title: Phosphorylation of FOXP3 by LCK downregulates MMP9 expression and represses cell invasion.
abstract: Forkhead Box P3 (FOXP3) is a member of the forkhead/winged helix family of the transcription factors and plays an important role not only as a master gene in T-regulatory cells, but also as a tumor suppressor. In this study, we identified lymphocyte-specific protein tyrosine kinase (LCK), which correlates with cancer malignancy, as a binding partner of FOXP3. FOXP3 downregulated LCK-induced MMP9, SKP2, and VEGF-A expression. We observed that LCK phosphorylated Tyr-342 of FOXP3 by immunoprecipitation and in vitro kinase assay, and the replacement of Tyr-342 with phenylalanine (Y342F) abolished the ability to suppress MMP9 expression. Although FOXP3 decreased the invasive ability induced by LCK in MCF-7 cells, Y342F mutation in FOXP3 diminished this suppressive effect. Thus we demonstrate for the first time that LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGF-A expression, and suppressed cellular invasion. We consider that further clarification of transcriptional mechanism of FOXP3 may facilitate the development of novel therapeutic approaches to suppress cancer malignancy.
authors.affiliation: Department of Developmental Medicine, Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakahira
authors.forename: Akihiro
authors.initials: A
authors.lastname: Morita
authors.forename: Nam-Soon
authors.initials: NS
authors.lastname: Kim
authors.forename: Itaru
authors.initials: I
authors.lastname: Yanagihara
mesh_terms: D000595:Amino Acid Sequence; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D044786:S-Phase Kinase-Associated Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019000:Phosphotyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9