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

Biochem J. 2021 Apr 30;478(8):1605-1615. doi: 10.1042/BCJ20200862.


The presence of adherens junctions and the associated protein β-catenin are requirements for the development of glucose-stimulated insulin secretion (GSIS) in β-cells. Evidence indicates that modulation of β-catenin function in response to changes in glucose levels can modulate the levels of insulin secretion from β-cells but the role of β-catenin phosphorylation in this process has not been established. We find that a Ser552Ala version of β-catenin attenuates glucose-stimulated insulin secretion indicating a functional role for Ser552 phosphorylation of β-catenin in insulin secretion. This is associated with alterations F/G actin ratio but not the transcriptional activity of β-catenin. Both glucose and GLP-1 stimulated phosphorylation of the serine 552 residue on β-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 β-catenin Ser552 and the effects of these on insulin secretion in β-cell models. Furthermore, both the EPAC inhibitor ESI-09 and the PAK1 inhibitor IPA3 do the same in both β-cell models and mouse islets. Together this identifies phosphorylation of β-catenin at Ser552 as part of a cell signalling mechanism linking nutrient and hormonal regulation of β-catenin to modulation of insulin secretory capacity of β-cells and indicates this phosphorylation event is regulated downstream of EPAC and PAK1 in β-cells.

Keywords: actin cytoskeleton; insulin secretion; p21-activated kinases; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Animals
  • Cell Line, Transformed
  • Disulfides / pharmacology
  • Gene Expression Regulation
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucose / metabolism
  • Glucose / pharmacology
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Hydrazones / pharmacology
  • Insulin / genetics*
  • Insulin / metabolism
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Isoxazoles / pharmacology
  • Male
  • Mice
  • Naphthols / pharmacology
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Signal Transduction
  • Tissue Culture Techniques
  • beta Catenin / genetics*
  • beta Catenin / metabolism
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / genetics*
  • p21-Activated Kinases / metabolism


  • 3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile
  • Actins
  • CTNNB1 protein, mouse
  • Disulfides
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Hydrazones
  • IPA-3 compound
  • Insulin
  • Isoxazoles
  • Naphthols
  • Protein Isoforms
  • RNA, Small Interfering
  • beta Catenin
  • Glucagon-Like Peptide 1
  • Pak1 protein, mouse
  • p21-Activated Kinases
  • Glucose