Skip to main content
SpringerLink
Log in

Regulation of Hedgehog signaling by ubiquitination

  • Review
  • Published:
Frontiers in Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Agyeman A, Mazumdar T, Houghton J A (2012). Regulation of DNA damage following termination of Hedgehog (HH) survival signaling at the level of the GLI genes in human colon cancer. Oncotarget, 3(8): 854–868

    PubMed  Google Scholar 

  • Allen B L, Song J Y, Izzi L, Althaus IW, Kang J S, Charron F, Krauss R S, McMahon A P (2011). Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell, 20(6): 775–787

    CAS  PubMed Central  PubMed  Google Scholar 

  • Apionishev S, Katanayeva N M, Marks S A, Kalderon D, Tomlinson A (2005). Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Nat Cell Biol, 7(1): 86–92

    CAS  PubMed  Google Scholar 

  • Aza-Blanc P, Lin H Y, Ruiz i Altaba A, Kornberg T B (2000). Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities. Development, 127(19): 4293–4301

    PubMed  Google Scholar 

  • Aza-Blanc P, Ramírez-Weber F A, Laget M P, Schwartz C, Kornberg T B (1997). Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell, 89(7): 1043–1053

    CAS  PubMed  Google Scholar 

  • Bai C B, Auerbach W, Lee J S, Stephen D, Joyner A L (2002). Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development, 129(20): 4753–4761

    CAS  PubMed  Google Scholar 

  • Bai C B, Stephen D, Joyner A L (2004). All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell, 6(1): 103–115

    CAS  PubMed  Google Scholar 

  • Barakat B, Yu L, Lo C, Vu D, De Luca E, Cain J E, Martelotto L G, Dedhar S, Sadler A J, Wang D, Watkins D N, Hannigan G E (2013). Interaction of smoothened with integrin-linked kinase in primary cilia mediates Hedgehog signalling. EMBO Rep, 14(9): 837–844

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baumeister W, Walz J, Zühl F, Seemüller E (1998). The proteasome: paradigm of a self-compartmentalizing protease. Cell, 92(3): 367–380

    CAS  PubMed  Google Scholar 

  • Beachy P A, Hymowitz S G, Lazarus R A, Leahy D J, Siebold C (2010). Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev, 24(18): 2001–2012

    CAS  PubMed Central  PubMed  Google Scholar 

  • Beachy P A, Karhadkar S S, Berman DM (2004). Tissue repair and stem cell renewal in carcinogenesis. Nature, 432(7015): 324–331

    CAS  PubMed  Google Scholar 

  • Bhatia N, Thiyagarajan S, Elcheva I, Saleem M, Dlugosz A, Mukhtar H, Spiegelman V S (2006). Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem, 281(28): 19320–19326

    CAS  PubMed  Google Scholar 

  • Bitgood MJ, Shen L, McMahon AP. 1996. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol, 6(3): 298–304

    CAS  PubMed  Google Scholar 

  • Briscoe J, Chen Y, Jessell TM, Struhl G (2001). A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol Cell, 7(6): 1279–1291

    CAS  PubMed  Google Scholar 

  • Briscoe J, Thérond P P (2013). The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol, 14(7): 416–429

    PubMed  Google Scholar 

  • Buttitta L, Mo R, Hui C C, Fan C M (2003). Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Development, 130(25): 6233–6243

    CAS  PubMed  Google Scholar 

  • Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, Pelloni M, De Simone G, Pedone E M, Gallinari P, Giorgi A, Steinkühler C, Vitagliano L, Pedone C, Schinin M E, Screpanti I, Gulino A (2010). Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol, 12(2): 132–142

    CAS  PubMed  Google Scholar 

  • Capdevila J, Estrada M P, Sánchez-Herrero E, Guerrero I (1994a). The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development. EMBO J, 13(1): 71–82

    CAS  PubMed Central  PubMed  Google Scholar 

  • Capdevila J, Pariente F, Sampedro J, Alonso J L, Guerrero I (1994b). Subcellular localization of the segment polarity protein patched suggests an interaction with the wingless reception complex in Drosophila embryos. Development, 120(4): 987–998

    CAS  PubMed  Google Scholar 

  • Chen C H, von Kessler D P, Park W, Wang B, Ma Y, Beachy P A (1999). Nuclear trafficking of Cubitus interruptus in the transcriptional regulation of Hedgehog target gene expression. Cell, 98(3): 305–316

    CAS  PubMed  Google Scholar 

  • Chen MH, Wilson CW, Li Y J, Law K K, Lu C S, Gacayan R, Zhang X, Hui C C, Chuang P T (2009). Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev, 23(16): 1910–1928

