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

Abstractβ-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/β-catenin pathway are found in many gastrointestinal cancers. Gastrins, including amidated (Gamide) and glycine-extended (Ggly) gastrin17, stimulate the proliferation of gastrointestinal cancer cells. Gastrins also regulate β-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 β-catenin signalling by gastrins. Here we report for the first time that PAK1 associated with β-catenin. Both Gamide and Ggly stimulated the phosphorylation and activation of β-catenin in a PAK1-dependent manner. A kinase-inactive mutant PAK1K299A blocked the gastrin-stimulated dissociation of β-catenin from E-cadherin, translocation of β-catenin from the cell membrane to the nucleus, and association of β-catenin with the transcription factor TCF4. The PAK1K299A 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 β-catenin signalling through a PAK1-dependent pathway. PAK1 seems to be the point of convergence of multiple signalling pathways activated by gastrins