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Frontiers in Biology

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ISSN 1674-7992(Online)

CN 11-5892/Q

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Front. Biol.    2015, Vol. 10 Issue (3) : 203-220    https://doi.org/10.1007/s11515-015-1343-5
REVIEW
Regulation of Hedgehog signaling by ubiquitination
Elaine Y. C. Hsia,Yirui Gui,Xiaoyan Zheng()
Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA
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Abstract

The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.
Keywords Hedgehog signaling      ubiquitination     
Corresponding Author(s): Xiaoyan Zheng   
Just Accepted Date: 06 January 2015   Online First Date: 04 February 2015    Issue Date: 23 June 2015
 Cite this article:   
Elaine Y. C. Hsia,Yirui Gui,Xiaoyan Zheng. Regulation of Hedgehog signaling by ubiquitination[J]. Front. Biol., 2015, 10(3): 203-220.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1343-5
https://academic.hep.com.cn/fib/EN/Y2015/V10/I3/203
Fig.1  Regulation of Hedgehog signaling by ubiquitination. (A) In Drosophila, dPtc localized at the plasma membrane suppresses dSmo activity in the absence of Hh. An unknown E3 ligase (E3?) promotes internalization and degradation of dSmo. Sufu sequesters full-length Ci (CiFL) in the cytoplasm and protects CiFL from spurious Cul3-HIB-mediated degradation. CiFL is also targeted by Cul1-Slimb for partial degradation to the repressor form CiR leading to repression of pathway target genes. Nuclear export of the spliceosome factor Crn by an unknown substrate (S) allows functional Sufu mRNA to be translated. (B) Hh binding to dPtc releases its inhibition on dSmo. UBPY/USP8 reverses dSmo ubiquitination and promotes dSmo accumulation at the plasma membrane, although this can also occur in the absence of Hh. Activated dSmo recruits Smurf to the plasma membrane where Smurf mediates the internalization and degradation of dPtc. Cul1-Slimb-mediated CiR formation is inhibited, allowing for formation of the activator form CiA and activation of pathway target genes including hib. HIB functions in a negative feedback manner by promoting the degradation of CiFL. Cul3-HIB also targets the unknown substrate S for degradation, allowing Crn to accumulate in the nucleus where it inhibits formation of functional Sufu mRNA and leads to reduced Sufu protein synthesis. (C) In vertebrates, in the absence of Hh ligands, Ptch1 suppresses activation of vSmo, which is internalized and degraded by an unknown E3 ligase. Sufu protects full-length Gli2 and Gli3 (GliFL) from Cul3-Spop-mediated degradation. Sufu also promotes the partial degradation of GliFL to GliR by Cul1-βTrCP. (D) In the presence of Hh ligands, Ptch1 is internalized and degraded by Smurf1/2. An unknown deubiquitinase (DUB) decreases vSmo ubiquitination and degradation. Sufu is degraded in a Cul3-Spop-dependent manner, and GliR formation by Cul1-βTrCP is inhibited, allowing for GliA formation.
Hh pathway component Regulation E3 ligase-adaptor complex Ub Lys linkage Deubiquitinase Outcome of ubiquitination Reference
Ptc Unknown Smurf K48, K63 Unknown Complete degradation* Huang et al., 2013,
(dPtc, Ptch1) poly-ubiquitination Endocytosis Yue et al., 2014
dPtc Unknown Nedd4 Unknown Unknown Complete degradation Formstecher et al., 2005
Lu et al., 2006
Ptch1 Unknown Itchy Unknown Unknown Complete degradation and endocytosis Chen et al., 2014
Smo Inhibited by PKA and CK1 Unknown K48 USP8 Complete degradation Li et al., 2012
(dSmo, vSmo) dependent phosphorylation multi-mono and Endocytosis Xia et al., 2012
poly-ubiquitination Yang et al., 2013
Fan et al., 2013
Sufu Inhibited by PKA and GSK3 Unknown K48 mono- and Unknown Complete degradation Yue et al., 2009
dependent phosphorylation poly-ubiquitination Chen et al., 2011b
Indirect through Crn Cul3-HIB/SPOP Unknown Unknown Inhibit Sufu mRNA translation Liu et al., 2014a
Ci Promoted by PKA, GSK3, Cul1-Slimb/βTrCP K11, K48 Unknown Partial degradation** Jiang and Struhl, 1998
and CKI dependent Jia et al., 2002
phosphorylation Price and Kalderon, 2002
Ou et al., 2002
Jia et al., 2005
Smelkinson and Kalderon, 2006
Zhang et al., 2013
HIB expression induced by Cul3-HIB/SPOP K48 Unknown Complete degradation Ou et al., 2002
activated Hh signaling Zhang et al., 2006
Kent et al., 2006
Gli1 Unknown Itchy Unknown Complete degradation Di Marcotullio et al., 2006
Genotoxic stress via p53 PCAF Mazza et al., 2013
Unknown Cul2-Fem1b K48 Gilder et al., 2013
Gli2 PKA, GSK3, and CK1 Cul1-Slimb/βTrCP Unknown Partial degradation Pan et al., 2006
dependent phosphorylation
Gli3 PKA, GSK3, and CK1 Cul1-Slimb/βTrCP Unknown Partial degradation Wang and Li, 2006
dependent phosphorylation Tempe et al., 2006
Gli1, Gli2 Promoted by PKA, GSK3β, Cul1-Slimb/βTrCP Unknown Complete degradation Bhatia,et al., 2006
and CK1 dependent phosphorylation Huntzicker et al., 2006
Indirect through HDAC Cul3-KCASH Inhibits deacetylation and activation of Gli1 Canettieri et al., 2010
and Gli2 De Smaele et al., 2011
Gli2, Gli3 Induced by activated Hh Cul3-HIB/SPOP Unknown Complete degradation Zhang et al., 2006a
signaling Chen et al., 2009
Wang et al., 2010
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