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen X L, Chinchilla P, Fombonne J, Ho L, Guix C, Keen J H, Mehlen P, Riobo N A (2014). Patched-1 proapoptotic activity is downregulated by modification of K1413 by the E3 ubiquitin-protein ligase Itchy homolog. Mol Cell Biol, 34(20): 3855–3866

    PubMed Central  PubMed  Google Scholar 

  • Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J (2011a). Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol, 9(6): e1001083

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen Y, Struhl G (1996). Dual roles for patched in sequestering and transducing Hedgehog. Cell, 87(3): 553–563

    CAS  PubMed  Google Scholar 

  • Chen Y, Yue S, Xie L, Pu X H, Jin T, Cheng S Y (2011b). Dual phosphorylation of suppressor of fused (Sufu) by PKA and GSK3β regulates its stability and localization in the primary cilium. J Biol Chem, 286(15): 13502–13511

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen Z J (2012). Ubiquitination in signaling to and activation of IKK. Immunol Rev, 246(1): 95–106

    PubMed Central  PubMed  Google Scholar 

  • Cheng S Y, Bishop J M (2002). Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci U S A, 99(8): 5442–5447

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chiang C, Litingtung Y, Lee E, Young K E, Corden J L, Westphal H, Beachy P A (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature, 383(6599): 407–413

    CAS  PubMed  Google Scholar 

  • Cooper A F, Yu K P, Brueckner M, Brailey L L, Johnson L, McGrath J M, Bale A E (2005). Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development, 132(19): 4407–4417

    CAS  PubMed  Google Scholar 

  • Corbit K C, Aanstad P, Singla V, Norman A R, Stainier D Y, Reiter J F (2005). Vertebrate Smoothened functions at the primary cilium. Nature, 437(7061): 1018–1021

    CAS  PubMed  Google Scholar 

  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S (1999). Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem, 274(12): 8143–8152

    CAS  PubMed  Google Scholar 

  • De Smaele E, Di Marcotullio L, Moretti M, Pelloni M, Occhione M A, Infante P, Cucchi D, Greco A, Pietrosanti L, Todorovic J, Coni S, Canettieri G, Ferretti E, Bei R, Maroder M, Screpanti I, Gulino A (2011). Identification and characterization of KCASH2 and KCASH3, 2 novel Cullin3 adaptors suppressing histone deacetylase and Hedgehog activity in medulloblastoma. Neoplasia, 13(4): 374–385

    PubMed Central  PubMed  Google Scholar 

  • Denef N, Neubüser D, Perez L, Cohen S M (2000). Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Cell, 102(4): 521–531

    CAS  PubMed  Google Scholar 

  • Deshaies R J (1999). SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol, 15(1): 435–467

    CAS  PubMed  Google Scholar 

  • Dessaud E, Yang L L, Hill K, Cox B, Ulloa F, Ribeiro A, Mynett A, Novitch B G, Briscoe J (2007). Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature, 450(7170): 717–720

    CAS  PubMed  Google Scholar 

  • Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Po A, Sico M A, Alimandi M, Giannini G, Maroder M, Screpanti I, Gulino A (2006). Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol, 8(12): 1415–1423

    PubMed  Google Scholar 

  • Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Screpanti I, Gulino A (2007). Multiple ubiquitin-dependent processing pathways regulate hedgehog/gli signaling: implications for cell development and tumorigenesis. Cell Cycle, 6(4): 390–393

    PubMed  Google Scholar 

  • Di Marcotullio L, Greco A, Mazzà D, Canettieri G, Pietrosanti L, Infante P, Coni S, Moretti M, De Smaele E, Ferretti E, Screpanti I, Gulino A (2011). Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal. Oncogene, 30(1): 65–76

    PubMed  Google Scholar 

  • Ding Q, Fukami S, Meng X, Nishizaki Y, Zhang X, Sasaki H, Dlugosz A, Nakafuku M, Hui CC (1999). Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol, 9(19): 1119–1122

    CAS  PubMed  Google Scholar 

  • Ding Q, Motoyama J, Gasca S, Mo R, Sasaki H, Rossant J, Hui C C (1998). Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development, 125(14): 2533–2543

    CAS  PubMed  Google Scholar 

  • Fan J, Jiang K, Liu Y, Jia J (2013). Hrs promotes ubiquitination and mediates endosomal trafficking of smoothened in Drosophila hedgehog signaling. PLoS One, 8(11): e79021

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fan J, Liu Y, Jia J (2012). Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner. Dev Biol, 366(2): 172–184

