title: 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.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yangguang
authors.initials: Y
authors.lastname: Shao
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Tong
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Gu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D028901:alpha Karyopherins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D028901:alpha Karyopherins; D051176:beta Catenin; D054462:p21-Activated Kinases; D000097606:Exportin 1 Protein