Development - Hedgehog signaling

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Hedgehog signaling

The Hedgehog (HH) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan [1], [2], [3]. Sonic hedgehog homolog (SHH) activation requires several steps: autocleavage, Cholesterol binding, palmitoylation by Hedgehog acyltransferase (HHAT) [2], [4], [5], [6]. Activated SHH is transported by binding to Dispatched homolog 1 (DISP1) into extracellular region [7]. Growth arrest-specific 1 (GAS1) [8], Boc homolog (BOC), Cdon homolog (CDON) [9], [10] bind to SHH and activate HH signaling. Ribosomal protein L29 (HIP) binds to SHH, Indian hedgehog homolog (IHH), Desert hedgehog homolog (DHH) and inhibits HH signaling pathway [11].

SHH, IHH, DHH are members of HH family, which induce HH signaling pathway activation by binding to Patched homolog 1 (PTHC1) [3], [12], [13]. Ligand-induced inhibition of PTCH1 leads to activation of Smoothened homolog (Smoothened) [14]. Smoothened function depends on intraflaggelar transport proteins Arrestin, beta 1 and 2 (Beta-arrestin1 and 2), Kinesin family member 3A (KIF3A), which bind to and activate Smoothened [15]. Adrenergic, beta, receptor kinase 1 (GRK2) phosphorylates Smoothened and induces it activation [16], [17]. Under SHH activation Smoothened can induce Ubiquitin-dependent degradation of Suppressor of fused homolog (SUFU), main regulator of HH signaling pathway [18], [19], [20]. Inhibition of SUFU leads to activation of GLI family zinc finger 3 and 2 (GLI-3 and GLI-2) transcriptional activity [1], [21]. GLI-2 and GLI-3 promote transcription of GLI family zinc finger 1 (GLI-1) [22], [23]. GLI-1 activates target genes, involved in regulation of HH signaling: PTCH1, HIP [24]. Activated GLI-2 and GLI-3 can be ubiquitinated by Cul3/SPOP/Rbx1 E3 ligase and then undergo 26S proteasome (20S core)-dependent degradation [25], [26].

SHH-activated Smoothened binds to Kinesin family member 27 (KIF27) and promotes activation of Serine/threonine kinase 36, fused homolog (STK36) [1], [27], [28]. Cell division cycle 37 homolog (CDC37) in cooperation with Heat shock protein 90kDa (HSP90) binds to and induces STK36 [27]. STK36 activates GLI-2, GLI-1 and inhibits SUFU [29].

SHH -induced Smoothened activates Mitogen-activated protein kinase kinase kinase 10 (MLK2(MAP3K10)) activity [13]. MLK2(MAP3K10) inhibits Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) [30], [31]. DYRK2 phosphorylation of GLI-2, GLI-3 induces degradation of transcription factors [21], [30].

In absence of HH ligand Protein kinase, cAMP dependent, catalytic (PKA-cat (cAMP-dependent)) phosphorylates GLI-3 [32] and induces several consecutive processes: SUFU binds to GLI-3 and promotes GLI-3 phosphorylation by Glycogen synthase kinase 3 beta (GSK3 beta) [33], Casein kinase I phosphorylates GLI-3 [34], Beta-transducin repeat containing (beta-TrCP) in complex with Cullin 1 binds to phosphorylated GLI-3 and promotes Ubiquitin-dependent processing of GLI-3 by 26S proteasome (20S core) into GLI family zinc finger 3, repressor form (GLI-3R) [26], [35]. GLI-3R acts as co-repressor of transcription: GLI-3R and SUFU bind to Catenin (cadherin-associated protein), beta 1, 88kDa (Beta-catenin) and inhibit it function [36], [37], [38].

On the other hand in absence of ligand PKA-cat (cAMP-dependent), GSK3 beta, Casein kinase I phosphorylate GLI-2 and induce Cul1/Rbx1 E3 ligase-dependent 26S proteasome (20S core) degradation of GLI-2 [13], [39], [40]. Degradation of GLI-1 in absence of HH signal is promoted by Numb homolog (NUMB) [41]. NUMB binds to GLI-1 and induce Itchy E3 ubiquitin protein ligase homolog (Itch)-dependent proteasome degradation of GLI-1. SUFU binds to and inhibits GLI-1, GLI-2 and GLI-3 activity [19], [25]. SUFU also recruits SIN3 homolog A, transcription regulator (Sin3A)/Histone deacetylase (HDAC) complex through interaction with Sin3A-associated protein, 18kDa (SAP18) to repress GLI-1 and enhance GLI-3R activity [42], [43].

Cyclin-dependent kinase 11B (CDK11) binds to and inhibits SUFU thereby activating Hedgehog signaling [44].