    CAS  PubMed Central  PubMed  Google Scholar 

  • Finley D (2009). Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem, 78(1): 477–513

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fombonne J, Bissey P A, Guix C, Sadoul R, Thibert C, Mehlen P (2012). Patched dependence receptor triggers apoptosis through ubiquitination of caspase-9. Proc Natl Acad Sci U S A, 109(26): 10510–10515

    CAS  PubMed Central  PubMed  Google Scholar 

  • Formstecher E, Aresta S, Collura V, Hamburger A, Meil A, Trehin A, Reverdy C, Betin V, Maire S, Brun C, Jacq B, Arpin M, Bellaiche Y, Bellusci S, Benaroch P, Bornens M, Chanet R, Chavrier P, Delattre O, Doye V, Fehon R, Faye G, Galli T, Girault J A, Goud B, de Gunzburg J, Johannes L, Junier M P, Mirouse V, Mukherjee A, Papadopoulo D, Perez F, Plessis A, Rossé C, Saule S, Stoppa-Lyonnet D, Vincent A, White M, Legrain P, Wojcik J, Camonis J, Daviet L (2005). Protein interaction mapping: a Drosophila case study. Genome Res, 15(3): 376–384

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gilder A S, Chen Y B, Jackson R J 3rd, Jiang J, Maher J F (2013). Fem1b promotes ubiquitylation and suppresses transcriptional activity of Gli1. Biochem Biophys Res Commun, 440(3): 431–436

    CAS  PubMed  Google Scholar 

  • Goetz S C, Anderson K V (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet, 11(5): 331–344

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goodrich L V, Johnson R L, Milenkovic L, McMahon J A, Scott M P (1996). Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev, 10(3): 301–312

    CAS  PubMed  Google Scholar 

  • Goodrich L V, Milenković L, Higgins K M, Scott M P (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science, 277(5329): 1109–1113

    CAS  PubMed  Google Scholar 

  • Gradilla A C, Guerrero I (2013). Hedgehog on the move: a precise spatial control of Hedgehog dispersion shapes the gradient. Curr Opin Genet Dev, 23(4): 363–373

    CAS  PubMed  Google Scholar 

  • Guerrero I, Chiang C (2007). A conserved mechanism of Hedgehog gradient formation by lipid modifications. Trends Cell Biol, 17(1): 1–5

    CAS  PubMed  Google Scholar 

  • Gulino A, Di Marcotullio L, Canettieri G, De Smaele E, Screpanti I (2012). Hedgehog/Gli control by ubiquitination/acetylation interplay. Vitam Horm, 88: 211–227

    CAS  PubMed  Google Scholar 

  • Haglund K, Dikic I (2005). Ubiquitylation and cell signaling. EMBO J, 24(19): 3353–3359

    CAS  PubMed Central  PubMed  Google Scholar 

  • Harfe B D, Scherz P J, Nissim S, Tian H, McMahon A P, Tabin C J (2004). Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell, 118(4): 517–528

    CAS  PubMed  Google Scholar 

  • Haycraft C J, Banizs B, Aydin-Son Y, Zhang Q, Michaud E J, Yoder B K (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet, 1(4): e53

    PubMed Central  PubMed  Google Scholar 

  • Hayer A, Stoeber M, Ritz D, Engel S, Meyer H H, Helenius A (2010). Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation. J Cell Biol, 191(3): 615–629

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hershko A, Ciechanover A (1998). The ubiquitin system. Annu Rev Biochem, 67(1): 425–479

    CAS  PubMed  Google Scholar 

  • Hu J, Wittekind S G, Barr M M (2007). STAM and Hrs down-regulate ciliary TRP receptors. Mol Biol Cell, 18(9): 3277–3289

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang K, Diener D R, Rosenbaum J L (2009). The ubiquitin conjugation system is involved in the disassembly of cilia and flagella. J Cell Biol, 186(4): 601–613

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang S, Zhang Z, Zhang C, Lv X, Zheng X, Chen Z, Sun L, Wang H, Zhu Y, Zhang J, Yang S, Lu Y, Sun Q, Tao Y, Liu F, Zhao Y, Chen D (2013). Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover. PLoS Biol, 11(11): e1001721

    PubMed Central  PubMed  Google Scholar 

  • Huangfu D, Anderson K V (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A, 102(32): 11325–11330

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huangfu D, Anderson K V (2006). Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development, 133(1): 3–14

    CAS  PubMed  Google Scholar 

  • Hui C C, Angers S (2011). Gli proteins in development and disease. Annu Rev Cell Dev Biol, 27(1): 513–537

