Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling

The canonical Wnt/beta-catenin signaling pathway plays a central role in development and cancer. The p21-activated kinase 4 (PAK4) involves in a wide range of cellular processes, including cytoskeletal reorganization, cell proliferation, gene transcription and oncogenic transformation. However, the cross talk between the Wnt and PAK4 signaling pathways is poorly understood. Here, we show that PAK4 is a nucleo-cytoplasmic shuttling protein, containing three nuclear export signals (NESS) and two nuclear localization signals (NLSs). PAK4 is exported by the chromosome region maintenance-1 (CRM-1)-dependent pathway and is imported into the nucleus in an importin alpha 5-dependent manner. PAK4 interacts with and phosphorylates beta-catenin on Ser675, which promotes the TCF/LEF transcriptional activity and stabilizes beta-catenin through inhibition of its degradation. Moreover, nuclear import of PAK4 accompanies with the nuclear import of beta-catenin and increased TCF/LEF transcriptional activity. We further demonstrated that PAK4 associates with the TCF/LEF transcriptional complex by ChIP assays. These findings uncover a novel role for PAK4 in modulating intracellular translocation and signaling of beta-catenin. (C) 2011 Elsevier B.V. All rights reserved.