinska, “because both Wnt signaling and protein N-glycosylation play pivotal roles in development and differentiation, and their dysregulation has a strong association with cancer. The understanding that there is interdependence between these pathways provides a molecular explanation for many previously reported observations showing correlations between Wnt signaling and N-glycosylation.”
Dr. Kukuruzinska completed this research with assistance from Research Associate Dr. Pritam Sengupta and Technical Assistant Ms. Meghan Bouchie. The paper titled “N-glycosylation Gene DPAGT1 is a Target of the Wnt/beta-catenin Signaling Pathway,” was published in the Journal of Biological Chemistry on August 6 and also highlighted in the Research Highlights section of the October 2010 edition of Nature Chemical Biology.