Hedgehog 'off' state (Homo sapiens)

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13, 15, 46, 841, 3, 16, 25, 662, 11, 603, 663, 54, 6613, 21, 682, 606613, 21, 6812, 44, 56, 64, 6947, 845, 49, 71, 76, 8249, 6811661, 7, 10, 33, 50...3, 11, 25, 546, 13, 15, 17-20, 26...38, 44, 53, 56, 64...3, 16, 25, 30, 342, 11, 601, 10, 14, 15, 19...3, 661, 16, 25, 3049, 6844, 56, 61, 6416, 255, 13, 21, 49, 68...4, 8, 9, 22, 32...2, 601, 10, 14, 15, 19...16, 2556, 61, 64cytosolendocytic vesicle lumenprimary ciliumnucleoplasmSUFU KIF7 SUFU UBC(533-608) GLI3 CSNK1A1PSMC6 PSME1 SCF beta-TrCPcomplexmicrotubulePSMC4 UBA52(1-76) GLI:SUFUIFT88 PSMD13 PSMB2 SUFU RPS27A(1-76) PSMD1 GLI3 GLI2 gene p10S-GLI3:SUFUPSMB11 GLI:SUFUPSMD14 GLI3RPSMC4 SUFU PSMD10 PSMC3 PSMC1 PSMC2 PSMB7 PSMA7 IFT-A complexGLI3RPSME3 UBB(77-152) UBC(533-608) PSMD7 PRKAR2A ADCY2 GLI2PTCH1 geneUBC(381-456) UBA52(1-76) UBB(1-76) PSMB11 PSMD1 ub-p11S-GLI2 SUFU GNAS UBB(153-228) NUMB:ITCH:ub-pS-GLI1:SUFUADCY10 GPR161:IFT-A:TULP3RPS27A(1-76) GLI1 gene:GLI3RNUMB:ITCHPRKAR1B INTU UBC(609-684) PSME1 p4S-GLI2:SUFUPSMD4 PSMB3 PSMA4 PSMD13 ub-pS-GLI:SUFUPSMD5 PSMA2 RPGRIP1L SKP1 UBC(457-532) GLI3 PSMB1 UBC(153-228) PTCH1 gene:GLI3RPSMA4 PSMF1 PSMB5 IFT122 PKA catalyticsubunitPSMA8 IFT140 UBB(1-76) UBB(153-228) MKS1 26S proteasomePSMD5 GSK3BPRKACA GLI1UBC(305-380) SCF beta-TrCPcomplexSMO PSMB6 GTP p8S-GLI2 UBC(1-76) PSMB6 UBC(533-608) UBC(457-532) PSMF1 ADPPSMB4 PSMB1 DYNC2H1 UBC(1-76) PSME2 PSMC5 PSMA1 PRKAR2B PSMD6 PSMD3 ADPTULP3TULP3 UbcAMPUBA52(1-76) PKA tetramerPSMD11 PSMD2 PSMC2 OFD1 GLI1,2,326S proteasomeADPADPSUFU UBC(153-228) PSME4 GLI2 geneSUFU PSME2 cAMP PRKACG UBC(457-532) IFT140 GLI3:SUFUp11S-GLI2:SUFUKIF7:microtubuleGLI3R PSMA3 UBC(229-304) UBB(77-152) PRKACA Mg2+ ATPPTCH1 gene GLI1 retrograde IFTregulators of HhPSMB10 PSMD6 ATPIFT57 SUFU p6S-GLI3:SUFUGLI1 WDR19 IFT122 SUFU PSMA5 GLI3 SKP1 ATPPSMA7 pS-GLI:SUFUATPPSMC5 ADCY7 PSMB8 ADCY9 SMO UBC(305-380) p10S-GLI3 GLI2 gene:GLI3RGLI1 RBX1 ADCY6 PSMD3 PRKAR2B GLI1:SUFUBTRC GLI2 PSMB8 ADCY1 GLI1 PSMD12 PSMD8 WDR19 ATPGLI2 IFT122 TTC21B GLI2:SUFUADCY4 p11S-GLI2 NUMB PRKAR2A UBC(381-456) UBB(77-152) IFT140 UBC(609-684) RBX1 ADPGLI2 WDR19 UBC(153-228) TULP3 PSMA8 SUFU PSMD9 ADPSMO dimerGPR161 CUL1 PSMB5 UBC(1-76) PCP regulators of HhUBC(609-684) PSME4 ITCHp4S-GLI2 IFT-A complex:TULP3UBC(305-380) TTC21B p8S-GLI2:SUFUGLI1 gene ADCY3 SUFU IFT122 GLI1 genep6S-GLI3 KIF7PSMC1 4xub-p13S-Gli3:SUFUADPPSMA3 SUFU FUZ ub-pS-GLI1 UbPRKAR1B PRKAR1A pS-GLI1 UBC(77-152) WDR35 NUMB WDR35 SUFU PSMD2 PSMB9 SUFU PSMD9 UbITCH anterograde IFTregulators of HhSUFU PSMB10 PSMD11 GLI2 TTC21B GLI3 PRKACB PSMD12 TTC21B PRKAR1A UBC(77-152) IFT172 ADCY5 PSMB9 GLI2 IFT52 RPS27A(1-76) adenylatecyclases:Mg2+PSMA2 PSMB4 UBB(1-76) p13S-GLI3:SUFUGLI3R UBC(229-304) UBC(381-456) PSME3 UBC(77-152) PSMC6 PSMD4 PSMD14 SUFU ATPPSMA6 ub-pS-GLI1 PSMA1 p13S-GLI3 PSMB3 PTCH1GLI3R PSMD10 SUFU NUMBmicrotubule ADCY8 GLI:SUFUBTRC PRKACB G-protein alpha(s):GTPSUFUGLI1 KIF3A UBC(229-304) PSMC3 PSMB2 PRKACG UBB(153-228) GPR161PSMD8 PSMD7 ATPATPPSMA5 ub-p13S-GLI3 SMO dimerPSMB7 CUL1 PPiub-p11S-GLI2:SUFUWDR35 ciliary basal bodyregulators of HhITCH PSMA6 PKA regulatorysubunits:cAMP16, 2516, 2516, 254471, 7616, 25792716, 2568446879


Description

Hedgehog is a secreted morphogen that has evolutionarily conserved roles in body organization by regulating the activity of the Ci/Gli transcription factor family. In Drosophila in the absence of Hh signaling, full-length Ci is partially degraded by the proteasome to generate a truncated repressor form that translocates to the nucleus to represses Hh-responsive genes. Binding of Hh ligand to the Patched (PTC) receptor allows the 7-pass transmembrane protein Smoothened (SMO) to be activated in an unknown manner, disrupting the partial proteolysis of Ci and allowing the full length activator form to accumulate (reviewed in Ingham et al, 2011; Briscoe and Therond, 2013).
