A novel bidirectional positive feedback loop between Wnt/ -catenin and EGFR/ERK: role of context-specific signalling crosstalk in modulating epithelial tissue regeneration

摘要

By operating as both a subunit of the cadherin complex and a key component of Wnt signalling, β-catenin constitutes the lynchpin between cell:cell contact and transcriptional regulation of proliferation to co-ordinate epithelial tissue homeostasis and regeneration. Integration of multiple growth-regulatory inputs with β-catenin signalling has been observed in cancer-derived cells, yet the existence of pathway cross-talk in normal cells is unknown. Using a highly-regenerative normal human epithelial culture system that displays contact-inhibition, we demonstrate that the RTK-driven MAPK and Wnt/β-catenin signalling axes form a bidirectional positive-feedback loop to drive cellular proliferation. We show that β-catenin both drives and is regulated by proliferative signalling cues and its down-regulation coincides with the switch from proliferation to contact-inhibited quiescence. We reveal a novel contextual interrelationship whereby positive and negative feedback between three major signalling pathways EGFR/ERK, PI3K/AKT and Wnt/β-catenin enable autocrine-regulated tissue homeostasis as an emergent property of physical interactions between cells. Our work has direct implications for normal epithelial tissue homeostasis and provides insight as to how dysregulation of these pathways may drive excessive and sustained cellular growth in disease.