SHH inhibits PTCH1-induced inhibition of Cyclin B1, results in activation of cell proliferation [45].

References:

  1. Jia J, Jiang J
    Decoding the Hedgehog signal in animal development. Cellular and molecular life sciences : CMLS 2006 Jun;63(11):1249-65
  2. Varjosalo M, Taipale J
    Hedgehog: functions and mechanisms. Genes & development 2008 Sep 15;22(18):2454-72
  3. Jenkins D
    Hedgehog signalling: emerging evidence for non-canonical pathways. Cellular signalling 2009 Jul;21(7):1023-34
  4. Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM
    Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 1995 May 5;81(3):445-55
  5. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, McMahon AP
    Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001 Jun 1;105(5):599-612
  6. Buglino JA, Resh MD
    Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. The Journal of biological chemistry 2008 Aug 8;283(32):22076-88
  7. Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA
    Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 2002 Oct 4;111(1):63-75
  8. Allen BL, Tenzen T, McMahon AP
    The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes & development 2007 May 15;21(10):1244-57
  9. Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS
    Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Developmental cell 2006 May;10(5):657-65
  10. Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP
    The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Developmental cell 2006 May;10(5):647-56
  11. Chuang PT, McMahon AP
    Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999 Feb 18;397(6720):617-21
  12. Jeong J, McMahon AP
    Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development (Cambridge, England) 2005 Jan;132(1):143-54
  13. Katoh Y, Katoh M
    Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). International journal of molecular medicine 2008 Sep;22(3):271-5
  14. Rohatgi R, Milenkovic L, Scott MP
    Patched1 regulates hedgehog signaling at the primary cilium. Science (New York, N.Y.) 2007 Jul 20;317(5836):372-6
  15. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ
    Beta-arrestin-mediated localization of smoothened to the primary cilium. Science (New York, N.Y.) 2008 Jun 27;320(5884):1777-81
  16. Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ
    Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science (New York, N.Y.) 2004 Dec 24;306(5705):2257-60
  17. Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ, Lefkowitz RJ, Caron MG
    Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Molecular and cellular biology 2006 Oct;26(20):7550-60
  18. Varjosalo M, Li SP, Taipale J
    Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Developmental cell 2006 Feb;10(2):177-86
  19. Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S
    Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Developmental cell 2006 Feb;10(2):187-97
  20. Yue S, Chen Y, Cheng SY
    Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway. Oncogene 2009 Jan 29;28(4):492-9
  21. Jiang J, Hui CC
    Hedgehog signaling in development and cancer. Developmental cell 2008 Dec;15(6):801-12
  22. Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S
    Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. The Journal of biological chemistry 1999 Mar 19;274(12):8143-52
  23. Bai CB, Stephen D, Joyner AL
    All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Developmental cell 2004 Jan;6(1):103-15
  24. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, Longabaugh WJ, Davidson EH, Wong WH, McMahon AP
    Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development (Cambridge, England) 2007 May;134(10):1977-89
  25. Chen MH, Wilson CW, Li YJ, Law KK, Lu CS, Gacayan R, Zhang X, Hui CC, Chuang PT
    Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes & development 2009 Aug 15;23(16):1910-28
  26. Wen X, Lai CK, Evangelista M, Hongo JA, de Sauvage FJ, Scales SJ
    Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Molecular and cellular biology 2010 Apr;30(8):1910-22
  27. Kise Y, Takenaka K, Tezuka T, Yamamoto T, Miki H
    Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels. Biochemical and biophysical research communications 2006 Dec 8;351(1):78-84
  28. Wilson CW, Nguyen CT, Chen MH, Yang JH, Gacayan R, Huang J, Chen JN, Chuang PT
    Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 2009 May 7;459(7243):98-102
  29. Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ
    Gli regulation by the opposing activities of fused and suppressor of fused. Nature cell biology 2000 May;2(5):310-2
  30. Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J
    Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell 2008 May 2;133(3):537-48
  31. Katoh Y, Katoh M
    Integrative genomic analyses on GLI2: mechanism of Hedgehog priming through basal GLI2 expression, and interaction map of stem cell signaling network with P53. International journal of oncology 2008 Oct;33(4):881-6
  32. Wang B, Fallon JF, Beachy PA
    Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000 Feb 18;100(4):423-34
  33. Kise Y, Morinaka A, Teglund S, Miki H
    Sufu recruits GSK3beta for efficient processing of Gli3. Biochemical and biophysical research communications 2009 Sep 25;387(3):569-74
  34. Tempé D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP
    Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Molecular and cellular biology 2006 Jun;26(11):4316-26
  35. Wang B, Li Y
    Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proceedings of the National Academy of Sciences of the United States of America 2006 Jan 3;103(1):33-8
  36. Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui CC, Alman B
    Suppressor of fused negatively regulates beta-catenin signaling. The Journal of biological chemistry 2001 Oct 26;276(43):40113-9
  37. Cayuso J, Ulloa F, Cox B, Briscoe J, Martí E
    The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity. Development (Cambridge, England) 2006 Feb;133(3):517-28
  38. Ulloa F, Itasaki N, Briscoe J
    Inhibitory Gli3 activity negatively regulates Wnt/beta-catenin signaling. Current biology : CB 2007 Mar 20;17(6):545-50
  39. Bhatia N, Thiyagarajan S, Elcheva I, Saleem M, Dlugosz A, Mukhtar H, Spiegelman VS
    Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. The Journal of biological chemistry 2006 Jul 14;281(28):19320-6
  40. Pan Y, Wang B
    A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. The Journal of biological chemistry 2007 Apr 13;282(15):10846-52
  41. Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Po A, Sico MA, Alimandi M, Giannini G, Maroder M, Screpanti I, Gulino A
    Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nature cell biology 2006 Dec;8(12):1415-23
  42. Cheng SY, Bishop JM
    Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proceedings of the National Academy of Sciences of the United States of America 2002 Apr 16;99(8):5442-7
  43. Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier MF
    The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. The Biochemical journal 2004 Mar 1;378(Pt 2):353-62
  44. Evangelista M, Lim TY, Lee J, Parker L, Ashique A, Peterson AS, Ye W, Davis DP, de Sauvage FJ
    Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Science signaling 2008 Sep 30;1(39):ra7
  45. Barnes EA, Kong M, Ollendorff V, Donoghue DJ
    Patched1 interacts with cyclin B1 to regulate cell cycle progression. The EMBO journal 2001 May 1;20(9):2214-23