While many of the core components of Hh signaling are conserved from flies to humans, the pathways do show points of significant divergence. Notably, the human genome encodes three Ci homologues, GLI1, 2 and 3 that each play slightly different roles in regulating Hh responsive genes. GLI3 is the primary repressor of Hh signaling in vertebrates, and is converted to the truncated GLI3R repressor form in the absence of Hh. GLI2 is a potent activator of transcription in the presence of Hh but contributes only minimally to the repression function. While a minor fraction of GLI2 protein is processed into the repressor form in the absence of Hh, the majority is either fully degraded by the proteasome or sequestered in the full-length form in the cytosol by protein-protein interactions. GLI1 lacks the repression domain and appears to be an obligate transcriptional activator (reviewed in Briscoe and Therond, 2013).
Vertebrate but not fly Hh signaling also depends on the movement of pathway components through the primary cilium. The primary cilium is a non-motile microtubule based structure whose construction and maintenance depends on intraflagellar transport (IFT). Anterograde IFT moves molecules from the ciliary base along the axoneme to the ciliary tip in a manner that requires the microtubule-plus-end directed kinesin KIF3 motor complex and the IFT-B protein complex, while retrograde IFT back to the ciliary base depends on the minus-end directed dynein motor and the IFT-A complex. Genetic screens have identified a number of cilia-related proteins that are required both to maintain Hh in the 'off' state and to transduce the signal when the pathway is activated (reviewed in Hui and Angers, 2011; Goetz and Anderson, 2010). View original pathway at:Reactome.

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History

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114910view16:42, 25 January 2021ReactomeTeamReactome version 75
113355view11:42, 2 November 2020ReactomeTeamReactome version 74
112564view15:53, 9 October 2020ReactomeTeamReactome version 73
101477view11:34, 1 November 2018ReactomeTeamreactome version 66
101015view21:14, 31 October 2018ReactomeTeamreactome version 65
100551view19:48, 31 October 2018ReactomeTeamreactome version 64
100099view16:32, 31 October 2018ReactomeTeamreactome version 63
99649view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99251view12:45, 31 October 2018ReactomeTeamreactome version 62
93840view13:40, 16 August 2017ReactomeTeamreactome version 61
93396view11:22, 9 August 2017ReactomeTeamreactome version 61
87141view18:52, 18 July 2016MkutmonOntology Term : 'Hedgehog signaling pathway' added !
86481view09:19, 11 July 2016ReactomeTeamreactome version 56
83587view07:34, 26 November 2015EgonwAdded missing ENSG parts of the Ensembl IDs.
83062view09:50, 18 November 2015ReactomeTeamVersion54
81377view12:54, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
4xub-p13S-Gli3:SUFUComplexR-HSA-5610526 (Reactome)
ADCY1 ProteinQ08828 (Uniprot-TrEMBL)
ADCY10 ProteinQ96PN6 (Uniprot-TrEMBL)
ADCY2 ProteinQ08462 (Uniprot-TrEMBL)
ADCY3 ProteinO60266 (Uniprot-TrEMBL)
ADCY4 ProteinQ8NFM4 (Uniprot-TrEMBL)
ADCY5 ProteinO95622 (Uniprot-TrEMBL)
ADCY6 ProteinO43306 (Uniprot-TrEMBL)
ADCY7 ProteinP51828 (Uniprot-TrEMBL)
ADCY8 ProteinP40145 (Uniprot-TrEMBL)
ADCY9 ProteinO60503 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CSNK1A1ProteinP48729 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
DYNC2H1 ProteinQ8NCM8 (Uniprot-TrEMBL)
FUZ ProteinQ9BT04 (Uniprot-TrEMBL)
G-protein alpha (s):GTPComplexR-HSA-164358 (Reactome)
GLI1 ProteinP08151 (Uniprot-TrEMBL)
GLI1 gene Protein00000111087 (Ensembl)
GLI1 geneGeneProduct00000111087 (Ensembl)
GLI1 gene:GLI3RComplexR-HSA-5617398 (Reactome)
GLI1,2,3ComplexR-HSA-5610616 (Reactome)
GLI1:SUFUComplexR-HSA-5610531 (Reactome)
GLI1ProteinP08151 (Uniprot-TrEMBL)
GLI2 ProteinP10070 (Uniprot-TrEMBL)
GLI2 gene Protein00000074047 (Ensembl)