    CAS  PubMed  Google Scholar 

  • Humke E W, Dorn K V, Milenkovic L, Scott M P, Rohatgi R (2010). The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev, 24(7): 670–682

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huntzicker E G, Estay I S, Zhen H, Lokteva L A, Jackson P K, Oro A E (2006). Dual degradation signals control Gli protein stability and tumor formation. Genes Dev, 20(3): 276–281

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ingham P W, Fietz M J (1995). Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing. Curr Biol, 5(4): 432–440

    CAS  PubMed  Google Scholar 

  • Ingham P W, Nakano Y, Seger C (2011). Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet, 12(6): 393–406

    CAS  PubMed  Google Scholar 

  • Izzi L, Lévesque M, Morin S, Laniel D, Wilkes B C, Mille F, Krauss R S, McMahon A P, Allen B L, Charron F (2011). Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell, 20(6): 788–801

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jackson P K, Eldridge A G, Freed E, Furstenthal L, Hsu J Y, Kaiser B K, Reimann J D R (2000). The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol, 10(10): 429–439

    CAS  PubMed  Google Scholar 

  • Jékely G, Rørth P (2003). Hrs mediates downregulation of multiple signalling receptors in Drosophila. EMBO Rep, 4(12): 1163–1168

    PubMed Central  PubMed  Google Scholar 

  • Jeong J, McMahon A P (2005). Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development, 132(1): 143–154

    CAS  PubMed  Google Scholar 

  • Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J (2002). Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature, 416(6880): 548–552

    CAS  PubMed  Google Scholar 

  • Jia J, Tong C, Wang B, Luo L, Jiang J (2004). Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature, 432(7020): 1045–1050

    CAS  PubMed  Google Scholar 

  • Jia J, Zhang L, Zhang Q, Tong C, Wang B, Hou F, Amanai K, Jiang J (2005). Phosphorylation by double-time/CKIepsilon and CKIalpha targets cubitus interruptus for Slimb/β-TRCP-mediated proteolytic processing. Dev Cell, 9(6): 819–830

    CAS  PubMed  Google Scholar 

  • Jiang J (2006). Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle, 5(21): 2457–2463

    CAS  PubMed  Google Scholar 

  • Jiang J, Hui C C (2008). Hedgehog signaling in development and cancer. Dev Cell, 15(6): 801–812

    CAS  PubMed  Google Scholar 

  • Kawamura S, Hervold K, Ramirez-Weber F A, Kornberg T B (2008). Two patched protein subtypes and a conserved domain of group I proteins that regulates turnover. J Biol Chem, 283(45): 30964–30969

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kent D, Bush E W, Hooper J E (2006). Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus. Development, 133(10): 2001–2010

    CAS  PubMed  Google Scholar 

  • Kim J, Kato M, Beachy P A (2009). Gli2 trafficking links Hedgehogdependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A, 106(51): 21666–21671

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kise Y, Morinaka A, Teglund S, Miki H (2009). Sufu recruits GSK3beta for efficient processing of Gli3. Biochem Biophys Res Commun, 387(3): 569–574

    CAS  PubMed  Google Scholar 

  • Kogerman P, Grimm T, Kogerman L, Krause D, Undén A B, Sandstedt B, ToftgÃ¥rd R, Zaphiropoulos P G (1999). Mammalian suppressor-offused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol, 1(5): 312–319

    CAS  PubMed  Google Scholar 

  • Koudijs MJ, den Broeder M J, Keijser A, Wienholds E, Houwing S, van Rooijen EM, Geisler R, van Eeden F J (2005). The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. PLoS Genet, 1(2): e19

    PubMed Central  PubMed  Google Scholar 

  • Kovacs J J, Whalen E J, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz R J (2008). Beta-arrestin-mediated localization of smoothened to the primary cilium. Science, 320(5884): 1777–1781

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee J D, Amanai K, Shearn A, Treisman J E (2002). The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms. Development, 129(24): 5697–5706

    CAS  PubMed  Google Scholar 

  • Lee TA, Tyers M (2001). Ubiquitin junction, what’s your function? Genome Biol, 2(10): reports 4025.1–4025.3

    Google Scholar 

  • Li S, Chen Y, Shi Q, Yue T, Wang B, Jiang J (2012). Hedgehogregulated ubiquitination controls smoothened trafficking and cell surface expression in Drosophila. PLoS Biol, 10(1): e1001239

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu A, Wang B, Niswander L A (2005). Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development, 132(13): 3103–3111

