Circadian Clock (Homo sapiens)

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13, 31, 33, 4615, 4717, 19, 32, 42344235, 2516, 21, 406, 12, 24, 4754739515, 472735, 5251, 536, 12, 24, 4748, 49158, 14, 23, 24, 28...2, 419, 56563, 5729, 37, 45, 5036, 57nucleoplasmcytosolMEF2C,D:PPARGC1ACSNK1E CLOCK gene PPARGC1A NR3C1 NPAS2 NCOR1 RORA geneCRY2 genep-PER1,p-PER2CRY2 NR1D1 geneRORA PPARGC1A PER2 PER1 p-S-ARNTL p-CRY1,p-CRY2p-CRY:p-PER:KinaseARNTL NR1D1 gene ARNTL gene NPAS2 UBC(1-76) PER2 CRY1,2p-S-ARNTL CLOCK geneUBC(153-228) CSNK1D p-T263,S266,T299-PPARGC1A EPA ferriheme bNRIP1 p-S-CRY1 UBC(533-608) RAI1PP1 catalyticsubunitPER1,PER2PPARGC1Ap-S-PER1 RPS27A(1-76) CSNK1E UbiquitinPPP1CC p-S-NPAS2 CRY1 gene RORA p-S-PER1 p-BMAL1:p-CLOCK,NPAS2:CRY1 genep-S-NPAS2 UBC(457-532) p-BMAL1:p-CLOCK,NPAS2:PER2 geneCRY1RORA:Coactivator:NR1D1 geneNR3C1:Dexamethasonep-S-NPAS2 ALA SCF-beta-TrCP1complexp-S-NPAS2 ARNTL geneub-p-PER1,ub-p-PER2EP300 ub-p-CRY1,ub-p-CRY2p-S-PER2 NR1D1BMAL1:CLOCK,NPAS2:CRY:PERPER1 p-S-CRY2 HIF1AUBC(457-532) ferriheme b p-BMAL1:p-CLOCK,NPAS2:NR1D1 genep-S-CLOCK p-BMAL1:p-CLOCK,NPAS2UBC(533-608) PER1SIRT1NR1D1 gene FBXL3PPARGC1A gene AA UBC(381-456) p-S-PER2 p-S-CRY2 CLOCK BTRCPPARGC1A PER1 gene NPAS2 gene SMARCD3 PPP1CB BMAL1:CLOCK,NPAS2activates circadiangene expressionUBC(229-304) UBB(153-228) CLOCK p-S-PER2 Ub-p-S-CRY2 UBB(153-228) UBC(305-380) NR1D1:heme:Corepressors:PPARGC1A geneCRY2p-S-CRY1 CSNK1D HDAC3 p-CREB:CRTC1:PER1genep-S-NPAS2 NRIP1p-S-ARNTL p-S-CRY2 SKP1 HDAC3HDAC3 Ub-p-S-PER1 EP300HELZ2 NR1D1:heme:Corepressors:CLOCK geneCUL1 UBC(381-456) EP300 CSNK1D NR1D1 gene p-S-CLOCK CRY1 p-S-ARNTL RORA:EP300:NPAS2geneNR1D1:heme:Corepressors:NR1D1 geneCSNK1D CLOCK,NPAS2UBB(77-152) CRY:PER:KinaseBeta-TrCP1:PERp-S-CLOCK RORAUb-p-S-CRY1 CSNK1E RORA:Coactivator:ARNTL geneARNTL gene CRY2 HDAC3 CSNK1E UBC(77-152) NR1D1 PPP1CA p-S-NPAS2 ferriheme b NPAS2 Peroxisome Proliferator Receptor Element (PPRE) UBC(305-380) NCOR1 NPAS2p-S-PER2 PER2 BTRC p-S-PER1 UBA52(1-76) ARNTL RORA PPARA p-BMAL1:p-CLOCK,NPAS2:PER1 geneNPAS2 geneCHD9 BMAL1:CLOCK,NPAS2:CRYCRY1 UbPER1 p-CRY:p-PER:KinaseNRIP1 PER2 genep-S-CRY2 NR1D1 RORA activates geneexpressionMEF2C p-S-CRY1 UBC(153-228) PER1 gene p-S-CLOCK SIK1NCOA2 p-T178,S539-PPARGC1A NCOR1 UBB(1-76) LINA p-T69,T71-ATF2MED1 CRY1 FBXL3 NR1D1 NR1D1:heme:Corepressors:NPAS2 geneferriheme b ferriheme b RXRA p-S-ARNTL BMAL1:CLOCK,NPAS2NPAS2 gene CLOCK TBL1XR1 NR1D1 CLOCKp-S-NPAS2 p-S133-CREB1 p-S-ARNTL CSNK1E TBL1X UBC(1-76) HDAC3 NCOR1 PPARGC1A geneUBC(77-152) PER2MEF2D NR1D1 NR1D1 (REV-ERBA)represses geneexpressionp-S-PER1 PPARA:RXRACoactivator complexp-S-CLOCK CRTC1 FBXL3:CRYPER2 gene p-S-CLOCK UBA52(1-76) Palm BTRC p-PPARGC1AUBB(77-152) TGS1 UBC(229-304) UBC(609-684) CARM1 p-S133-CREB1NCOA6 p-BMAL1:p-CLOCK,NPAS2:RORA geneNCOA1 p-S-CRY1 UBB(1-76) EP300 RPS27A(1-76) DEXA NR1D1:heme:Corepressors:ARNTL geneCRY2 RORA gene CRY1 geneCSNK1D PER1 geneNCOR1 UBC(609-684) p-S-CRY2 NCOR1CSNK1E,CSNK1DUb-p-S-PER2 ferriheme b p-S-CLOCK p-S-ARNTL p-S-CRY1 ARNTLHDAC3 CREBBP 16, 441, 10, 18233817, 19, 22, 4211272630, 436, 12, 24, 4716, 4416, 4416, 4420, 501534


At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning.
Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA (NR1D1), both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha (RORA) activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1.
BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening.
PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.
The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients. View original pathway at:Reactome.


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101648view11:51, 1 November 2018ReactomeTeamreactome version 66
101184view21:39, 31 October 2018ReactomeTeamreactome version 65
100710view20:11, 31 October 2018ReactomeTeamreactome version 64
100260view16:56, 31 October 2018ReactomeTeamreactome version 63
99813view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93971view13:48, 16 August 2017ReactomeTeamreactome version 61
93571view11:27, 9 August 2017ReactomeTeamreactome version 61
87160view19:15, 18 July 2016MkutmonOntology Term : 'regulatory pathway' added !
86673view09:23, 11 July 2016ReactomeTeamreactome version 56
83282view10:37, 18 November 2015ReactomeTeamVersion54
81401view12:55, 21 August 2015ReactomeTeamVersion53
76871view08:14, 17 July 2014ReactomeTeamFixed remaining interactions
76576view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75909view09:56, 11 June 2014ReactomeTeamRe-fixing comment source
75609view10:46, 10 June 2014ReactomeTeamReactome 48 Update
74964view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74608view08:39, 30 April 2014ReactomeTeamReactome46
42020view21:50, 4 March 2011MaintBotAutomatic update
39823view05:51, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
AA MetaboliteCHEBI:15843 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
ARNTL ProteinO00327 (Uniprot-TrEMBL)
ARNTL gene ProteinENSG00000133794 (Ensembl)
ARNTL geneGeneProductENSG00000133794 (Ensembl)
ARNTLProteinO00327 (Uniprot-TrEMBL)

activates circadian

gene expression
PathwayR-HSA-1368108 (Reactome) As inferred from mouse, BMAL1:CLOCK (ARNTL:CLOCK) and BMAL1:NPAS2 (ARNTL:NPAS2) heterodimers bind to sequence elements (E boxes) in the promoters of target genes and enhance transcription (Gekakis et al. 1998, reviewed in Munoz and Baler 2003).
BMAL1:CLOCK,NPAS2:CRY:PERComplexR-HSA-400273 (Reactome)
BMAL1:CLOCK,NPAS2:CRYComplexR-HSA-549449 (Reactome)
BMAL1:CLOCK,NPAS2ComplexR-HSA-400360 (Reactome) BMAL1 (ARNTL) contains both a nuclear localization signal and a nuclear export signal. The shuttling of BMAL1 between the nucleus and cytoplasm is important for transactivation by BMAL1:CLOCK/NPAS2 and degradation of BMAL1:CLOCK/NPAS2. BMAL1 initially forms a heterodimer with CLOCK or NPAS2 in the cytosol. The heterodimer is then phosphorylated and translocated into the nucleus.
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
BTRCProteinQ9Y297 (Uniprot-TrEMBL)
Beta-TrCP1:PERComplexR-HSA-400368 (Reactome)
CARM1 ProteinQ86X55 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CLOCK ProteinO15516 (Uniprot-TrEMBL)
CLOCK gene ProteinENSG00000134852 (Ensembl)
CLOCK geneGeneProductENSG00000134852 (Ensembl)
CLOCK,NPAS2ComplexR-HSA-400343 (Reactome)
CLOCKProteinO15516 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CRTC1 ProteinQ6UUV9 (Uniprot-TrEMBL)
CRY1 ProteinQ16526 (Uniprot-TrEMBL)
CRY1 gene ProteinENSG00000008405 (Ensembl)
CRY1 geneGeneProductENSG00000008405 (Ensembl)
CRY1,2ComplexR-HSA-400223 (Reactome)
CRY1ProteinQ16526 (Uniprot-TrEMBL)
CRY2 ProteinQ49AN0 (Uniprot-TrEMBL)
CRY2 geneGeneProductENSG00000121671 (Ensembl)
CRY2ProteinQ49AN0 (Uniprot-TrEMBL)
CRY:PER:KinaseComplexR-HSA-421287 (Reactome) As inferred from mouse, PER proteins can form homodimers and CRY proteins can form heterodimers with PER proteins. CRY and PER proteins may therefore form trimers (PER:PER:CRY).