GLI2 geneGeneProduct00000074047 (Ensembl)
GLI2 gene:GLI3RComplexR-HSA-5617399 (Reactome)
GLI2:SUFUComplexR-HSA-5610536 (Reactome)
GLI2ProteinP10070 (Uniprot-TrEMBL)
GLI3 ProteinP10071 (Uniprot-TrEMBL)
GLI3:SUFUComplexR-HSA-5610542 (Reactome)
GLI3R ProteinP10071 (Uniprot-TrEMBL)
GLI3RProteinP10071 (Uniprot-TrEMBL)
GLI:SUFUComplexR-HSA-5621780 (Reactome)
GLI:SUFUComplexR-HSA-5621783 (Reactome)
GLI:SUFUComplexR-HSA-5621787 (Reactome)
GNAS ProteinP63092 (Uniprot-TrEMBL)
GPR161 ProteinQ8N6U8 (Uniprot-TrEMBL)
GPR161:IFT-A:TULP3ComplexR-HSA-5610579 (Reactome)
GPR161ProteinQ8N6U8 (Uniprot-TrEMBL)
GSK3BProteinP49841 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
IFT-A complex:TULP3ComplexR-HSA-5610556 (Reactome)
IFT-A complexComplexR-HSA-5610555 (Reactome)
IFT122 ProteinQ9HBG6 (Uniprot-TrEMBL)
IFT140 ProteinQ96RY7 (Uniprot-TrEMBL)
IFT172 ProteinQ9UG01 (Uniprot-TrEMBL)
IFT52 ProteinQ9Y366 (Uniprot-TrEMBL)
IFT57 ProteinQ9NWB7 (Uniprot-TrEMBL)
IFT88 ProteinQ13099 (Uniprot-TrEMBL)
INTU ProteinQ9ULD6 (Uniprot-TrEMBL)
ITCH ProteinQ96J02 (Uniprot-TrEMBL)
ITCHProteinQ96J02 (Uniprot-TrEMBL)
KIF3A ProteinQ9Y496 (Uniprot-TrEMBL)
KIF7 ProteinQ2M1P5 (Uniprot-TrEMBL)
KIF7:microtubuleComplexR-HSA-5610559 (Reactome)
KIF7ProteinQ2M1P5 (Uniprot-TrEMBL)
MKS1 ProteinQ9NXB0 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NUMB ProteinP49757 (Uniprot-TrEMBL)
NUMB:ITCH:ub-pS-GLI1:SUFUComplexR-HSA-5610565 (Reactome)
NUMB:ITCHComplexR-HSA-5610562 (Reactome)
NUMBProteinP49757 (Uniprot-TrEMBL)
OFD1 ProteinO75665 (Uniprot-TrEMBL)
PCP regulators of HhComplexR-HSA-5610624 (Reactome)
PKA catalytic subunitComplexR-HSA-5610569 (Reactome)
PKA regulatory subunits:cAMPComplexR-HSA-5610566 (Reactome)
PKA tetramerComplexR-HSA-5610571 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAR1A ProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PTCH1 gene Protein00000185920 (Ensembl)
PTCH1 geneGeneProduct00000185920 (Ensembl)
PTCH1 gene:GLI3RComplexR-HSA-5612507 (Reactome)
PTCH1ProteinQ13635 (Uniprot-TrEMBL)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RPGRIP1L ProteinQ68CZ1 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SCF beta-TrCP complexComplexR-HSA-206748 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SMO ProteinQ99835 (Uniprot-TrEMBL)
SMO dimerComplexR-HSA-5610573 (Reactome)
SMO dimerComplexR-HSA-5610574 (Reactome)
SUFU ProteinQ9UMX1 (Uniprot-TrEMBL)
SUFUProteinQ9UMX1 (Uniprot-TrEMBL)
TTC21B ProteinQ7Z4L5 (Uniprot-TrEMBL)
TULP3 ProteinO75386 (Uniprot-TrEMBL)
TULP3ProteinO75386 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
WDR19 ProteinQ8NEZ3 (Uniprot-TrEMBL)
WDR35 ProteinQ9P2L0 (Uniprot-TrEMBL)
adenylate cyclases:Mg2+ComplexR-HSA-5610577 (Reactome)
anterograde IFT regulators of HhComplexR-HSA-5610625 (Reactome)
cAMP MetaboliteCHEBI:17489 (ChEBI)
cAMPMetaboliteCHEBI:17489 (ChEBI)
ciliary basal body regulators of HhComplexR-HSA-5610628 (Reactome)
microtubule R-HSA-5610520 (Reactome)
microtubuleR-HSA-5610520 (Reactome)
p10S-GLI3 ProteinP10071 (Uniprot-TrEMBL)
p10S-GLI3:SUFUComplexR-HSA-5610581 (Reactome)
p11S-GLI2 ProteinP10070 (Uniprot-TrEMBL)
p11S-GLI2:SUFUComplexR-HSA-5610584 (Reactome)
p13S-GLI3 ProteinP10071 (Uniprot-TrEMBL)
p13S-GLI3:SUFUComplexR-HSA-5610587 (Reactome)
p4S-GLI2 ProteinP10070 (Uniprot-TrEMBL)
p4S-GLI2:SUFUComplexR-HSA-5610589 (Reactome)
p6S-GLI3 ProteinP10071 (Uniprot-TrEMBL)
p6S-GLI3:SUFUComplexR-HSA-5610595 (Reactome)
p8S-GLI2 ProteinP10070 (Uniprot-TrEMBL)
p8S-GLI2:SUFUComplexR-HSA-5610598 (Reactome)
pS-GLI1 ProteinP08151 (Uniprot-TrEMBL)
pS-GLI:SUFUComplexR-HSA-5610605 (Reactome)
retrograde IFT regulators of HhComplexR-HSA-5610630 (Reactome)
ub-p11S-GLI2 ProteinP10070 (Uniprot-TrEMBL)
ub-p11S-GLI2:SUFUComplexR-HSA-5610608 (Reactome)
ub-p13S-GLI3 ProteinP10071 (Uniprot-TrEMBL)
ub-pS-GLI1 ProteinP08151 (Uniprot-TrEMBL)
ub-pS-GLI:SUFUComplexR-HSA-5610612 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-5610754 (Reactome)
26S proteasomemim-catalysisR-HSA-5610757 (Reactome)
