Research Article A role for PAK1 mediated phosphorylation of β-catenin Ser552 in the regulation of insulin secretion

The presence of adherens junctions and the associated protein 0-catenin are requirements for the development of glucose-stimulated insulin secretion (GSIS) in 0-cells. Evidence indicates that modulation of 0-catenin function in response to changes in glucose levels can modulate the levels of insulin secretion from 0-cells but the role of 0-catenin phosphorylation in this process has not been established. We find that a Ser552Ala version of 0-catenin attenuates glucose-stimulated insulin secretion indicating a functional role for Ser552 phosphorylation of 0-catenin in insulin secretion. This is associated with alterations F/G actin ratio but not the transcriptional activity of 0-catenin. Both glucose and GLP-1 stimulated phosphorylation of the serine 552 residue on 0-catenin. We investigated the possibility that an EPAC-PAK1 pathway might be involved in this phosphorylation event. We find that reduction in PAK1 levels using siRNA attenuates both glucose and GLP-1 stimulated phosphorylation of 0-catenin Ser552 and the effects of these on insulin secretion in 0-cell models. Furthermore, both the EPAC inhibitor ESI09 and the PAK1 inhibitor IPA3 do the same in both 0-cell models and mouse islets. Together this identifies phosphorylation of 0-catenin at Ser552 as part of a cell signalling mechanism linking nutrient and hormonal regulation of 0-catenin to modulation of insulin secretory capacity of 0-cells and indicates this phosphorylation event is regulated downstream of EPAC and PAK1 in 0-cells.

Automated summary

Research shows that adherens junctions and the protein 0-catenin play crucial roles in glucose-stimulated insulin secretion in 0-cells, with Ser552 phosphorylation of 0-catenin being key to its function. Both glucose and GLP-1 can stimulate phosphorylation of 0-catenin at Ser552, with modulation of insulin secretion being regulated downstream of EPAC and PAK1 pathways.