    CAS  PubMed  Google Scholar 

  • Liu C, Zhou Z, Yao X, Chen P, Sun M, Su M, Chang C, Yan J, Jiang J, Zhang Q (2014a). Hedgehog signaling downregulates suppressor of fused through the HIB/SPOP-Crn axis in Drosophila. Cell Res, 24(5): 595–609

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Z, Li T, Reinhold MI, Naski MC (2014b). MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination. Oncogene, 33(1): 65–73

    PubMed  Google Scholar 

  • Lu X, Liu S, Kornberg T B (2006). The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover. Genes Dev, 20(18): 2539–2551

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lum L, Beachy P A (2004). The Hedgehog response network: sensors, switches, and routers. Science, 304(5678): 1755–1759

    CAS  PubMed  Google Scholar 

  • Marigo V, Davey R A, Zuo Y, Cunningham J M, Tabin C J (1996). Biochemical evidence that patched is the Hedgehog receptor. Nature, 384(6605): 176–179

    CAS  PubMed  Google Scholar 

  • Matise MP, Epstein D J, Park H L, Platt K A, Joyner A L (1998). Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development, 125(15): 2759–2770

    CAS  PubMed  Google Scholar 

  • May S R, Ashique A M, Karlen M, Wang B, Shen Y, Zarbalis K, Reiter J, Ericson J, Peterson A S (2005). 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. Dev Biol, 287(2): 378–389

    CAS  PubMed  Google Scholar 

  • Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A, Houghton J A (2011). Hedgehog signaling drives cellular survival in human colon carcinoma cells. Cancer Res, 71(3): 1092–1102

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mazzà D, Infante P, Colicchia V, Greco A, Alfonsi R, Siler M, Antonucci L, Po A, De Smaele E, Ferretti E, Capalbo C, Bellavia D, Canettieri G, Giannini G, Screpanti I, Gulino A, Di Marcotullio L (2013). PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress. Cell Death Differ, 20(12): 1688–1697

    PubMed Central  PubMed  Google Scholar 

  • McDermott A, Gustafsson M, Elsam T, Hui C C, Emerson C P Jr, Borycki A G (2005). Gli2 and Gli3 have redundant and contextdependent function in skeletal muscle formation. Development, 132(2): 345–357

    CAS  PubMed  Google Scholar 

  • McGlinn E, Tabin C J (2006). Mechanistic insight into how Shh patterns the vertebrate limb. Curr Opin Genet Dev, 16(4): 426–432

    CAS  PubMed  Google Scholar 

  • McLellan J S, Yao S, Zheng X, Geisbrecht B V, Ghirlando R, Beachy P A, Leahy D J (2006). Structure of a heparin-dependent complex of Hedgehog and Ihog. Proc Natl Acad Sci U S A, 103(46): 17208–17213

    CAS  PubMed Central  PubMed  Google Scholar 

  • Méthot N, Basler K (1999). Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell, 96(6): 819–831

    PubMed  Google Scholar 

  • Méthot N, Basler K (2000). Suppressor of fused opposes hedgehog signal transduction by impeding nuclear accumulation of the activator form of Cubitus interruptus. Development, 127(18): 4001–4010

    PubMed  Google Scholar 

  • Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, Corset V, Reed J C, Mehlen P (2009). The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nat Cell Biol, 11(6): 739–746

    CAS  PubMed Central  PubMed  Google Scholar 

  • Monnier V, Dussillol F, Alves G, Lamour-Isnard C, Plessis A. 1998. Suppressor of fused links fused and Cubitus interruptus on the hedgehog signalling pathway. Curr Biol, 8(10): 583–586

    CAS  PubMed  Google Scholar 

  • Motoyama J, Milenkovic L, Iwama M, Shikata Y, Scott M P, Hui C C (2003). Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev Biol, 259(1): 150–161

    CAS  PubMed  Google Scholar 

  • Nachury M V, Seeley E S, Jin H (2010). Trafficking to the ciliary membrane: how to get across the periciliary diffusion barrier? Annu Rev Cell Dev Biol, 26(1): 59–87

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nakano Y, Nystedt S, Shivdasani A A, Strutt H, Thomas C, Ingham PW (2004). Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila. Mech Dev, 121(6): 507–518

    CAS  PubMed  Google Scholar 

  • Nieuwenhuis E, Hui C C (2005). Hedgehog signaling and congenital malformations. Clin Genet, 67(3): 193–208

    CAS  PubMed  Google Scholar 

  • Nieuwenhuis E, Motoyama J, Barnfield P C, Yoshikawa Y, Zhang X, Mo R, Crackower M A, Hui C C (2006). Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia. Mol Cell Biol, 26(17): 6609–6622