26S proteasomemim-catalysisR-HSA-5610758 (Reactome)
26S proteasomemim-catalysisR-HSA-5610760 (Reactome)
4xub-p13S-Gli3:SUFUArrowR-HSA-5610746 (Reactome)
4xub-p13S-Gli3:SUFUR-HSA-5610754 (Reactome)
ADPArrowR-HSA-5610717 (Reactome)
ADPArrowR-HSA-5610718 (Reactome)
ADPArrowR-HSA-5610720 (Reactome)
ADPArrowR-HSA-5610722 (Reactome)
ADPArrowR-HSA-5610730 (Reactome)
ADPArrowR-HSA-5610732 (Reactome)
ADPArrowR-HSA-5610741 (Reactome)
ATPR-HSA-5610717 (Reactome)
ATPR-HSA-5610718 (Reactome)
ATPR-HSA-5610720 (Reactome)
ATPR-HSA-5610722 (Reactome)
ATPR-HSA-5610727 (Reactome)
ATPR-HSA-5610730 (Reactome)
ATPR-HSA-5610732 (Reactome)
ATPR-HSA-5610741 (Reactome)
CSNK1A1mim-catalysisR-HSA-5610718 (Reactome)
CSNK1A1mim-catalysisR-HSA-5610722 (Reactome)
G-protein alpha (s):GTPArrowR-HSA-5610727 (Reactome)
GLI1 gene:GLI3RArrowR-HSA-5617408 (Reactome)
GLI1 gene:GLI3RTBarR-HSA-5617412 (Reactome)
GLI1 geneR-HSA-5617408 (Reactome)
GLI1 geneR-HSA-5617412 (Reactome)
GLI1,2,3R-HSA-5610723 (Reactome)
GLI1:SUFUR-HSA-5610741 (Reactome)
GLI1ArrowR-HSA-5617412 (Reactome)
GLI2 gene:GLI3RArrowR-HSA-5617410 (Reactome)
GLI2 gene:GLI3RTBarR-HSA-5617413 (Reactome)
GLI2 geneR-HSA-5617410 (Reactome)
GLI2 geneR-HSA-5617413 (Reactome)
GLI2:SUFUR-HSA-5610717 (Reactome)
GLI2ArrowR-HSA-5617413 (Reactome)
GLI3:SUFUR-HSA-5610720 (Reactome)
GLI3RArrowR-HSA-5610752 (Reactome)
GLI3RArrowR-HSA-5610754 (Reactome)
GLI3RR-HSA-5610752 (Reactome)
GLI3RR-HSA-5612508 (Reactome)
GLI3RR-HSA-5617408 (Reactome)
GLI3RR-HSA-5617410 (Reactome)
GLI:SUFUArrowR-HSA-5610723 (Reactome)
GLI:SUFUArrowR-HSA-5610766 (Reactome)
GLI:SUFUArrowR-HSA-5610767 (Reactome)
GLI:SUFUR-HSA-5610766 (Reactome)
GLI:SUFUR-HSA-5610767 (Reactome)
GPR161:IFT-A:TULP3ArrowR-HSA-5610725 (Reactome)
GPR161:IFT-A:TULP3ArrowR-HSA-5610727 (Reactome)
GPR161R-HSA-5610725 (Reactome)
GSK3Bmim-catalysisR-HSA-5610730 (Reactome)
GSK3Bmim-catalysisR-HSA-5610732 (Reactome)
IFT-A complex:TULP3ArrowR-HSA-5610726 (Reactome)
IFT-A complex:TULP3R-HSA-5610725 (Reactome)
IFT-A complexR-HSA-5610726 (Reactome)
ITCHR-HSA-5610735 (Reactome)
KIF7:microtubuleArrowR-HSA-5610733 (Reactome)
KIF7:microtubuleArrowR-HSA-5610767 (Reactome)
KIF7R-HSA-5610733 (Reactome)
NUMB:ITCH:ub-pS-GLI1:SUFUArrowR-HSA-5610737 (Reactome)
NUMB:ITCH:ub-pS-GLI1:SUFUR-HSA-5610760 (Reactome)
NUMB:ITCHArrowR-HSA-5610735 (Reactome)
NUMB:ITCHArrowR-HSA-5610760 (Reactome)
NUMB:ITCHR-HSA-5610737 (Reactome)
NUMB:ITCHmim-catalysisR-HSA-5610737 (Reactome)
NUMBR-HSA-5610735 (Reactome)
PCP regulators of HhArrowR-HSA-5610766 (Reactome)
PCP regulators of HhArrowR-HSA-5610767 (Reactome)
PKA catalytic subunitArrowR-HSA-5610749 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-5610717 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-5610720 (Reactome)
PKA catalytic subunitmim-catalysisR-HSA-5610741 (Reactome)
PKA regulatory subunits:cAMPArrowR-HSA-5610749 (Reactome)
PKA tetramerR-HSA-5610749 (Reactome)
PPiArrowR-HSA-5610727 (Reactome)
PTCH1 gene:GLI3RArrowR-HSA-5612508 (Reactome)
PTCH1 gene:GLI3RTBarR-HSA-5612510 (Reactome)
PTCH1 geneR-HSA-5612508 (Reactome)
PTCH1 geneR-HSA-5612510 (Reactome)
PTCH1ArrowR-HSA-5612510 (Reactome)
PTCH1TBarR-HSA-5610763 (Reactome)
R-HSA-5610717 (Reactome) Despite sharing 44% amino acid identity with GLI3, only a small fraction of GLI2 appears to be processed to a repressor form in the absence of Hh signaling; the bulk of the protein is completely degraded in a phosphorylation- and proteasome-dependent manner (Pan et al, 2007; Pan et al, 2009; Pan and Wang, 2007). Degradation of GLI2 depends on phosphorylation of four consensus PKA sites in the C-terminal region. This phosphorylation primes GLI2 for subsequent phosphorylation by CK1 and GSK3, creating a binding site for betaTrCP and promoting its subsequent ubiquitination and degradation (Pan et al, 2006; Pan and Wang, 2007; Pan et al, 2009).
R-HSA-5610718 (Reactome) Phosphorylation by PKA primes GLI2 for subsequent phosphorylation at adjacent CK sites (Pan et al, 2006; Pan and Wang, 2007).
