title: Ikaros, CK2 kinase, and the road to leukemia.
abstract: Ikaros encodes a zinc finger protein that is essential for hematopoiesis and that acts as a tumor suppressor in leukemia. Ikaros function depends on its ability to localize to pericentromeric-heterochromatin (PC-HC). Ikaros protein binds to the upstream regulatory elements of target genes, aids in their recruitment to PC-HC, and regulates their transcription via chromatin remodeling. We identified four novel Ikaros phosphorylation sites that are phosphorylated by CK2 kinase. Using Ikaros phosphomimetic and phosphoresistant mutants of the CK2 phosphorylation sites, we demonstrate that (1) CK2-mediated phosphorylation inhibits Ikaros' localization to PC-HC; (2) dephosphorylation of Ikaros at CK2 sites increases its binding to the promoter of the terminal deoxynucleotidetransferase (TdT) gene, leading to TdT repression during thymocyte differentiation; and (3) hyperphosphorylation of Ikaros promotes its degradation by the ubiquitin/proteasome pathway. We show that Ikaros is dephosphorylated by Protein Phosphatase 1 (PP1) via interaction at a consensus PP1-binding motif, RVXF. Point mutations that abolish Ikaros-PP1 interaction result in functional changes in DNA-binding affinity and subcellular localization, similar to those observed in hyperphosphorylated Ikaros and/or Ikaros phosphomimetic mutants. Phosphoresistant Ikaros mutations at CK2 sites restored Ikaros' DNA-binding activity and localization to PC-HC and prevented accelerated Ikaros degradation. These results demonstrate the role of CK2 kinase in lymphocyte differentiation and in regulation of Ikaros' function, and suggest that CK2 promotes leukemogenesis by inhibiting the tumor suppressor activity of Ikaros. We propose a model whereby a balance between CK2 kinase and PP1 phosphatase is essential for normal lymphocyte differentiation and for the prevention of malignant transformation.
authors.affiliation: Department of Pediatrics, H085, Division of Pediatric, Hematology/Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA. sdovat@hmc.psu.edu
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D051740:Ikaros Transcription Factor; D047390:Casein Kinase II