Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1

Marcela Popescu, Zafer Gurel, Tapani Ronni, Chunhua Song, Ka Ying Hung, Kimberly J. Payne, Sinisa Dovat

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13869-13880
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number20
DOIs
StatePublished - May 15 2009

Fingerprint

Protein Phosphatase 1
Ikaros Transcription Factor
Heterochromatin
Ubiquitin
Degradation
Chromatin
Signal transduction
Phosphorylation
Chromatin Assembly and Disassembly
DNA
Zinc Fingers
Proteasome Endopeptidase Complex
Post Translational Protein Processing
Cell Cycle Checkpoints
Point Mutation
Gene expression
Alanine
Half-Life
Zinc
Signal Transduction

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Popescu, Marcela ; Gurel, Zafer ; Ronni, Tapani ; Song, Chunhua ; Hung, Ka Ying ; Payne, Kimberly J. ; Dovat, Sinisa. / Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 20. pp. 13869-13880.
@article{5ac94212fe9549cbb33d8b30e7f51504,
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.",
author = "Marcela Popescu and Zafer Gurel and Tapani Ronni and Chunhua Song and Hung, {Ka Ying} and Payne, {Kimberly J.} and Sinisa Dovat",
year = "2009",
month = "5",
day = "15",
doi = "10.1074/jbc.M900209200",
language = "English (US)",
volume = "284",
pages = "13869--13880",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "20",

}

Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. / Popescu, Marcela; Gurel, Zafer; Ronni, Tapani; Song, Chunhua; Hung, Ka Ying; Payne, Kimberly J.; Dovat, Sinisa.

In: Journal of Biological Chemistry, Vol. 284, No. 20, 15.05.2009, p. 13869-13880.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1

AU - Popescu, Marcela

AU - Gurel, Zafer

AU - Ronni, Tapani

AU - Song, Chunhua

AU - Hung, Ka Ying

AU - Payne, Kimberly J.

AU - Dovat, Sinisa

PY - 2009/5/15

Y1 - 2009/5/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67649405070&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649405070&partnerID=8YFLogxK

U2 - 10.1074/jbc.M900209200

DO - 10.1074/jbc.M900209200

M3 - Article

C2 - 19282287

AN - SCOPUS:67649405070

VL - 284

SP - 13869

EP - 13880

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 20

ER -