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ohlmeyer J T, Kalderon D (1998). Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator. Nature, 396(6713): 749–753

    CAS  PubMed  Google Scholar 

  • Okada A, Charron F, Morin S, Shin D S, Wong K, Fabre P J, Tessier-Lavigne M, McConnell S K (2006). Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature, 444(7117): 369–373

    CAS  PubMed  Google Scholar 

  • Oshiumi H, Matsumoto M, Seya T (2012). Ubiquitin-mediated modulation of the cytoplasmic viral RNA sensor RIG-I. J Biochem, 151(1): 5–11

    CAS  PubMed  Google Scholar 

  • Ou C Y, Wang C H, Jiang J, Chien C T (2007). Suppression of Hedgehog signaling by Cul3 ligases in proliferation control of retinal precursors. Dev Biol, 308(1): 106–119

    CAS  PubMed  Google Scholar 

  • Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier M F (2004). The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. Biochem J, 378(Pt 2): 353–362

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pan Y, Wang C, Wang B (2009). Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev Biol, 326(1): 177–189

    CAS  PubMed Central  PubMed  Google Scholar 

  • Park H L, Bai C, Platt K A, Matise MP, Beeghly A, Hui C C, Nakashima M, Joyner A L (2000). Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development, 127(8): 1593–1605

    CAS  PubMed  Google Scholar 

  • Persson M, Stamataki D, te Welscher P, Andersson E, Böse J, Rüther U, Ericson J, Briscoe J (2002). Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev, 16(22): 2865–2878

    CAS  PubMed Central  PubMed  Google Scholar 

  • Petrova R, Joyner A L (2014). Roles for Hedgehog signaling in adult organ homeostasis and repair. Development, 141(18): 3445–3457

    CAS  PubMed  Google Scholar 

  • Pickart C M (2001). Mechanisms underlying ubiquitination. Annu Rev Biochem, 70(1): 503–533

    CAS  PubMed  Google Scholar 

  • Pickart CM (2004). Back to the future with ubiquitin. Cell, 116(2): 181–190

    CAS  PubMed  Google Scholar 

  • Pickart C M, Eddins M J (2004). Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta, 1695(1–3): 55–72

    CAS  PubMed  Google Scholar 

  • Polo S, Di Fiore P P (2006). Endocytosis conducts the cell signaling orchestra. Cell, 124(5): 897–900

    CAS  PubMed  Google Scholar 

  • Préat T (1992). Characterization of Suppressor of fused, a complete suppressor of the fused segment polarity gene of Drosophila melanogaster. Genetics, 132(3): 725–736

    PubMed Central  PubMed  Google Scholar 

  • Price M A, Kalderon D (2002). Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1. Cell, 108(6): 823–835

    CAS  PubMed  Google Scholar 

  • Quirin K, Eschli B, Scheu I, Poort L, Kartenbeck J, Helenius A (2008). Lymphocytic choriomeningitis virus uses a novel endocytic pathway for infectious entry via late endosomes. Virology, 378(1): 21–33

    CAS  PubMed  Google Scholar 

  • Rohatgi R, Milenkovic L, Corcoran R B, Scott M P (2009). Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A, 106(9): 3196–3201

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rohatgi R, Milenkovic L, Scott M P (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science, 317(5836): 372–376

    CAS  PubMed  Google Scholar 

  • Rohatgi R, Scott M P (2007). Patching the gaps in Hedgehog signalling. Nat Cell Biol, 9(9): 1005–1009

    CAS  PubMed  Google Scholar 

  • Sandvig K, Pust S, Skotland T, van Deurs B (2011). Clathrinindependent endocytosis: mechanisms and function. Curr Opin Cell Biol, 23(4): 413–420

    CAS  PubMed  Google Scholar 

  • Santos N, Reiter J F (2014). A central region of Gli2 regulates its localization to the primary cilium and transcriptional activity. J Cell Sci, 127(Pt 7): 1500–1510

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sasaki H, Nishizaki Y, Hui C, Nakafuku M, Kondoh H (1999). Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development, 126(17): 3915–3924

    CAS  PubMed  Google Scholar 

  • Scherz P J, McGlinn E, Nissim S, Tabin C J (2007). Extended exposure to Sonic hedgehog is required for patterning the posterior digits of the vertebrate limb. Dev Biol, 308(2): 343–354

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sigismund S, Polo S, Di Fiore P P (2004). Signaling through monoubiquitination. Curr Top Microbiol Immunol, 286: 149–185