CSNK1D ProteinP48730 (Uniprot-TrEMBL)
CSNK1E ProteinP49674 (Uniprot-TrEMBL)
CSNK1E,CSNK1DComplexR-HSA-421289 (Reactome)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
DEXA MetaboliteCHEBI:41879 (ChEBI)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
FBXL3 ProteinQ9UKT7 (Uniprot-TrEMBL)
FBXL3:CRYComplexR-HSA-400351 (Reactome)
FBXL3ProteinQ9UKT7 (Uniprot-TrEMBL)
HDAC3 ProteinO15379 (Uniprot-TrEMBL)
HDAC3ProteinO15379 (Uniprot-TrEMBL)
HELZ2 ProteinQ9BYK8 (Uniprot-TrEMBL)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
LINA MetaboliteCHEBI:17351 (ChEBI)
MED1 ProteinQ15648 (Uniprot-TrEMBL) MED1 is a component of each of the various Mediator complexes, that function as transcription co-activators. The MED1-containing compolexes include the DRIP, ARC, TRIP and CRSP compllexes.
MEF2C ProteinQ06413 (Uniprot-TrEMBL)
MEF2C,D:PPARGC1AComplexR-HSA-1605560 (Reactome)
MEF2D ProteinQ14814 (Uniprot-TrEMBL)
NCOA1 ProteinQ15788 (Uniprot-TrEMBL)
NCOA2 ProteinQ15596 (Uniprot-TrEMBL)
NCOA6 ProteinQ14686 (Uniprot-TrEMBL)
NCOR1 ProteinO75376 (Uniprot-TrEMBL)
NCOR1ProteinO75376 (Uniprot-TrEMBL)
NPAS2 ProteinQ99743 (Uniprot-TrEMBL)
NPAS2 gene ProteinENSG00000170485 (Ensembl)
NPAS2 geneGeneProductENSG00000170485 (Ensembl)
NPAS2ProteinQ99743 (Uniprot-TrEMBL)

represses gene

PathwayR-HSA-1368071 (Reactome) REV-ERBA binds DNA elements very similar to those bound by the transcription activator RORA. RORAREV-ERBA bound to DNA and heme recruits the corepressors NCoR and HDAC3 to repress transcription. Thus REV-ERBA and RORA appear to compete to repress or activate genes, repectively.
NR1D1 ProteinP20393 (Uniprot-TrEMBL)
NR1D1 gene ProteinENSG00000126368 (Ensembl)
NR1D1 geneGeneProductENSG00000126368 (Ensembl)
NR1D1:heme:Corepressors:ARNTL geneComplexR-HSA-5663269 (Reactome)
NR1D1:heme:Corepressors:CLOCK geneComplexR-HSA-5663248 (Reactome)
NR1D1:heme:Corepressors:NPAS2 geneComplexR-HSA-5663274 (Reactome)
NR1D1:heme:Corepressors:NR1D1 geneComplexR-HSA-5663262 (Reactome)
NR1D1:heme:Corepressors:PPARGC1A geneComplexR-HSA-5663272 (Reactome)
NR1D1ProteinP20393 (Uniprot-TrEMBL)
NR3C1 ProteinP04150 (Uniprot-TrEMBL)
NR3C1:DexamethasoneComplexR-HSA-879850 (Reactome)
NRIP1 ProteinP48552 (Uniprot-TrEMBL)
NRIP1ProteinP48552 (Uniprot-TrEMBL)
PER1 ProteinO15534 (Uniprot-TrEMBL)
PER1 gene ProteinENSG00000179094 (Ensembl)
PER1 geneGeneProductENSG00000179094 (Ensembl)
PER1,PER2ComplexR-HSA-400344 (Reactome)
PER1ProteinO15534 (Uniprot-TrEMBL)
PER2 ProteinO15055 (Uniprot-TrEMBL)
PER2 gene ProteinENSG00000132326 (Ensembl)
PER2 geneGeneProductENSG00000132326 (Ensembl)
PER2ProteinO15055 (Uniprot-TrEMBL)
PP1 catalytic subunitComplexR-HSA-163538 (Reactome)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARA:RXRA Coactivator complexComplexR-HSA-400154 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1A gene ProteinENSG00000109189 (Ensembl)
PPARGC1A geneGeneProductENSG00000109189 (Ensembl)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
PPP1CA ProteinP62136 (Uniprot-TrEMBL)
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1CC ProteinP36873 (Uniprot-TrEMBL)
Palm MetaboliteCHEBI:15756 (ChEBI)
Peroxisome Proliferator Receptor Element (PPRE) R-NUL-422139 (Reactome) Peroxisome proliferator receptor elements bind heterodimers containing a peroxisome proliferator receptor and a retinoic acid receptor. The consensus sequence is TGAMCTTTGNCCTAGWTYYG.
