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

Abstract

The canonical Wnt/β-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 α5-dependent manner. PAK4 interacts with and phosphorylates β-catenin on Ser675, which promotes the TCF/LEF transcriptional activity and stabilizes β-catenin through inhibition of its degradation. Moreover, nuclear import of PAK4 accompanies with the nuclear import of β-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 β-catenin.

P21‐Activated Kinase 4 Regulates the Cyclin‐Dependent Kinase Inhibitor P57Kip2 in Human Breast Cancer

“…Our previous study showed that nuclear PAK4 promotes b-cateninmediated gene expression including c-Myc (Li et al, 2012). In the present study, our results suggested that PAK4 enhanced p57 Kip2 protein degradation via ubiquitin-proteasome system in breast cancer cells.…”

The p21-activated kinase Mbt is a component of the apical protein complex in central brain neuroblasts and controls cell proliferation

“…Yet PAK proteins are known to affect the actin and microtubule cytoskeleton via a number of effector pathways (reviewed by Arias-Romero and Chernoff, 2008;Eswaran et al, 2008;Wells and Jones, 2010). β-Catenin and its Drosophila homolog Armadillo, proteins that are also associated with the cytoskeleton, were recently identified as binding partners and phosphorylation substrates of PAK proteins (He and Baldwin, 2008;Menzel et al, 2008;Li et al, 2012). However, we did not observe significant changes in the localization patterns of F-actin ( Fig.…”

PAK6 targets to cell-cell adhesions via its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape

“…However, Cdc42 binding is not sufficient for cell-cell adhesion targeting and we find that a polybasic region, just N-terminal to the Cdc42-binding region, is also required. This polybasic region has previously been characterized as a membrane-binding domain in yeast PAK (Takahashi and Pryciak, 2007) and a nuclear localization signal in mammalian PAK4 (Li et al, 2012). Notably, we demonstrate that disruption of cell-cell adhesion targeting impairs the ability of PAK6 to drive epithelial cell colony escape.…”

“…This is further corroborated by reports that the polybasic regions of the yeast ortholog STE20 bind lipids (Takahashi and Pryciak, 2007), which could potentially aid in kinase interactions with the membrane. The PAK4 polybasic region has previously been characterized as a nuclear localization signal (Li et al, 2012), but in the context of cell-cell adhesion localization, we propose that the membrane-binding role is likely to be the most relevant.…”