Journal article
The Antagonistic Action of B56-containing Protein Phosphatase 2As and Casein Kinase 2 Controls the Phosphorylation and Gli Turnover Function of Daz Interacting Protein 1
The Journal of biological chemistry, Vol.286(42), pp.36171-36179
10/21/2011
DOI: 10.1074/jbc.M111.274761
PMCID: PMC3196143
PMID: 21878643
Abstract
Background:
The stability of Gli proteins is important for the outcome of Hedgehog signaling.
Results:
Dzip1 is involved in a novel Gli turnover mechanism. This function of Dzip1 is regulated by CK2 and PP2A-dependent reversible phosphorylation.
Conclusion:
The antagonistic action of PP2A and CK2 controls the phosphorylation and Gli turnover function of Dzip1.
Significance:
Our studies have identified a novel Gli regulatory mechanism.
The Hedgehog (Hh) pathway is evolutionarily conserved and plays critical roles during embryonic development and adult tissue homeostasis. Defective Hh signaling has been linked to a wide range of birth defects and cancers. Hh family proteins regulate the expression of their downstream target genes through the control of proteolytic processing and the transcriptional activation function of Gli transcription factors. Although Hh-dependent regulation of Gli has been studied extensively, other Gli regulatory mechanisms remain relatively unappreciated. Here we report our identification of a novel signaling cascade that controls the stability of Gli proteins. This cascade consists of Daz interacting protein 1 (Dzip1), casein kinase 2 (CK2), and B56 containing protein phosphatase 2As (PP2As). We provide evidence that Dzip1 is involved in a novel Gli turnover pathway. We show that CK2 directly phosphorylates Dzip1 at four serine residues, Ser-664/665/706/714. B56-containing PP2As, through binding to a domain located between amino acid residue 474 and 550 of Dzip1, dephosphorylate Dzip1 on these CK2 sites. Our mutagenesis analysis further demonstrates that the unphosphorylatable form of Dzip1 is more potent in promoting Gli turnover. Consistently, we found that the stability of Gli proteins was decreased upon CK2 inhibition and increased by inhibition of B56-containing PP2As. Thus, reversible phosphorylation of Dzip1, which is controlled by the antagonistic action of CK2 and B56-containing PP2As, has an important impact on the stability of Gli transcription factors and Hh signaling.
Details
- Title: Subtitle
- The Antagonistic Action of B56-containing Protein Phosphatase 2As and Casein Kinase 2 Controls the Phosphorylation and Gli Turnover Function of Daz Interacting Protein 1
- Creators
- Zhigang JinWenyan MeiStefan StrackJianhang JiaJing Yang
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.286(42), pp.36171-36179
- DOI
- 10.1074/jbc.M111.274761
- PMID
- 21878643
- PMCID
- PMC3196143
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- R01GM093217; 1R01GM079684 / National Institutes of Health
- Alternative title
- Phosphorylation of Dzip1 and Gli Turnover
- Language
- English
- Date published
- 10/21/2011
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040540102771
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