    CAS  PubMed  Google Scholar 

  • Smelkinson MG, Kalderon D (2006). Processing of the Drosophila hedgehog signaling effector Ci-155 to the repressor Ci-75 is mediated by direct binding to the SCF component Slimb. Curr Biol, 16: 110–116

    CAS  PubMed  Google Scholar 

  • St-Jacques B, Hammerschmidt M, McMahon A P (1999). Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev, 13(16): 2072–2086

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stamataki D, Ulloa F, Tsoni S V, Mynett A, Briscoe J (2005). A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube. Genes Dev, 19(5): 626–641

    CAS  PubMed Central  PubMed  Google Scholar 

  • Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, ToftgÃ¥rd R, Teglund S (2006). Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell, 10(2): 187–197

    PubMed  Google Scholar 

  • Tabata T, Kornberg T B (1994). Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell, 76(1): 89–102

    CAS  PubMed  Google Scholar 

  • Taipale J, Beachy P A (2001). The Hedgehog and Wnt signalling pathways in cancer. Nature, 411(6835): 349–354

    CAS  PubMed  Google Scholar 

  • Teglund S, ToftgÃ¥rd R (2010). Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta, 1805(2): 181–208

    CAS  PubMed  Google Scholar 

  • Tempé D, Casas M, Karaz S, Blanchet-Tournier M F, Concordet J P (2006). Multisite protein kinase A and glycogen synthase kinase 3βphosphorylation leads to Gli3 ubiquitination by SCFβTrCP. Mol Cell Biol, 26(11): 4316–4326

    PubMed Central  PubMed  Google Scholar 

  • Tenzen T, Allen B L, Cole F, Kang J S, Krauss R S, McMahon A P (2006). The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell, 10(5): 647–656

    CAS  PubMed  Google Scholar 

  • Thibert C, Teillet M A, Lapointe F,, Mazelin L, Le Douarin N M, Mehlen P (2003). Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science, 301: 843–846

    CAS  PubMed  Google Scholar 

  • Torroja C, Gorfinkiel N, Guerrero I (2004). Patched controls the Hedgehog gradient by endocytosis in a dynamin-dependent manner, but this internalization does not play a major role in signal transduction. Development, 131(10): 2395–2408

    CAS  PubMed  Google Scholar 

  • Torroja C, Gorfinkiel N, Guerrero I (2005). Mechanisms of Hedgehog gradient formation and interpretation. J Neurobiol, 64(4): 334–356

    CAS  PubMed  Google Scholar 

  • Tukachinsky H, Lopez L V, Salic A (2010). A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol, 191(2): 415–428

    CAS  PubMed Central  PubMed  Google Scholar 

  • Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg H G, He WW, Ojala P, Taipale J (2008). Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell, 133(3): 537–548

    CAS  PubMed  Google Scholar 

  • Varjosalo M, Taipale J (2008). Hedgehog: functions and mechanisms. Genes Dev, 22(18): 2454–2472

    CAS  PubMed  Google Scholar 

  • Verma R, Deshaies R J (2000). A proteasome howdunit: the case of the missing signal. Cell, 101(4): 341–344

    CAS  PubMed  Google Scholar 

  • Voges D, Zwickl P, Baumeister W (1999). The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem, 68(1): 1015–1068

    CAS  PubMed  Google Scholar 

  • Wang B, Fallon J F, Beachy P A (2000a). Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell, 100(4): 423–434

    CAS  PubMed  Google Scholar 

  • Wang B, Li Y (2006). Evidence for the direct involvement of βTrCP in Gli3 protein processing. Proc Natl Acad Sci U S A, 103(1): 33–38

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang C, Pan Y, Wang B (2010). Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development, 137(12): 2001–2009

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang G, Amanai K, Wang B, Jiang J (2000b). Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus. Genes Dev, 14(22): 2893–2905

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang G, Tang X, Chen Y, Cao J, Huang Q, Ling X, Ren W, Liu S, Wu Y, Ray L, Lin X (2014). Hyperplastic discs differentially regulates the transcriptional outputs of hedgehog signaling. Mech Dev, 133: 117–125

    CAS  PubMed  Google Scholar 

  • Wang G, Wang B, Jiang J (1999). Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes Dev, 13(21): 2828–2837

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Q T, Holmgren R A (1999). The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels. Development, 126(22): 5097–5106

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhou Z, Walsh C T, McMahon A P (2009). Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci U S A, 106(8): 2623–2628

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weissman A M (2001). Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol, 2(3): 169–178