RAI1ProteinQ7Z5J4 (Uniprot-TrEMBL)
RORA ProteinP35398 (Uniprot-TrEMBL)
RORA activates gene expressionPathwayR-HSA-1368082 (Reactome) As inferred from mouse, RORA binds ROR elements (ROREs) in DNA and recruits the coactivators PPARGC1A (PGC-1alpha) and p300 (EP300, a histone acetylase) to activate transcription.
RORA gene ProteinENSG00000069667 (Ensembl)
RORA geneGeneProductENSG00000069667 (Ensembl)
RORA:Coactivator:ARNTL geneComplexR-HSA-5663268 (Reactome)
RORA:Coactivator:NR1D1 geneComplexR-HSA-5663260 (Reactome)
RORA:EP300:NPAS2 geneComplexR-HSA-5663257 (Reactome)
RORAProteinP35398 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RXRA ProteinP19793 (Uniprot-TrEMBL)
SCF-beta-TrCP1 complexComplexR-HSA-174155 (Reactome)
SIK1ProteinP57059 (Uniprot-TrEMBL)
SIRT1ProteinQ96EB6 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (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)
Ub-p-S-CRY1 ProteinQ16526 (Uniprot-TrEMBL)
Ub-p-S-CRY2 ProteinQ49AN0 (Uniprot-TrEMBL)
Ub-p-S-PER1 ProteinO15534 (Uniprot-TrEMBL)
Ub-p-S-PER2 ProteinO15055 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
UbiquitinComplexR-HSA-68524 (Reactome)
ferriheme b MetaboliteCHEBI:36144 (ChEBI)
ferriheme bMetaboliteCHEBI:36144 (ChEBI)
p-BMAL1:p-CLOCK,NPAS2:CRY1 geneComplexR-HSA-5663148 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:NR1D1 geneComplexR-HSA-5663173 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER1 geneComplexR-HSA-5663110 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER2 geneComplexR-HSA-5663176 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:RORA geneComplexR-HSA-5669290 (Reactome)
p-BMAL1:p-CLOCK,NPAS2ComplexR-HSA-421315 (Reactome)
p-CREB:CRTC1:PER1 geneComplexR-HSA-5656495 (Reactome)
p-CRY1,p-CRY2ComplexR-HSA-400237 (Reactome)
p-CRY:p-PER:KinaseComplexR-HSA-400277 (Reactome)
p-CRY:p-PER:KinaseComplexR-HSA-421296 (Reactome)
p-PER1,p-PER2ComplexR-HSA-400346 (Reactome)
p-PPARGC1AComplexR-HSA-1592227 (Reactome)
p-S-ARNTL ProteinO00327 (Uniprot-TrEMBL)
p-S-CLOCK ProteinO15516 (Uniprot-TrEMBL)
p-S-CRY1 ProteinQ16526 (Uniprot-TrEMBL)
p-S-CRY2 ProteinQ49AN0 (Uniprot-TrEMBL)
p-S-NPAS2 ProteinQ99743 (Uniprot-TrEMBL)
p-S-PER1 ProteinO15534 (Uniprot-TrEMBL)
p-S-PER2 ProteinO15055 (Uniprot-TrEMBL)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-T178,S539-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T263,S266,T299-PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
ub-p-CRY1,ub-p-CRY2ComplexR-HSA-517938 (Reactome)
ub-p-PER1,ub-p-PER2ComplexR-HSA-517830 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ARNTL geneR-HSA-1368069 (Reactome)
ARNTL geneR-HSA-1368087 (Reactome)
ARNTL geneR-HSA-400342 (Reactome)
ARNTLArrowR-HSA-400342 (Reactome)
ARNTLR-HSA-400228 (Reactome)
BMAL1:CLOCK,NPAS2:CRY:PERArrowR-HSA-400256 (Reactome)
BMAL1:CLOCK,NPAS2:CRYArrowR-HSA-549355 (Reactome)
BMAL1:CLOCK,NPAS2ArrowR-HSA-400228 (Reactome)
BMAL1:CLOCK,NPAS2R-HSA-421320 (Reactome)
BMAL1:CLOCK,NPAS2R-HSA-549355 (Reactome)
BTRCArrowR-HSA-400267 (Reactome)
BTRCR-HSA-400219 (Reactome)
Beta-TrCP1:PERArrowR-HSA-400219 (Reactome)