R-HSA-5610720 (Reactome) Phosphorylation of GLI3 by PKA on up to six sites in the C-terminal region primes the protein for subsequent phosphorylation by CK1 and GSK3 and is required for the ubiquitin-mediated processing by the proteasome to yield the truncated repressor form (Tempe et al, 2006; Pan et al, 2006; Pan and Wang, 2007; Wang and Li, 2006). Processing of GLI3 is regulated in part by movement through the primary cilia, and disruption of intraflagellar transport abrogates processing (Wen et al, 2010)
R-HSA-5610722 (Reactome) Phosphorylation by PKA primes GLI3 for subsequent phosphorylation by CK1 at four or more sites. These serial phosphorylations are required for the recruitment of beta-TrCP and subsequent ubiquitination and processing of GLI3 (Tempe et al, 2006; Wang and Li, 2006; Wen et al, 2010; Schrader et al, 2011)
R-HSA-5610723 (Reactome) Vertebrate SUFU plays a critical role in the negative regulation of Hh signaling in the absence of ligand. Disruption of SUFU causes constitutive activation of the pathway, and is associated with the development of medulloblastoma in humans (Cooper et al, 2005; Svard et al, 2006; Taylor et al, 2002; Pastorino et al, 2009). SUFU binds directly to all three GLI proteins (Pearse et al, 1999; Stone et al, 1999; Jia et al, 2009; Svard et al, 2006). Formation of a SUFU:GLI complex is required for the processing of GLI3 to the GLI3R repressor form, and the processing depends on transit through the primary cilia (Kise et al, 2009; Humke et al, 2010; Huangfu and Anderson, 2005). Despite this, primary cilia are not required for SUFU to inhibit GLI activity; SUFU may also serve in a cilia-independent manner to sequester the full-length protein in the cytoplasm in the absence of Hh signal (Chen et al, 2009; Humke et al, 2010; Jia et al, 2009; Tukachinsky et al, 2010). After processing, GLI3R dissociates from SUFU and its activity is SUFU-independent (Humke et al, 2010; Tukachinsky et al, 2010). Nuclear SUFU may also play a direct role as a transcriptional co-repressor through interaction with the N-terminal DNA-binding domain of GLI proteins, though this remains to be fully elaborated (Monnier et al, 1998; Pearse et al, 1999; Cheng and Bishop, 2002; Paces-Fessy et al, 2004; Dunaeva et al, 2003; Szczepny et al, 2014).
R-HSA-5610725 (Reactome) TULP3 and the retrograde complex IFT-A are required to recruit GPR161 to the cilium in the absence of Hh ligand (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013; reviewed in Mukhopadhyay and Rohtagi, 2014). TULP3 is a negative regulator of Hh signaling and siRNA depletion of TULP3 reduces the ciliary accumulation of GPR161 (Norman et al, 2009; Patterson et al, 2009; Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013).
R-HSA-5610726 (Reactome) TULP3 is recruited to the primary cilium through a direct interaction with the retrograde transport IFT-A complex and with membrane phosphoinositides (Santagata et al, 2001; Mukhopadhyay et al, 2010; Qin et al, 2011; reviewed in Mukhopadhyay and Rohatgi, 2014). TULP3 facilitates GLI processing by recruiting the GPCR GPR161, which in turn activates PKA by increasing cAMP levels in a G alpha s-dependent manner (Mukhopadhyay et al, 2013, reviewed in Hwang and Mukhopadhyay, 2014; Pal and Mukhopadhyay, 2014).
R-HSA-5610727 (Reactome) cAMP is generated by the action of adenylate cyclases (reviewed in Sassone-Corsi, 2012). GPR161 is an orphan GPCR that has recently been identified as a negative regulator of Hh signaling that acts by increasing cellular cAMP levels in the absence of ligand. Overexpression of GPR161 increases cellular cAMP levels in a manner that depends on the G alpha s subunit, and depletion of GPR161 results in aberrant Hh signaling and a decrease in the ratio of processed GLI3R (Mukhopadhyay et al, 2013). These data suggest that GPR161 negatively regulates GLI processing in the absence of Hh signal by modulating PKA activity through cAMP levels (Mukhopadhyay et al, 2013; reviewed in Mukhopadhyay and Rohatgi, 2014).
R-HSA-5610730 (Reactome) Like GLI3, GLI2 has putative GSK3 sites that contribute to the proteasome-dependent degradation of the protein in the absence of Hh signal. Deletion of the GSK3 phosphorylation sites abrogates the interaction with beta-TrCP, stabilizes GLI2 protein and increases the expression of a GLI-dependent reporter, consistent with a role for GSK3 in promoting GLI2 degradation (Pan et al, 2006).
R-HSA-5610732 (Reactome) GSK3-mediated phosphorylation of GLI3 is primed by earlier phosphorylations by PKA and CK1 and is required for the subsequent recruitment of beta-TrCP (Tempe et al, 2006; Wang and Li, 2006).
R-HSA-5610733 (Reactome) KIF7, the human ortholog of Drosophila COS2, is a kinesin-4 motor protein that binds directly to the plus ends of axonemal microtubules and inhibits their growth in an ATP-dependent manner (He et al, 2014). KIF7 is required for the processing and activity of GLI in the absence of Hh signal, and KIF7 function depends on the primary cilium (Liem et al, 2009; Cheung et al, 2009; Endoh-Yamagami et al, 2009). KIF7 has been shown to bind to GLI3 and to SUFU and may act in part by promoting the transit of the GLI:SUFU complex through the primary cilium, which is required for GLI processing (Endoh-Yamagami et al, 2009; Maurya et al, 2013). How KIF7 itself is localized to the cilia tip is unknown, although localization depends on the KIF7 motor domain (Liem et al, 2009; He et al, 2014). KIF7 localization is further enhanced at the primary cilia tip in response to Hh signaling, as is also the case for GLI2, GLI3 and SUFU (He et al, 2014; Varjosalo et al, 2008; Haycraft et al, 2005; Wen et al, 2010; Qin et al, 2011; Tukachinsky et al, 2010).
