title: Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1.
abstract: Ikaros encodes a zinc finger protein that is involved in gene regulation and chromatin remodeling. The majority of Ikaros localizes at pericentromeric heterochromatin (PC-HC) where it regulates expression of target genes. Ikaros function is controlled by posttranslational modification. Phosphorylation of Ikaros by CK2 kinase determines its ability to bind DNA and exert cell cycle control as well as its subcellular localization. We report that Ikaros interacts with protein phosphatase 1 (PP1) via a conserved PP1 binding motif, RVXF, in the C-terminal end of the Ikaros protein. Point mutations of the RVXF motif abolish Ikaros-PP1 interaction and result in decreased DNA binding, an inability to localize to PC-HC, and rapid degradation of the Ikaros protein. The introduction of alanine mutations at CK2-phosphorylated residues increases the half-life of the PP1-nonbinding Ikaros mutant. This suggests that dephosphorylation of these sites by PP1 stabilizes the Ikaros protein and prevents its degradation. In the nucleus, Ikaros forms complexes with ubiquitin, providing evidence that Ikaros degradation involves the ubiquitin/proteasome pathway. In vivo, Ikaros can target PP1 to the nucleus, and a fraction of PP1 colocalizes with Ikaros at PC-HC. These data suggest a novel function for the Ikaros protein; that is, the targeting of PP1 to PC-HC and other chromatin structures. We propose a model whereby the function of Ikaros is controlled by the CK2 and PP1 pathways and that a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation.
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108.
authors.forename: Marcela
authors.initials: M
authors.lastname: Popescu
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108.
authors.forename: Zafer
authors.initials: Z
authors.lastname: Gurel
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108.
authors.forename: Tapani
authors.initials: T
authors.lastname: Ronni
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108.
authors.forename: Ka Ying
authors.initials: KY
authors.lastname: Hung
authors.affiliation: Center for Health Disparities and Molecular Medicine and Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, California 92350.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792-4108. Electronic address: dovat@wisc.edu.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002503:Centromere / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000502:physiology; D017354:Point Mutation; D011485:Protein Binding / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
chemical_list: C497239:IKZF1 protein, human; D025801:Ubiquitin; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D004247:DNA; D054645:Protein Phosphatase 1