  1. Jia J, Jiang J
    Decoding the Hedgehog signal in animal development. Cellular and molecular life sciences : CMLS 2006 Jun;63(11):1249-65
  2. Varjosalo M, Taipale J
    Hedgehog: functions and mechanisms. Genes & development 2008 Sep 15;22(18):2454-72
  3. Jenkins D
    Hedgehog signalling: emerging evidence for non-canonical pathways. Cellular signalling 2009 Jul;21(7):1023-34
  4. Roelink H, Porter JA, Chiang C, Tanabe Y, Chang DT, Beachy PA, Jessell TM
    Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell 1995 May 5;81(3):445-55
  5. Lewis PM, Dunn MP, McMahon JA, Logan M, Martin JF, St-Jacques B, McMahon AP
    Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 2001 Jun 1;105(5):599-612
  6. Buglino JA, Resh MD
    Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. The Journal of biological chemistry 2008 Aug 8;283(32):22076-88
  7. Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA
    Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 2002 Oct 4;111(1):63-75
  8. Allen BL, Tenzen T, McMahon AP
    The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes & development 2007 May 15;21(10):1244-57
  9. Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS
    Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Developmental cell 2006 May;10(5):657-65
  10. Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP
    The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Developmental cell 2006 May;10(5):647-56
  11. Chuang PT, McMahon AP
    Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 1999 Feb 18;397(6720):617-21
  12. Jeong J, McMahon AP
    Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development (Cambridge, England) 2005 Jan;132(1):143-54
  13. Katoh Y, Katoh M
    Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). International journal of molecular medicine 2008 Sep;22(3):271-5
  14. Rohatgi R, Milenkovic L, Scott MP
    Patched1 regulates hedgehog signaling at the primary cilium. Science (New York, N.Y.) 2007 Jul 20;317(5836):372-6
  15. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ
    Beta-arrestin-mediated localization of smoothened to the primary cilium. Science (New York, N.Y.) 2008 Jun 27;320(5884):1777-81
  16. Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ
    Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science (New York, N.Y.) 2004 Dec 24;306(5705):2257-60
  17. Meloni AR, Fralish GB, Kelly P, Salahpour A, Chen JK, Wechsler-Reya RJ, Lefkowitz RJ, Caron MG
    Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2. Molecular and cellular biology 2006 Oct;26(20):7550-60
  18. Varjosalo M, Li SP, Taipale J
    Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Developmental cell 2006 Feb;10(2):177-86
  19. Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S
    Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Developmental cell 2006 Feb;10(2):187-97
  20. Yue S, Chen Y, Cheng SY
    Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway. Oncogene 2009 Jan 29;28(4):492-9
  21. Jiang J, Hui CC
    Hedgehog signaling in development and cancer. Developmental cell 2008 Dec;15(6):801-12
  22. Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S
    Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. The Journal of biological chemistry 1999 Mar 19;274(12):8143-52
  23. Bai CB, Stephen D, Joyner AL
    All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Developmental cell 2004 Jan;6(1):103-15
  24. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, Longabaugh WJ, Davidson EH, Wong WH, McMahon AP
    Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development (Cambridge, England) 2007 May;134(10):1977-89
  25. Chen MH, Wilson CW, Li YJ, Law KK, Lu CS, Gacayan R, Zhang X, Hui CC, Chuang PT
    Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes & development 2009 Aug 15;23(16):1910-28
  26. Wen X, Lai CK, Evangelista M, Hongo JA, de Sauvage FJ, Scales SJ
    Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Molecular and cellular biology 2010 Apr;30(8):1910-22
  27. Kise Y, Takenaka K, Tezuka T, Yamamoto T, Miki H
    Fused kinase is stabilized by Cdc37/Hsp90 and enhances Gli protein levels. Biochemical and biophysical research communications 2006 Dec 8;351(1):78-84
  28. Wilson CW, Nguyen CT, Chen MH, Yang JH, Gacayan R, Huang J, Chen JN, Chuang PT
    Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 2009 May 7;459(7243):98-102
  29. Murone M, Luoh SM, Stone D, Li W, Gurney A, Armanini M, Grey C, Rosenthal A, de Sauvage FJ
    Gli regulation by the opposing activities of fused and suppressor of fused. Nature cell biology 2000 May;2(5):310-2
  30. Varjosalo M, Björklund M, Cheng F, Syvänen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J
    Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell 2008 May 2;133(3):537-48
  31. Katoh Y, Katoh M
    Integrative genomic analyses on GLI2: mechanism of Hedgehog priming through basal GLI2 expression, and interaction map of stem cell signaling network with P53. International journal of oncology 2008 Oct;33(4):881-6
  32. Wang B, Fallon JF, Beachy PA
    Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000 Feb 18;100(4):423-34
  33. Kise Y, Morinaka A, Teglund S, Miki H
    Sufu recruits GSK3beta for efficient processing of Gli3. Biochemical and biophysical research communications 2009 Sep 25;387(3):569-74
  34. Tempé D, Casas M, Karaz S, Blanchet-Tournier MF, Concordet JP
    Multisite protein kinase A and glycogen synthase kinase 3beta phosphorylation leads to Gli3 ubiquitination by SCFbetaTrCP. Molecular and cellular biology 2006 Jun;26(11):4316-26
  35. Wang B, Li Y
    Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proceedings of the National Academy of Sciences of the United States of America 2006 Jan 3;103(1):33-8
  36. Meng X, Poon R, Zhang X, Cheah A, Ding Q, Hui CC, Alman B
    Suppressor of fused negatively regulates beta-catenin signaling. The Journal of biological chemistry 2001 Oct 26;276(43):40113-9
  37. Cayuso J, Ulloa F, Cox B, Briscoe J, Martí E
    The Sonic hedgehog pathway independently controls the patterning, proliferation and survival of neuroepithelial cells by regulating Gli activity. Development (Cambridge, England) 2006 Feb;133(3):517-28
  38. Ulloa F, Itasaki N, Briscoe J
    Inhibitory Gli3 activity negatively regulates Wnt/beta-catenin signaling. Current biology : CB 2007 Mar 20;17(6):545-50
  39. Bhatia N, Thiyagarajan S, Elcheva I, Saleem M, Dlugosz A, Mukhtar H, Spiegelman VS
    Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. The Journal of biological chemistry 2006 Jul 14;281(28):19320-6
  40. Pan Y, Wang B
    A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. The Journal of biological chemistry 2007 Apr 13;282(15):10846-52
  41. Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Po A, Sico MA, Alimandi M, Giannini G, Maroder M, Screpanti I, Gulino A
    Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nature cell biology 2006 Dec;8(12):1415-23
  42. Cheng SY, Bishop JM
    Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proceedings of the National Academy of Sciences of the United States of America 2002 Apr 16;99(8):5442-7
  43. Paces-Fessy M, Boucher D, Petit E, Paute-Briand S, Blanchet-Tournier MF
    The negative regulator of Gli, Suppressor of fused (Sufu), interacts with SAP18, Galectin3 and other nuclear proteins. The Biochemical journal 2004 Mar 1;378(Pt 2):353-62
  44. Evangelista M, Lim TY, Lee J, Parker L, Ashique A, Peterson AS, Ye W, Davis DP, de Sauvage FJ
    Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Science signaling 2008 Sep 30;1(39):ra7
  45. Barnes EA, Kong M, Ollendorff V, Donoghue DJ
    Patched1 interacts with cyclin B1 to regulate cell cycle progression. The EMBO journal 2001 May 1;20(9):2214-23

Target Details

Click on a target from the pathway image to view related information.