R-HSA-5610735 (Reactome) NUMB is a negative regulator of Hh signaling that acts by promoting the ITCH-dependent ubiquitination of GLI1. ITCH is an E3 ligase that is kept in an inactive conformation by an intramolecular interaction between the HECT domain and a WW motif. Binding of the adaptor protein NUMB to the WW region of ITCH displaces the HECT domain and promotes the catalytic activity of the E3 ligase (di Marcotullio et al, 2006; 2011).
R-HSA-5610737 (Reactome) GLI1 is recruited to the NUMB:ITCH complex through a direct interaction with both proteins. Once recruited, GLI1 is ubiquitinated by ITCH and subsequently degraded by the proteasome. ITCH-mediated degradation of GLI1 does not depend on the Dc or Dn degrons required for interaction with beta-TrCP, but instead relies on a novel PPXYs/pSP degron of GLI1 (di Marcotullio et al, 2006, 2011; Huntzicker et al, 2006). How these two apparently parallel systems of GLI1 ubiquitination and degradation are coordinated is not yet clear.
R-HSA-5610741 (Reactome) Although direct phosphorylation of GLI1 by PKA has not been demonstrated, deletion of the putative PKA sites abrogates the interaction of GLI1 with beta-TrCP and stabilizes GLI1 protein levels; similarly, treatment of GLI1-expressing cells with PKA inhibitors delays the kinetics of GLI1 degradation (Huntzicker et al, 2006). These data are consistent with a role for PKA-mediated phosphorylation in promoting the proteasome-dependent degradation of GLI1 in the absence of Hh signal, as is the case for GLI2 and GLI3 (Huntzicker et al, 2006; Tempe et al, 2006; Pan and Wang, 2007; Pan et al, 2009). Potential roles for CK2 and GSK3 in promoting the phosphorylation-dependent degradation of GLI1 have not been investigated.
R-HSA-5610742 (Reactome) GLI1 protein is degraded by the proteasome in the absence of Hh signal. GLI1 levels are stabilized by treatment of cells with the proteasome inhibitor MG312, and GLI1 and beta-TrCP1 co-precipitate when expressed in NIH 3T3 cells.
Two SCF(beta-TrCP)-dependent degradation sites, Dn and Dc, have been identified in human GLI1. Removal of these sites abrogates the interaction with beta-TrCP, reduces the beta-TrCP-dependent ubiquitination of GLI1 and stabilizes the GLI1 protein levels. As is the case for GLI2 and GLI3, ubiquitination of GLI1 depends on the its prior phosphorylation by PKA, as GLI1 degradation is sensitive to PKA inhibitors and removal of the putative PKA sites abrogates the interaction with beta-TrCP and delays the kinetics of degradation (Huntzicker et al, 2006).
R-HSA-5610745 (Reactome) GLI2 interacts directly with beta-TrCP and is polyubiquitinated in a phosphorylation-dependent manner. Binding and ubiquitination by beta-TrCP depends on 2 motifs located in the region of GLI2 phosphorylated by PKA, CK1 and GSK3 (Pan et al, 2006).
R-HSA-5610746 (Reactome) Hyperphosphorylated GLI3 binds directly with beta-TrCP though at least three independent domains and is polyubiquitinated at lysines 773, 778, 784 and 800 (Tempe et al, 2006). After ubiquitination, GLI3 is processed to the truncated repressor form by the proteasome (Tempe et al, 2006; Wang and Li, 2006)
R-HSA-5610749 (Reactome) cAMP is a known regulator of PKA activity and works by binding to the regulatory subunits and promoting dissociation of the tetramer, freeing the active catalytic subunits (reviewed in Sassone-Corsi, 2012). In the Hh pathway in the absence of ligand, cAMP levels increase in response to the recruitment of GPR161 to the ciliary base by TULP3 and the IFT-A retrograde complex (Mukhopadhyay et al, 2010; Mukhopadhyay et al, 2013). Activated PKA then initiates the phosphorylation cascade that regulates processing and/or degradation of the GLI proteins (reviewed in Briscoe and Therond, 2013; Mukhopadhyay and Rohatgi, 2014).
R-HSA-5610752 (Reactome) After processing by the proteasome, the truncated GLI3 translocates into the nucleus where it acts as the primary repressor for Hh-responsive genes (reviewed in Briscoe and Therond, 2013). Based on sequence comparisons with Ci and GLI1, GLI3 is predicted to have a bipartite NLS signal near the zinc finger domain, and import to the nucleus may be mediated by Importin alpha3, although the details remain to be worked out (reviewed in Hatayama and Aruga, 2012).
R-HSA-5610754 (Reactome) After phosphorylation and ubiquitination, GLI3 is processed by the proteasome to an 83-kDa repressor form that lacks the C-terminal activation domain (Wang et al, 2000; Tempe et al, 2006; Wang and Li, 2006). Partial processing appears to rely on at least three features of the GLI3 protein: the folded N-terminal zinc finger domain, an adjacent simple linker sequence, and the degron in the C-terminus that contains the phosphorylation and ubiquitination target residues (Pan and Wang, 2007; Schrader et al, 2011). The C-terminal end of the processed repressor form is not precisely defined.
R-HSA-5610757 (Reactome) After being ubiquitinated, the bulk of GLI2 is fully degraded by the proteasome; a small fraction of GLI2 may be converted to the repressor form after ubiquitination (Pan et al, 2006; Pan and Wang, 2007).
R-HSA-5610758 (Reactome) In the absence of Hh signal, GLI1 is degraded by the proteasome. Degradation depends on GLI1 ubiquitination by SCF(beta-TrCP) and by the E3 ligase ITCH (Huntzicker et al, 2006; di Marcotullio et al, 2006, 2011).