Beta-TrCP1:PERR-HSA-400267 (Reactome)
CLOCK geneR-HSA-1368119 (Reactome)
CLOCK geneR-HSA-5663271 (Reactome)
CLOCK,NPAS2R-HSA-400228 (Reactome)
CLOCKArrowR-HSA-1368119 (Reactome)
CRY1 geneR-HSA-549467 (Reactome)
CRY1 geneR-HSA-5663120 (Reactome)
CRY1,2R-HSA-1856948 (Reactome)
CRY1,2R-HSA-549355 (Reactome)
CRY1ArrowR-HSA-549467 (Reactome)
CRY2 geneR-HSA-549470 (Reactome)
CRY2ArrowR-HSA-549470 (Reactome)
CRY:PER:KinaseArrowR-HSA-1856948 (Reactome)
CRY:PER:KinaseR-HSA-400382 (Reactome)
CSNK1E,CSNK1DR-HSA-1856948 (Reactome)
CSNK1E,CSNK1Dmim-catalysisR-HSA-400382 (Reactome)
EP300R-HSA-1368087 (Reactome)
EP300R-HSA-5663246 (Reactome)
EP300R-HSA-5663273 (Reactome)
FBXL3:CRYArrowR-HSA-400272 (Reactome)
FBXL3:CRYR-HSA-400282 (Reactome)
FBXL3ArrowR-HSA-400282 (Reactome)
FBXL3R-HSA-400272 (Reactome)
HDAC3R-HSA-1368069 (Reactome)
HDAC3R-HSA-5663245 (Reactome)
HDAC3R-HSA-5663258 (Reactome)
HDAC3R-HSA-5663265 (Reactome)
HDAC3R-HSA-5663271 (Reactome)
HIF1AArrowR-HSA-1368133 (Reactome)
MEF2C,D:PPARGC1AArrowR-HSA-1368140 (Reactome)
NCOR1R-HSA-1368069 (Reactome)
NCOR1R-HSA-5663245 (Reactome)
NCOR1R-HSA-5663258 (Reactome)
NCOR1R-HSA-5663265 (Reactome)
NCOR1R-HSA-5663271 (Reactome)
NPAS2 geneR-HSA-1368065 (Reactome)
NPAS2 geneR-HSA-5663245 (Reactome)
NPAS2 geneR-HSA-5663246 (Reactome)
NPAS2ArrowR-HSA-1368065 (Reactome)
NR1D1 geneR-HSA-549475 (Reactome)
NR1D1 geneR-HSA-5663155 (Reactome)
NR1D1 geneR-HSA-5663265 (Reactome)
NR1D1 geneR-HSA-5663273 (Reactome)
NR1D1:heme:Corepressors:ARNTL geneArrowR-HSA-1368069 (Reactome)
NR1D1:heme:Corepressors:ARNTL geneTBarR-HSA-400342 (Reactome)
NR1D1:heme:Corepressors:CLOCK geneArrowR-HSA-5663271 (Reactome)
NR1D1:heme:Corepressors:CLOCK geneTBarR-HSA-1368119 (Reactome)
NR1D1:heme:Corepressors:NPAS2 geneArrowR-HSA-5663245 (Reactome)
NR1D1:heme:Corepressors:NPAS2 geneTBarR-HSA-1368065 (Reactome)
NR1D1:heme:Corepressors:NR1D1 geneArrowR-HSA-5663265 (Reactome)
NR1D1:heme:Corepressors:NR1D1 geneTBarR-HSA-549475 (Reactome)
NR1D1:heme:Corepressors:PPARGC1A geneArrowR-HSA-5663258 (Reactome)
NR1D1:heme:Corepressors:PPARGC1A geneTBarR-HSA-1368140 (Reactome)
NR1D1ArrowR-HSA-549475 (Reactome)
NR1D1R-HSA-1368069 (Reactome)
NR1D1R-HSA-5663245 (Reactome)
NR1D1R-HSA-5663258 (Reactome)
NR1D1R-HSA-5663265 (Reactome)
NR1D1R-HSA-5663271 (Reactome)
NR3C1:DexamethasoneArrowR-HSA-549493 (Reactome)
NRIP1R-HSA-1368087 (Reactome)
NRIP1R-HSA-5663273 (Reactome)
PER1 geneR-HSA-549533 (Reactome)
PER1 geneR-HSA-5663174 (Reactome)
PER1,PER2R-HSA-1856948 (Reactome)
PER1ArrowR-HSA-549533 (Reactome)
PER2 geneR-HSA-549493 (Reactome)
PER2 geneR-HSA-5663118 (Reactome)
PER2ArrowR-HSA-549493 (Reactome)
PP1 catalytic subunitTBarR-HSA-400382 (Reactome)
PPARA:RXRA Coactivator complexArrowR-HSA-1368065 (Reactome)
PPARGC1A geneR-HSA-1368140 (Reactome)
PPARGC1A geneR-HSA-5663258 (Reactome)
PPARGC1AArrowR-HSA-1368140 (Reactome)
PPARGC1AR-HSA-1368087 (Reactome)
PPARGC1AR-HSA-5663273 (Reactome)
R-HSA-1368065 (Reactome) The NPAS2 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of NPAS2 is enhanced by the RORA:Coactivator complex and repressed by the REV-ERBA:Corepressor complex.
