title: Y654 of β-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β-catenin.
abstract: β-Catenin plays a dual role as a key effecter in the regulation of adherens junctions as well as a transcriptional co-activator. Tyrosine phosphorylation of β-catenin affects the cell adhesion, migration, and gene transcription in many types of human cancer cells, including acute myeloid leukemia cells with FLT3 internal tandem duplication (FLT3/ITD-AML). Here, we investigated the relationship between three tyrosine residues (Y86, Y142, and Y654) in β-catenin and oncogenic FLT3/ITD kinase. In the experiments using COS-7 cells expressing FLT3/ITD and Wt or mutant β-catenin, FLT3/ITD phosphorylated Y654, and this residue was essential for β-catenin's nuclear localization by FLT3/ITD. Promoter-reporter assays demonstrated that Y654 phosphorylation of β-catenin was closely related to TCF transcriptional activity. In vitro kinase assays, using recombinant FLT3 and biotinylated β-catenin peptide including Y654 showed that FLT3 directly phosphorylated Y654 of β-catenin. These results explain how FLT3/ITD affects the tyrosine phosphorylation, nuclear localization, and transcriptional activity of β-catenin. Targeting Y654 phosphorylation may lead to the development of novel approaches to therapy for FLT3/ITD-AML.
authors: Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.tomokaji@med.nagoya-u.ac.jp
authors: Tomohiro
authors: T
authors: Kajiguchi
authors: Akira
authors: A
authors: Katsumi
authors: Ryohei
authors: R
authors: Tanizaki
authors: Hitoshi
authors: H
authors: Kiyoi
authors: Tomoki
authors: T
authors: Naoe
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D010766:Phosphorylation; D014158:Transcription, Genetic; D014443:Tyrosine / Q000737:chemistry*; D051176:beta Catenin / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D014443:Tyrosine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3