Circadian Clock (Homo sapiens)

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35, 43, 50, 60392, 8, 58, 6227, 4713, 21, 25, 28, 54...14, 5320, 31, 5168383, 34, 45, 5210, 679, 33, 54, 611718, 26551, 6, 36, 716941654249, 6114, 40, 48115, 19, 44, 5718, 3022, 462113, 25Coactivators of PPARalpha p-S-PER1,2 p-CRY1/2 cytosolnucleoplasmPER1/2 Glucocorticoid receptorDexamethasone Complex endoplasmic reticulum lumenp-CRY1/2 CLOCK/NPAS2 Beta-TrCP1PER SCF-beta-TrCP1 complex BMAL2CLOCK CLOCK/NPAS2 CRYPERKinase MEF2C/D CRY1/2 Ligands of PPARA Activated PPARARXRA Heterodimer FBXL3CRY p-CRYp-PERKinase MEF2C/DPPARGC1A BMAL1CLOCK/NPAS2 BMAL1CLOCK/NPAS2CRY ROR-alphaCoactivator BMAL1CLOCK/NPAS2CRYPER p-CRYp-PERKinase NR1D1 mitochondrial outer membranep-PER1/2 PER1/2 PPARARXRA Coactivator Complex p-BMAL1p-CLOCK/NPAS2DNA p-CLOCK/p-NPAS2 p-CRY1/2 CRY1/2 PPARA Fatty Acid Complex p-CRYp-PERKinase p-S-PER1,2 p-CRY1/2 BMAL1CLOCK/NPAS2 NR1D1 p-BMAL1p-CLOCK/NPAS2DNA p-CLOCK/p-NPAS2 p-S-PER2 HELZ2 NCOR1 FBXL3AVPNAMPTBeta-TrCP1PERCLOCKNR1D1 ARNTL FBXL3 TBL1XR1 PER2 p-S-PER2 BMAL1CLOCK/NPAS2CRYPERub-p-CRY1/2p-CRY1/2BMAL1CLOCK/NPAS2p-S-PER2 PER1PER2ubiquitinHDAC3 p-S-CRY2 p-S-CRY2 p-S-CRY1 CLOCK CLOCK/NPAS2p-S-ARNTL CUL1 AA EP300SCF-beta-TrCP1 complexp-CRYp-PERKinasep-PER1/2BMAL1CLOCK/NPAS2CRYPPARGC1A SKP1 CPT1ANCOA2 NPAS2 PER1 MED1 FBXL3CRYp-S-CRY2 CRY1p-S-CRY1 RORA NPAS2 PER1/2TBL1X p-S-ARNTL p-S-CLOCK ARNTLPER2 ferriheme b MEF2C p-S-NPAS2 MEF2C/DPPARGC1ACHD9 ARNTL MEF2D CLOCK ROR-alphaCoactivatorBTRC p-T69,T71-ATF2RORE LINA NR1D1p-S-PER1 CCRN4Lp-S-CRY2 UbE-box CREBBPp-S-CRY1 p-S-PER1 p-BMAL1p-CLOCK/NPAS2DNAp-S-CRY1 BHLHE41HIF1ACRY1 PPARGC1A BMAL2CLOCKTGS1 p-S-PER1 NCOA6 CRY1/2SREBF1PPARARXRA NR3C1 DBPARNTL2 PPARARXRA Coactivator Complexpro-factor VIIELOVL3NCOR1ALA CRY2 CRYPERKinaseSERPINE1CRY2 p-PPARGC1APPARGC1ACSNK1E/CSNK1DPalm NPAS2PER1 ub-p-PER1/2SMARCD3 CRY2CRY1 ferriheme bDEXA HDAC3BHLHE40p-CRYp-PERKinaseNCOA1 EP300NR1D1 EPA p-S-CLOCK p-S-NPAS2 PPARA p-S133-CREB1BTRC RORABTRCGlucocorticoid receptorDexamethasone ComplexCLOCK CARM116, 327, 207, 2012, 292336372, 8, 62157, 2056, 59, 704, 24, 6321


Description

At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1: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, 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 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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=400253