R-HSA-1368069 (Reactome) NR1D1 (REV-ERBA) binds heme. The NR1D1:heme complex is then able to recruit the corepressors NCoR and HDAC3. Corepressors do not bind NR1D1 in the absence of heme. NR1D1:heme binds a RRE element in the promoter of the ARNTL (BMAL1) gene, recruits corepressors, and represses transcription.
R-HSA-1368087 (Reactome) As inferred from mouse, RORA binds RRE DNA elements and recruits the coactivators PGC-1alpha (PPARGC1A), p300 (EP300, a histone acetylase), and NRIP1. Activation of BMAL1 (ARNTL) expression by ROR-alpha (RORA) is inferred from mouse. In mouse, Rora together with coactivators Ep300 and Ppargc1a bind the promoter of Bmal1 and activate transcription.
R-HSA-1368119 (Reactome) The CLOCK gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of CLOCK is repressed by REV-ERBA. The promoter of CLOCK contains an RRE element that may bind REV-ERBA and RORA.
R-HSA-1368133 (Reactome) The RORA gene is transcribed to yield mRNA and the mRNA is transcribed to yield protein.
R-HSA-1368140 (Reactome) The PPARGC1A (PGC-1alpha) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PPARGC1A protein is located in the nucleus where it coactivates transcription.
R-HSA-1856948 (Reactome) CRYPTOCHROME, PERIOD, and a kinase (CKIepsilon or CKIdelta) form a ternary complex in the cytosol.
R-HSA-400219 (Reactome) Beta-TrCP1 is an F-box type component of a particular SKP/CUL/F-Box (SCF) E3 ubiquitin ligase. Beta-TrCP1 interacts specifically with phosphorylated PER proteins and directs their polyubiquitination.
R-HSA-400228 (Reactome) BMAL1 (ARNTL), CLOCK, and NPAS2 are basic helix-loop-helix transcription factors. In humans BMAL1 has been demonstrated to form a heterodimer with CLOCK. In mouse, BMAL1 can form a heterodimer with either CLOCK or NPAS2. By analogy with other basic helix-loop-helix proteins the basic domain binds DNA, in this case the E-box motif, and the helix-loop-helix domains interact to form the heterodimer. BMAL1 and CLOCK/NPAS2 are codependently phosphorylated by unknown kinases after dimerization. The phosphorylation enhances transactivation activity and is inhibited by PER:CRY complexes. Both CLOCK and NPAS2 are expressed in the suprachiasmatic nucleus of the hypothalamus and act redundantly there. The tissue distributions of CLOCK and NPAS2 do not entirely overlap, however. For example, NPAS2 but not CLOCK is found in forebrain.
R-HSA-400256 (Reactome) CRY (CRY1 and CRY2) and PER (PER1, PER2, PER3) proteins form complex in the cytoplasm where they are phosphorylated by CSNK1D and CSNK1E kinases. CRY:PER complexes appear to form stable complexes with a kinase. Because of the nuclear localization signals of PER and CRY, the complexes are translocated to the nucleus where they bind BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) heterodimers and inhibit the transactivation activity of BMAL1:CLOCK/NPAS2.
CRY and PER proteins are themselves transcriptionally activated by BMAL1:CLOCK/NPAS2 thus they participate in a negative loop inhibiting their own synthesis and the synthesis of other targets of BMAL1:CLOCK/NPAS2.
Experiments with two-hybrid interactions and in vitro associations show that CRY1, CRY2, and PER2 bind BMAL1 at two different sites on BMAL1. PER2 but not CRY1 or CRY2 binds CLOCK. Different combinations of PER and CRY proteins in PER:CRY complexes have different inhibitory activities.
R-HSA-400267 (Reactome) Polyubiquitination of PER proteins is directed by the Beta-TrCP1 component of SCF E3 ubiquitin ligase. The polyubiquitinated PER proteins are recognized and degraded by the 26S proteasome. Degradation of PER proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) targets in the morning during the circadian cycle.
R-HSA-400272 (Reactome) FBXL3 is an F-box type component of a particular SKP/CUL/F-Box E3 ubiquitin ligase. FBXL3 interacts specifically with CRY1 and CRY2 in the cytosol to direct the polyubiquitination of CRY1 and CRY2. It is unknown if FBXL3 requires phosphorylation or other modification of CRY proteins in order to bind and ubiquitinate them. Phosphorylation of CRY by Adenosine monophosphate-dependent kinase increases degradation of CRY, apparently by increasing association of CRY with FBXL3 Polyubiquitination of CRY proteins directs them to the 26S proteasome for degradation.