R-HSA-5610760 (Reactome) In the absence of Hh signal, GLI1 is degraded by the proteasome. Degradation depends on GLI1 ubiquitination by SCF(beta-TrCP) and by the E3 ligase ITCH (Huntzicker et al, 2006; di Marcotullio et al, 2006, 2011).
R-HSA-5610763 (Reactome) In the absence of Hh ligand, the Hh receptor PTCH inhibits signaling by negatively regulating the activity of SMO, a candidate member of the GPCR superfamily that transduces the Hh signal to downstream pathway components (reviewed in Ayers and Therond, 2010; Briscoe and Therond, 2013). Neither the mechanism by which SMO activates Hh signaling nor the manner in which PTCH represses this activty are fully elucidated, but these may involve regulation of putative SMO ligand(s) or changes in cellular localization, protein conformation and phosphorylation status, among other possibilities (reviewed in Briscoe and Therond, 2013; Ayers and Therond; 2010).
PTCH is a 7 transmembrane protein that is localized to the primary cilium in the absence of Hh ligand (Rohatgi et al, 2007). PTCH regulates SMO in a non-stoichiometric manner and there is little evidence that endogenous PTCH and SMO interact directly (Taipale et al, 2002; reviewed in Huangfu and Anderson, 2006). PTCH has a sterol sensing domain (SSD) and structural similarity to bacterial RND transporters. Mutation in conserved motifs in the RND domain abrogate the ability of PTCH to negatively regulate SMO activity (Taipale et al, 2002). The transmembrane heptahelical domain of SMO has been shown to bind to a number of natural and synthetic molecules, many of which are structurally related to sterols, and this binding can activate or repress SMO activity (Mas et al, 2010; Dwyer et al, 2007; Nachtergaele et al, 2012; Corcoran et al, 2006). Together, these data suggest a speculative model where PTCH regulates SMO activity by controlling the flux of sterol-related SMO agonists and/or antagonists, although this has not been fully substantiated (Khaliullina et al, 2009; reviewed in Rohatgi and Scott, 2007; Briscoe and Therond, 2013).
In the absence of Hh signal, SMO is largely found in intracellular vesicles, with a fraction localized to the plasma membrane (Milenkovic et al, 2009; Huangfu et al, 2006; Corbit et al, 2005; Rohatgi et al, 2007; Wang et al, 2009; Wilson et al, 2009). Like GLI2, 3 and SUFU, however, SMO may traffic through the cilium in the absence of ligand (Wilson et al, 2009; Kim et al, 2009). SMO and PTCH appear to have opposing localizations in both the 'off' and 'on' state, with PTCH exiting and SMO entering the cilium upon Hh pathway activation (Denef et al, 2000; Rohatgi et al, 2007; reviewed in Goetz and Anderson, 2010; Hui and Angers, 2011). Clearance of PTCH from the ciliary membrane in the presence of Hh is promoted by its ubiquitination by the E3 ligase SMURF (Huang et al, 2013; Yue et al, 2014)
Like the Drosophila homologue, vertebrate SMO appears to exists as a constitutive dimer. Dimerization is mediated by the N-terminal Cys-rich domain (CRD) and is required for function (Zhao et al, 2007). The C-terminal tail of SMO has arginine-rich clusters that appear to regulate the conformation of the tails in the dimer, maintaining the SMO dimer in an inactive state. In Drosophila, the inhibitory effect of the arginine-rich region is counteracted upon Hh pathway activation by PKA-mediated phosphorylation of adjacent serine residues. This promotes an open tail conformation that is required for cell surface accumulation and signaling (Zhao et al, 2007; Chen et al, 2010). These consensus PKA motifs are not conserved in the vertebrate SMO C-terminal tail, and a role for PKA-mediated phosphorylation and direct activation of SMO appears not to hold true in mammalian cells (Zhao et al, 2007; Tuson et al, 2011). A similar activating phosphorylation of vertebrate SMO may be CK1 or GRK2-dependent (Chen et al, 2011).
R-HSA-5610766 (Reactome) Vertebrate hedgehog signaling depends on the passage and/or localization of many of the pathway components through the primary cilium (reviewed in Goetz and Anderson, 2010). Although GLI and SUFU proteins are not concentrated in the cilium in the absence of Hh signaling, processing and/or degradation of the transcription factors requires transit through the cilium and basal levels of these proteins can be detected there (Wen et al, 2010; Tukachinsky et al, 2010; Kim et al, 2006; Liu et al, 2005; Haycraft et 2005). Consistent with this, members of both the IFT-B and IFT-A complex, as well as components of the ciliary basal body and the kinesin-2 and dynein motor proteins have been identified as regulators of Hh signaling (Huangfu et al, 2003; Tran et al, 2008; Liu et al, 2005; Houde et al, 2006; Huangfu et al, 2005; May et al, 2005; Cortellino et al, 2009; Vierkotten et al, 2007; Ferrante et al, 2006; Weatherbee et al, 2009; Liem et al, 2012; Qin et al 2011). KIF7, a microtubule-associated kinesin-type motor that negatively regulates the length of axonemal microtubules, is also required for correct localization of GLI:SUFU (He et al, 2014). Finally, a number of PCP pathway effectors have recently been shown to be required for ciliogenesis, and mutations in these genes disrupt GLI processing (Zeng et al, 2010; Gray et al, 2009; Heydeck et al, 2009; Park et al, 2006).
