Phosphorylation of α-and ß-catenin by ALR through EGF-Receptor dependent mechanisms may results in disruption of cell-cells contacts

The liver is known for its remarkable regenerative capacity, primarily regulated by various factors, notably Augmenter of Liver Regeneration (ALR) and ß-catenin. ALR, has anti-oxidative, anti-apoptotic and anti-inflammatory properties and plays a pivotal role for hepatic functionality. ß-catenin is the key nuclear effector of canonical Wnt signaling and, in addition, serves as integral structural component of cadherin-based adherens junctions. ß-catenin may be released from membrane bound E-cadherin upon activation of EGF receptor (EGFR) followed by specific phosphorylation of α- and ß-catenin (catenin-complex). Since ALR can activate EGFR, this study aims to analyze the impact of recombinant ALR (rALR) on membrane-bound ß-catenin phosphorylation and its underlying signaling pathways. Hepatoma cell lines (HepG2, Huh7) were treated with rALR or EGF, and specific inhibitors of signal transduction pathways, followed by western blotting analysis. Application of rALR results in phosphorylation of ß-catenin at Y654 and S552, as well as α-catenin at S641. Phosphorylation of α-catenin at S641 is mediated by activation of ERK1/2 and ß-catenin at S552 by activation of PI3K/Akt signaling pathways – both downstream effectors of EGFR activation. Furthermore, rALR can activate src, a non-receptor tyrosin kinase, known to activate the EGFR and directly phosphorylate ß-catenin at Y654. Taken together, rALR activates EGFR tyrosine kinase by phosphorylation of EGFR at specific sites, which in turn activates src, MAPK and PI3/Akt pathways. Therefore, as reported for EGF earlier, rALR can lead to phosphorylation of α- and ß-catenin and their dissociation from E-cadherin-complex, loss of cell-cell contacts and nuclear translocation of ß-catenin.

Publication History

Article published online:
23 January 2024