R-HSA-400282 (Reactome) Polyubiquitination of CRY proteins is directed by the FBXL3 component of SCF E3 ubiquitin ligase. The polyubiquitinated CRY proteins are recognized and degraded by the 26S proteasome. Degradation of CRY proteins occurs during the night and is necessary to allow new transcription of BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) targets in the morning during the circadian cycle.
R-HSA-400342 (Reactome) The BMAL1 (ARNTL) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The ROR-alpha transcription factor binds the RORE element of the BMAL1 (ARNTL) promoter and activates transcription of the BMAL1 gene. The REV-ERBA transcription factor binds the same RORE element and represses transcription of the BMAL1 gene.
R-HSA-400382 (Reactome) In the cytosol the kinases CSNK1D (casein kinase I delta) and CSNK1E (casein kinase I epsilon) phosphorylate PER1, PER2, CRY1, and CRY2 at multiple sites. Evidence indicates that PER:CRY complexes form a stable ternary complex with either CSNK1E or CSNK1D. Both kinases are able to bind and phosphorylate PER proteins. CSNK1E has been shown to phosphorylate CRY proteins only when they are complexed with PER proteins.
PER proteins contain a nuclear localization sequence and a nuclear export sequence allowing their movement into and out of the nucleus. Phosphorylation is required for transit of PER:CRY:kinase complexes into the nucleus and for interaction of PER proteins with the ubiquitin-mediated degradation process in the cytoplasm.
A mutation at Serine662 of PER2 is responsible for familial advanced phase sleep syndrome, however the particular kinase responsible for phosphorylating Serine662 is unknown.
R-HSA-421320 (Reactome) As inferred from mouse, BMAL1 (ARNTL), CLOCK, and NPAS2 are phosphorylated by unknown kinases. The phosphorylation is dependent on the heterodimerization of BMAL1 with CLOCK or NPAS2. Phosphorylated BMAL1:CLOCK/NPAS2 is a much stronger transactivator of gene expression than is unphosphorylated BMAL1:CLOCK/NPAS2.
R-HSA-549355 (Reactome) CRY1 and CRY2 bind the unphosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and by homology the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer) and prolong its half-life. The unphosphorylated BMAL1:CLOCK heterodimer only weakly activates transcription and is therefore believed to competitively reduce transcription by phosphorylated BMAL1:CLOCK heterodimer. The complex of unphosphorylated BMAL1:CLOCK with CRY may contain additional components and may traffic into the nucleus.
R-HSA-549385 (Reactome) The ternary complex containing phosphorylated CRY and PER proteins with a kinase (CSNK1D or CSNK1E) is translocated to the nucleus. Phosphorylation controls transfer to the nucleus and retention in the nucleus.
R-HSA-549467 (Reactome) The CRYPTOCHROME-1 (CRY1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. CRY1 mRNA and protein show circadian expression. The promoter of the CRY1 gene contains an E-box which is bound by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 heterodimer), which activates transcription of CRY1.
R-HSA-549470 (Reactome) The CRYPTOCHROME-2 (CRY2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the CRY2 protein shows circadian rhythm in the suprachiasmatic nucleus (SCN) and in peripheral tissues. The mRNA shows circadian rhythm in muscle but not in the SCN. Expression is dependent on CLOCK.
R-HSA-549475 (Reactome) The NR1D1 (REV-ERBA) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the Rev-erba gene shows circadian expression due to transactivation by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer. REV-ERBA binds the promoter of its own gene and represses its own expression (Adelmont et al. 1996).
R-HSA-549493 (Reactome) The PERIOD-2 (PER2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER2 gene contains an E-box which binds the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER2.
R-HSA-549533 (Reactome) The PERIOD-1 (PER1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The promoter of the PER1 gene contains E-boxes which are bound by the BMAL1:CLOCK (ARNTL:CLOCK) heterodimer (and probably also the BMAL1:NPAS2 (ARNTL:NPAS2) heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER1.
R-HSA-5663118 (Reactome) As inferred from mouse, the phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds a noncanonical E-box in the promoter of the PER2 gene and activates transcription of PER2. NPAS2 is predicted to act redundantly with CLOCK.
R-HSA-5663120 (Reactome) The phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds an E-box in the promoter of the CRY1 gene and activates transcription of CRY1. NPAS2 is predicted to act redundantly with CLOCK.
R-HSA-5663155 (Reactome) Activation of NR1D1 (REV-ERBA) expression by phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) is inferred from mouse. NPAS2 is predicted to act redundantly with CLOCK.
R-HSA-5663174 (Reactome) The phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) heterodimer binds E-boxes in the promoter of the PER1 gene and activates transcription of PER1. NPAS2 is predicted to act redundantly with CLOCK.
R-HSA-5663245 (Reactome) NR1D1 (REV-ERBA) binds the promoter of the NPAS2 gene and recruits corepressors to repress transcription. Recruitment of repressors appears to depend on the binding of heme by NR1D1.
