Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2011 Oct 21;28642:36171-9. doi: 10.1074/jbc.M111.274761.
Show Gene links
Show Anatomy links
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.
???displayArticle.abstract???
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.
Aza-Blanc,
Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
1997, Pubmed
Aza-Blanc,
Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor.
1997,
Pubmed
Chen,
Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved.
2009,
Pubmed
Di Marcotullio,
Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination.
2006,
Pubmed
Di Marcotullio,
Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal.
2011,
Pubmed
Glazer,
The Zn finger protein Iguana impacts Hedgehog signaling by promoting ciliogenesis.
2010,
Pubmed
Hannus,
Planar cell polarization requires Widerborst, a B' regulatory subunit of protein phosphatase 2A.
2002,
Pubmed
Haycraft,
Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function.
2005,
Pubmed
Huangfu,
Cilia and Hedgehog responsiveness in the mouse.
2005,
Pubmed
Huntzicker,
Dual degradation signals control Gli protein stability and tumor formation.
2006,
Pubmed
,
Xenbase
Ingham,
Hedgehog signaling in animal development: paradigms and principles.
2001,
Pubmed
Jia,
PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation.
2009,
Pubmed
Jia,
Casein kinase 2 promotes Hedgehog signaling by regulating both smoothened and Cubitus interruptus.
2010,
Pubmed
Jiang,
Hedgehog signaling in development and cancer.
2008,
Pubmed
Jin,
The 48-kDa alternative translation isoform of PP2A:B56epsilon is required for Wnt signaling during midbrain-hindbrain boundary formation.
2009,
Pubmed
,
Xenbase
Jin,
PP2A:B56{epsilon}, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development.
2010,
Pubmed
,
Xenbase
Kent,
Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus.
2006,
Pubmed
Kim,
Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish.
2010,
Pubmed
Krauss,
Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3.
2008,
Pubmed
Krauss,
Point mutations in GLI3 lead to misregulation of its subcellular localization.
2009,
Pubmed
Li,
B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster.
2002,
Pubmed
Liu,
Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors.
2005,
Pubmed
Lum,
The Hedgehog response network: sensors, switches, and routers.
2004,
Pubmed
May,
Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli.
2005,
Pubmed
McMahon,
Developmental roles and clinical significance of hedgehog signaling.
2003,
Pubmed
Nybakken,
A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway.
2005,
Pubmed
Pan,
Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation.
2006,
Pubmed
Rorick,
PP2A:B56epsilon is required for eye induction and eye field separation.
2007,
Pubmed
,
Xenbase
Saraf,
Differential expression of the B'beta regulatory subunit of protein phosphatase 2A modulates tyrosine hydroxylase phosphorylation and catecholamine synthesis.
2007,
Pubmed
Sasaki,
A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro.
1997,
Pubmed
,
Xenbase
Sekimizu,
The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling.
2004,
Pubmed
Silverstein,
Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits.
2002,
Pubmed
Strack,
Critical role for protein phosphatase 2A heterotrimers in mammalian cell survival.
2004,
Pubmed
Stubbs,
Radial intercalation of ciliated cells during Xenopus skin development.
2006,
Pubmed
,
Xenbase
Tay,
The iguana/DZIP1 protein is a novel component of the ciliogenic pathway essential for axonemal biogenesis.
2010,
Pubmed
Van Kanegan,
Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt.
2005,
Pubmed
Virshup,
From promiscuity to precision: protein phosphatases get a makeover.
2009,
Pubmed
Vokes,
Hedgehog signaling: iguana debuts as a nuclear gatekeeper.
2004,
Pubmed
Wang,
Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors.
2010,
Pubmed
Wang,
Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb.
2000,
Pubmed
,
Xenbase
Wolff,
iguana encodes a novel zinc-finger protein with coiled-coil domains essential for Hedgehog signal transduction in the zebrafish embryo.
2004,
Pubmed
Yang,
hnRNP I inhibits Notch signaling and regulates intestinal epithelial homeostasis in the zebrafish.
2009,
Pubmed
,
Xenbase
Yang,
Functions of B56-containing PP2As in major developmental and cancer signaling pathways.
2010,
Pubmed
Yang,
PP2A:B56epsilon is required for Wnt/beta-catenin signaling during embryonic development.
2003,
Pubmed
,
Xenbase
Zhang,
A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor.
2006,
Pubmed
Zhang,
Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase.
2009,
Pubmed
