PAK1 interacts with beta-catenin and is required for the regulation of the beta-catenin signalling pathway by gastrins

Biochim Biophys Acta. 2008 Oct;1783(10):1943-54. doi: 10.1016/j.bbamcr.2008.04.016. Epub 2008 May 3.


Beta-catenin regulates cell-cell adhesion by binding to E-cadherin at the cell membrane and, when translocated into the nucleus, mediates signalling by activation of transcription factors such as TCF4. Mutations of the components of the Wnt/beta-catenin pathway are found in many gastrointestinal cancers. Gastrins, including amidated (Gamide) and glycine-extended (Ggly) gastrin(17), stimulate the proliferation of gastrointestinal cancer cells. Gastrins also regulate beta-catenin signalling through multiple pathways which seem to converge on p21-activated kinase 1 (PAK1). In this study, we have investigated the role of PAK1 in the regulation of beta-catenin signalling by gastrins. Here we report for the first time that PAK1 associated with beta-catenin. Both Gamide and Ggly stimulated the phosphorylation and activation of beta-catenin in a PAK1-dependent manner. A kinase-inactive mutant PAK1(K299A) blocked the gastrin-stimulated dissociation of beta-catenin from E-cadherin, translocation of beta-catenin from the cell membrane to the nucleus, and association of beta-catenin with the transcription factor TCF4. The PAK1(K299A) mutant also inhibited the stimulation of the expression of c-myc and cyclin D1, and of cell proliferation and migration, by gastrins. The results indicate that gastrins regulate beta-catenin signalling through a PAK1-dependent pathway. PAK1 seems to be the point of convergence of multiple signalling pathways activated by gastrins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cadherins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclin D1 / metabolism
  • Gastrins / pharmacology*
  • Gene Expression Regulation
  • Mice
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction / drug effects*
  • TCF Transcription Factors / metabolism
  • Transcription Factor 4
  • beta Catenin / metabolism*
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cadherins
  • Gastrins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-myc
  • TCF Transcription Factors
  • Tcf4 protein, mouse
  • Transcription Factor 4
  • beta Catenin
  • Cyclin D1
  • p21-Activated Kinases