R-HSA-5663246 (Reactome) As inferred from mouse, RORA binds RRE DNA elements and recruits the coactivators PGC-1alpha (PPARGC1A) and p300 (EP300, a histone acetylase). As inferred from mouse, ROR-alpha binds the promoter of the NPAS2 gene and enhances transcription.
R-HSA-5663258 (Reactome) NR1D1 (REV-ERBA) binds heme and the promoter of the PGC-1alpha (PPARGC1A) gene. The REV-ERBA:heme complex recruits the corepressors NCoR and HDAC3 and represses transcription.
R-HSA-5663265 (Reactome) NR1D1 (REV-ERBA) binds its own promoter and represses its own expression.
R-HSA-5663271 (Reactome) NR1D1 (REV-ERBA) binds the promoter of the CLOCK gene and recruits corepressors to repress transcription. Recruitment of repressors appears to depend on the binding of heme by NR1D1.
R-HSA-5663273 (Reactome) As inferred from mouse, RORA binds RRE DNA elements and recruits the coactivators PGC-1alpha (PPARGC1A) and p300 (EP300, a histone acetylase). RORA binds the NR1D1 (REV-ERBA) promoter and activates transcription.
R-HSA-5669302 (Reactome) As inferred from mouse homologs, the p-BMAL1:p-CLOCK,NPAS2 heterodimer binds the promoter of the RORA gene and activates transcription.
RAI1ArrowR-HSA-1368119 (Reactome)
RORA geneR-HSA-1368133 (Reactome)
RORA geneR-HSA-5669302 (Reactome)
RORA:Coactivator:ARNTL geneArrowR-HSA-1368087 (Reactome)
RORA:Coactivator:ARNTL geneArrowR-HSA-400342 (Reactome)
RORA:Coactivator:NR1D1 geneArrowR-HSA-549475 (Reactome)
RORA:Coactivator:NR1D1 geneArrowR-HSA-5663273 (Reactome)
RORA:EP300:NPAS2 geneArrowR-HSA-1368065 (Reactome)
RORA:EP300:NPAS2 geneArrowR-HSA-5663246 (Reactome)
RORAArrowR-HSA-1368133 (Reactome)
RORAR-HSA-1368087 (Reactome)
RORAR-HSA-5663246 (Reactome)
RORAR-HSA-5663273 (Reactome)
SCF-beta-TrCP1 complexmim-catalysisR-HSA-400267 (Reactome)
SIK1TBarR-HSA-549533 (Reactome)
SIRT1ArrowR-HSA-1368119 (Reactome)
SIRT1ArrowR-HSA-400342 (Reactome)
UbR-HSA-400267 (Reactome)
UbiquitinR-HSA-400282 (Reactome)
ferriheme bR-HSA-1368069 (Reactome)
ferriheme bR-HSA-5663245 (Reactome)
ferriheme bR-HSA-5663258 (Reactome)
ferriheme bR-HSA-5663265 (Reactome)
ferriheme bR-HSA-5663271 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:CRY1 geneArrowR-HSA-549467 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:CRY1 geneArrowR-HSA-5663120 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:NR1D1 geneArrowR-HSA-549475 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:NR1D1 geneArrowR-HSA-5663155 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER1 geneArrowR-HSA-549533 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER1 geneArrowR-HSA-5663174 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER2 geneArrowR-HSA-549493 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:PER2 geneArrowR-HSA-5663118 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:RORA geneArrowR-HSA-1368133 (Reactome)
p-BMAL1:p-CLOCK,NPAS2:RORA geneArrowR-HSA-5669302 (Reactome)
p-BMAL1:p-CLOCK,NPAS2ArrowR-HSA-421320 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-400256 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-5663118 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-5663120 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-5663155 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-5663174 (Reactome)
p-BMAL1:p-CLOCK,NPAS2R-HSA-5669302 (Reactome)
p-CREB:CRTC1:PER1 geneArrowR-HSA-549533 (Reactome)
p-CRY1,p-CRY2R-HSA-400272 (Reactome)
p-CRY:p-PER:KinaseArrowR-HSA-400382 (Reactome)
p-CRY:p-PER:KinaseArrowR-HSA-549385 (Reactome)
p-CRY:p-PER:KinaseR-HSA-400256 (Reactome)
p-CRY:p-PER:KinaseR-HSA-549385 (Reactome)
p-PER1,p-PER2R-HSA-400219 (Reactome)
p-PPARGC1AArrowR-HSA-1368140 (Reactome)
p-S133-CREB1ArrowR-HSA-1368140 (Reactome)
p-T69,T71-ATF2ArrowR-HSA-1368140 (Reactome)
ub-p-CRY1,ub-p-CRY2ArrowR-HSA-400282 (Reactome)
ub-p-PER1,ub-p-PER2ArrowR-HSA-400267 (Reactome)
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