Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 20, Pages 13869-13880Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M900209200
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Funding
- National Institutes of Health [T32 HL07899, K12 CA 087718, 5K01 DK066163, K22 CA 111392]
- University of Wisconsin Institute for Clinical and Translational Research through National Institutes of Health Clinical and Translational Science Award [1UL1RR025011]
- Midwest Athletes Against Childhood Cancer Award
- St. Baldrick's Foundation Career Development
- University of Wisconsin Medical Education and Research Committee New Investigator Program
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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-non-binding 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.
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