    CAS  PubMed  Google Scholar 

  • Wen X, Lai C K, Evangelista M, Hongo J A, de Sauvage F J, Scales S J (2010). Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol, 30(8): 1910–1922

    CAS  PubMed Central  PubMed  Google Scholar 

  • Williams R L, Urbé S (2007). The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol, 8(5): 355–368

    CAS  PubMed  Google Scholar 

  • Wilson C W, Chen M H, Chuang P T (2009). Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS One, 4(4): e5182

    PubMed Central  PubMed  Google Scholar 

  • Woelk T, Sigismund S, Penengo L, Polo S (2007). The ubiquitination code: a signalling problem. Cell Div, 2(1): 11

    PubMed Central  PubMed  Google Scholar 

  • Wolff C, Roy S, Ingham PW (2003). Multiple muscle cell identities induced by distinct levels and timing of hedgehog activity in the zebrafish embryo. Curr Biol, 13: 1169–1181

    CAS  PubMed  Google Scholar 

  • Xia R, Jia H, Fan J, Liu Y, Jia J (2012). USP8 promotes smoothened signaling by preventing its ubiquitination and changing its subcellular localization. PLoS Biol, 10(1): e1001238

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu P, Duong D M, Seyfried N T, Cheng D, Xie Y, Robert J, Rush J, Hochstrasser M, Finley D, Peng J (2009). Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell, 137(1): 133–145

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang X, Mao F, Lv X, Zhang Z, Fu L, Lu Y, Wu W, Zhou Z, Zhang L, Zhao Y (2013). Drosophila Vps36 regulates Smo trafficking in Hedgehog signaling. J Cell Sci, 126(Pt 18): 4230–4238

    CAS  PubMed  Google Scholar 

  • Yao S, Lum L, Beachy P (2006). The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell, 125(2): 343–357

    CAS  PubMed  Google Scholar 

  • Yue S, Chen Y, Cheng S Y (2009). Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitinproteasome pathway. Oncogene, 28(4): 492–499

    CAS  PubMed  Google Scholar 

  • Yue S, Tang LY, Tang Y, Tang Y, Shen QH, Ding J, Chen Y, Zhang Z, Yu TT, Zhang YE, Cheng S Y (2014). Requirement of Smurfmediated endocytosis of Patched1 in Sonic Hedgehog signal reception. eLife, 3: e02555

    PubMed Central  Google Scholar 

  • Zeng H, Jia J, Liu A (2010). Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS One, 5(12): e15900

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang C, Williams E H, Guo Y, Lum L, Beachy P A (2004). Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci U S A, 101(52): 17900–17907

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Q, Zhang L, Wang B, Ou C Y, Chien C T, Jiang J (2006a). A hedgehog-induced BTB protein modulates hedgehog signaling by degrading Ci/Gli transcription factor. Dev Cell, 10(6): 719–729

    CAS  PubMed  Google Scholar 

  • Zhang W, Kang J S, Cole F, Yi M J, Krauss R S (2006b). Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell, 10(5): 657–665

    CAS  PubMed  Google Scholar 

  • Zhang W, Zhao Y, Tong C, Wang G, Wang B, Jia J, Jiang J (2005). Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Dev Cell, 8(2): 267–278

    CAS  PubMed  Google Scholar 

  • Zhang X M, Ramalho-Santos M, McMahon A P (2001). Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell, 106(2): 781–792

    CAS  PubMed  Google Scholar 

  • Zhang Z, Lv X, Yin W C, Zhang X, Feng J, Wu W, Hui C C, Zhang L, Zhao Y (2013). Ter94 ATPase complex targets k11-linked ubiquitinated ci to proteasomes for partial degradation. Dev Cell, 25(6): 636–644

    CAS  PubMed  Google Scholar 

  • Zhao Y, Tong C, Jiang J (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature, 450(7167): 252–258

    CAS  PubMed  Google Scholar 

  • Zheng X, Mann R K, Sever N, Beachy P A (2010). Genetic and biochemical definition of the Hedgehog receptor. Genes Dev, 24(1): 57–71

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhu A J, Zheng L, Suyama K, Scott M P (2003). Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Genes Dev, 17(10): 1240–1252

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA

    Elaine Y. C. Hsia, Yirui Gui & Xiaoyan Zheng

Authors
  1. Elaine Y. C. Hsia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yirui Gui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoyan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaoyan Zheng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsia, E.Y.C., Gui, Y. & Zheng, X. Regulation of Hedgehog signaling by ubiquitination. Front. Biol. 10, 203–220 (2015). https://doi.org/10.1007/s11515-015-1343-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-015-1343-5

Keywords

Search

Navigation