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Title: PAK1 interacts with beta-catenin and is required for the regulation of the beta-catenin signalling pathway by gastrins.
Austin Authors: He, Hong ;Shulkes, Arthur;Baldwin, Graham S
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Studley Road, Heidelberg, Melbourne, Victoria 3084, Australia
Issue Date: 3-May-2008
Publication information: Biochimica Et Biophysica Acta 2008; 1783(10): 1943-54
Abstract: 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.
Gov't Doc #: 18515095
DOI: 10.1016/j.bbamcr.2008.04.016
Type: Journal Article
Subjects: Active Transport, Cell Nucleus
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cell Line
Cell Nucleus.metabolism
Cyclin D1.metabolism
Gene Expression Regulation
Nerve Tissue Proteins.metabolism
Protein Binding
Proto-Oncogene Proteins c-myc.metabolism
Signal Transduction.drug effects
TCF Transcription Factors.metabolism
beta Catenin.metabolism
p21-Activated Kinases.genetics.metabolism
Appears in Collections:Journal articles

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