R-HSA-5610767 (Reactome) Vertebrate hedgehog signaling depends on the passage and/or localization of many of the pathway components through the primary cilium (reviewed in Goetz and Anderson, 2010). Although GLI and SUFU proteins are not concentrated in the cilium in the absence of Hh signaling, processing and/or degradation of the transcription factors requires transit through the cilium and basal levels of these proteins can be detected there (Wen et al, 2010; Tukachinsky et al, 2010; Kim et al, 2006; Liu et al, 2005; Haycraft et 2005). Consistent with this, members of both the IFT-B and IFT-A complex, as well as components of the ciliary basal body and the kinesin-2 and dynein motor proteins have been identified as regulators of Hh signaling (Huangfu et al, 2003; Tran et al, 2008; Liu et al, 2005; Houde et al, 2006; Huangfu et al, 2005; May et al, 2005; Cortellino et al, 2009; Vierkotten et al, 2007; Ferrante et al, 2006; Weatherbee et al, 2009; Liem et al, 2012; Qin et al 2011). KIF7, a microtubule-associated kinesin-type motor that negatively regulates the length of axonemal microtubules, is also required for correct localization of GLI:SUFU (He et al, 2014). Finally, a number of PCP pathway effectors have recently been shown to be required for ciliogenesis, and mutations in these genes disrupt GLI processing (Zeng et al, 2010; Gray et al, 2009; Heydeck et al, 2009; Park et al, 2006).
R-HSA-5612508 (Reactome) GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). GLI-dependent target genes have been identified by a number of ChIP based screens, and one well established target of GLI3R is the Hh receptor, PTCH1 (Lee et al, 2010; Vokes et al, 2007; Vokes et al, 2008). GLI3R has been shown to bind to a GLI-consensus sequence in the PTCH1 promoter as assesed by electrophoretic mobility shift assay and the protein is able to repress expression of a reporter gene driven by this element (Agren et al, 2004). GLI3R may promote repressive complexes at the PTCH1 promoter by the SKI1-dependent recruitment of HDAC complexes (Dai et al, 2002). Other GLI3R transcriptional targets include GLI1 and GLI2 (Hu et al, 2006).
R-HSA-5612510 (Reactome) Expression of the PTCH1 gene is repressed in the absence of Hh signaling by GLI3R (Agren et al, 2004; Lee et al, 2010; Vokes et al, 2007; Vokes et al, 2008). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).
R-HSA-5617408 (Reactome) GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). In the absence of Hh signaling, GLI3R has been shown to bind to the promoters of the GLI1 and GLI2 genes as assesed by ChIP and to repress gene expression (Hu et al, 2006).
R-HSA-5617410 (Reactome) GLI3R is a DNA-binding transcriptional repressor that recognizes consensus GLI sites 5'-GACCACCC-3' in the promoters of target genes (Kinzler and Vogelstein, 1990). DNA-binding is mediated through 5 C2H2 Kruppel zinc fingers in the N-terminal region of the protein, which remains intact after proteasome-mediated processing (reviewed in Hui and Angers, 2011). In the absence of Hh signaling, GLI3R has been shown to bind to the promoters of the GLI1 and GLI2 genes as assesed by ChIP and to repress gene expression (Hu et al, 2006).
R-HSA-5617412 (Reactome) Expression of the GLI1 gene is repressed in the absence of Hh signaling by GLI3R (Hu et al, 2006). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).
R-HSA-5617413 (Reactome) Expression of the GLI2 gene is repressed in the absence of Hh signaling by GLI3R (Hu et al, 2006). GLI3R may exert its repression activity through the SKI-dependent recruitment of HDACs (Dai et al, 2002).
SCF beta-TrCP complexmim-catalysisR-HSA-5610742 (Reactome)
SCF beta-TrCP complexmim-catalysisR-HSA-5610745 (Reactome)
SCF beta-TrCP complexmim-catalysisR-HSA-5610746 (Reactome)
SMO dimerArrowR-HSA-5610763 (Reactome)
SMO dimerR-HSA-5610763 (Reactome)
SUFUArrowR-HSA-5610754 (Reactome)
SUFUArrowR-HSA-5610757 (Reactome)
SUFUArrowR-HSA-5610758 (Reactome)
SUFUArrowR-HSA-5610760 (Reactome)
SUFUR-HSA-5610723 (Reactome)
TULP3R-HSA-5610726 (Reactome)
UbR-HSA-5610742 (Reactome)
UbR-HSA-5610745 (Reactome)
UbR-HSA-5610746 (Reactome)
adenylate cyclases:Mg2+mim-catalysisR-HSA-5610727 (Reactome)
anterograde IFT regulators of HhArrowR-HSA-5610767 (Reactome)
cAMPArrowR-HSA-5610727 (Reactome)
cAMPR-HSA-5610749 (Reactome)
ciliary basal body regulators of HhArrowR-HSA-5610766 (Reactome)
ciliary basal body regulators of HhArrowR-HSA-5610767 (Reactome)
microtubuleR-HSA-5610733 (Reactome)
p10S-GLI3:SUFUArrowR-HSA-5610722 (Reactome)
p10S-GLI3:SUFUR-HSA-5610732 (Reactome)
p11S-GLI2:SUFUArrowR-HSA-5610730 (Reactome)
p11S-GLI2:SUFUR-HSA-5610745 (Reactome)
p13S-GLI3:SUFUArrowR-HSA-5610732 (Reactome)
p13S-GLI3:SUFUR-HSA-5610746 (Reactome)
p4S-GLI2:SUFUArrowR-HSA-5610717 (Reactome)
p4S-GLI2:SUFUR-HSA-5610718 (Reactome)
p6S-GLI3:SUFUArrowR-HSA-5610720 (Reactome)
p6S-GLI3:SUFUR-HSA-5610722 (Reactome)
p8S-GLI2:SUFUArrowR-HSA-5610718 (Reactome)
p8S-GLI2:SUFUR-HSA-5610730 (Reactome)
pS-GLI:SUFUArrowR-HSA-5610741 (Reactome)
pS-GLI:SUFUR-HSA-5610737 (Reactome)
pS-GLI:SUFUR-HSA-5610742 (Reactome)
retrograde IFT regulators of HhArrowR-HSA-5610766 (Reactome)
ub-p11S-GLI2:SUFUArrowR-HSA-5610745 (Reactome)
ub-p11S-GLI2:SUFUR-HSA-5610757 (Reactome)
ub-pS-GLI:SUFUArrowR-HSA-5610742 (Reactome)
ub-pS-GLI:SUFUR-HSA-5610758 (Reactome)
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