- Although AGS cells do not express functional E-cadherin, Helicobacter pylori can still modulate β-catenin signaling in these cells through E-cadherin–independent mechanisms.
- In typical epithelial cells, β-catenin is sequestered at the cell membrane by E-cadherin, limiting its availability for nuclear signaling. However, in AGS cells where E-cadherin is absent, β-catenin is more freely distributed in the cytoplasm and nucleus. This altered localization makes AGS cells especially suitable for studying Wnt/β-catenin signaling activation.
- Upon infection with CagA-expressing H. pylori strains, AGS cells exhibit enhanced β-catenin nuclear accumulation and transcriptional activity, despite lacking membrane-bound E-cadherin. This effect is primarily mediated through phosphorylation-independent pathways.
- For example, CagA can activate upstream kinases such as PI3K and AKT, which in turn inhibit GSK3β—a kinase responsible for marking β-catenin for proteasomal degradation. As a result, β-catenin becomes stabilized and translocates to the nucleus, where it interacts with TCF/LEF transcription factors to promote the expression of target genes such as c-MYC, cyclin D1, and CDX1. These genes are associated with increased cellular proliferation and features of intestinal metaplasia, contributing to the early stages of gastric epithelial transformation.
- Importantly, these changes occur without the need for E-cadherin disruption, highlighting that CagA has context-specific effects depending on the cell type. In the case of AGS cells, where β-catenin is already unanchored due to the absence of E-cadherin, CagA further pushes β-catenin toward a signaling-active state. This makes AGS a valuable model for dissecting E-cadherin–independent oncogenic signaling driven by CagA.