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Bibliography

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  1. van der Spek PJ, Kobayashi K, Bootsma D, Takao M, Eker AP, Yasui A.; ''Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors.''; PubMed Europe PMC Scholia
  2. Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ.; ''Modeling of a human circadian mutation yields insights into clock regulation by PER2.''; PubMed Europe PMC Scholia
  3. Motzkus D, Loumi S, Cadenas C, Vinson C, Forssmann WG, Maronde E.; ''Activation of human period-1 by PKA or CLOCK/BMAL1 is conferred by separate signal transduction pathways.''; PubMed Europe PMC Scholia
  4. Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y.; ''Circadian oscillation of a mammalian homologue of the Drosophila period gene.''; PubMed Europe PMC Scholia
  5. Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, Hashimoto S.; ''System-level identification of transcriptional circuits underlying mammalian circadian clocks.''; PubMed Europe PMC Scholia
  6. Ikeda M, Nomura M.; ''cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage.''; PubMed Europe PMC Scholia
  7. Kobayashi K, Kanno S, Smit B, van der Horst GT, Takao M, Yasui A.; ''Characterization of photolyase/blue-light receptor homologs in mouse and human cells.''; PubMed Europe PMC Scholia
  8. Matsumura R, Matsubara C, Node K, Takumi T, Akashi M.; ''Nuclear receptor-mediated cell-autonomous oscillatory expression of the circadian transcription factor, neuronal PAS domain protein 2 (NPAS2).''; PubMed Europe PMC Scholia
  9. Yin L, Wu N, Lazar MA.; ''Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism.''; PubMed Europe PMC Scholia
  10. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA.; ''Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.''; PubMed Europe PMC Scholia
  11. Ko CH, Takahashi JS.; ''Molecular components of the mammalian circadian clock.''; PubMed Europe PMC Scholia
  12. Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, Yamamoto T.; ''Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus.''; PubMed Europe PMC Scholia
  13. Tamaru T, Hirayama J, Isojima Y, Nagai K, Norioka S, Takamatsu K, Sassone-Corsi P.; ''CK2alpha phosphorylates BMAL1 to regulate the mammalian clock.''; PubMed Europe PMC Scholia
  14. Adelmant G, Bègue A, Stéhelin D, Laudet V.; ''A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.''; PubMed Europe PMC Scholia
  15. Poliandri AH, Gamsby JJ, Christian M, Spinella MJ, Loros JJ, Dunlap JC, Parker MG.; ''Modulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140).''; PubMed Europe PMC Scholia
  16. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM.; ''A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.''; PubMed Europe PMC Scholia
  17. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH.; ''Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.''; PubMed Europe PMC Scholia
  18. Dardente H, Fortier EE, Martineau V, Cermakian N.; ''Cryptochromes impair phosphorylation of transcriptional activators in the clock: a general mechanism for circadian repression.''; PubMed Europe PMC Scholia
  19. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F.; ''Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta.''; PubMed Europe PMC Scholia
  20. Nakamura K, Inoue I, Takahashi S, Komoda T, Katayama S.; ''Cryptochrome and Period Proteins Are Regulated by the CLOCK/BMAL1 Gene: Crosstalk between the PPARs/RXRalpha-Regulated and CLOCK/BMAL1-Regulated Systems.''; PubMed Europe PMC Scholia
  21. Thompson CL, Bowes Rickman C, Shaw SJ, Ebright JN, Kelly U, Sancar A, Rickman DW.; ''Expression of the blue-light receptor cryptochrome in the human retina.''; PubMed Europe PMC Scholia
  22. Crumbley C, Wang Y, Kojetin DJ, Burris TP.; ''Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene.''; PubMed Europe PMC Scholia
  23. Reick M, Garcia JA, Dudley C, McKnight SL.; ''NPAS2: an analog of clock operative in the mammalian forebrain.''; PubMed Europe PMC Scholia
  24. Sato TK, Yamada RG, Ukai H, Baggs JE, Miraglia LJ, Kobayashi TJ, Welsh DK, Kay SA, Ueda HR, Hogenesch JB.; ''Feedback repression is required for mammalian circadian clock function.''; PubMed Europe PMC Scholia
  25. Crumbley C, Burris TP.; ''Direct regulation of CLOCK expression by REV-ERB.''; PubMed Europe PMC Scholia
  26. Muñoz E, Baler R.; ''The circadian E-box: when perfect is not good enough.''; PubMed Europe PMC Scholia
  27. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH.; ''An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.''; PubMed Europe PMC Scholia
  28. Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC.; ''Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.''; PubMed Europe PMC Scholia
  29. Pilegaard H, Saltin B, Neufer PD.; ''Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle.''; PubMed Europe PMC Scholia
  30. Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert SM.; ''Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei.''; PubMed Europe PMC Scholia
  31. Takahashi JS, Hong HK, Ko CH, McDearmon EL.; ''The genetics of mammalian circadian order and disorder: implications for physiology and disease.''; PubMed Europe PMC Scholia
  32. Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B.; ''DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region.''; PubMed Europe PMC Scholia
  33. Akashi M, Tsuchiya Y, Yoshino T, Nishida E.; ''Control of intracellular dynamics of mammalian period proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured cells.''; PubMed Europe PMC Scholia
  34. Eide EJ, Vielhaber EL, Hinz WA, Virshup DM.; ''The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.''; PubMed Europe PMC Scholia
  35. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G.; ''Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors.''; PubMed Europe PMC Scholia
  36. Hastings MH, Maywood ES, O'Neill JS.; ''Cellular circadian pacemaking and the role of cytosolic rhythms.''; PubMed Europe PMC Scholia
  37. Green CB, Takahashi JS, Bass J.; ''The meter of metabolism.''; PubMed Europe PMC Scholia
  38. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM.; ''Posttranslational mechanisms regulate the mammalian circadian clock.''; PubMed Europe PMC Scholia
  39. Larrouy D, Vidal H, Andreelli F, Laville M, Langin D.; ''Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.''; PubMed Europe PMC Scholia
  40. Latres E, Chiaur DS, Pagano M.; ''The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.''; PubMed Europe PMC Scholia
  41. Rutter J, Reick M, Wu LC, McKnight SL.; ''Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.''; PubMed Europe PMC Scholia
  42. Raspè E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B.; ''Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha.''; PubMed Europe PMC Scholia
  43. Yin L, Lazar MA.; ''The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.''; PubMed Europe PMC Scholia
  44. Steeves TD, King DP, Zhao Y, Sangoram AM, Du F, Bowcock AM, Moore RY, Takahashi JS.; ''Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei.''; PubMed Europe PMC Scholia
  45. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA.; ''Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.''; PubMed Europe PMC Scholia
  46. Hogenesch JB, Gu YZ, Jain S, Bradfield CA.; ''The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors.''; PubMed Europe PMC Scholia
  47. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M.; ''SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.''; PubMed Europe PMC Scholia
  48. Camacho F, Cilio M, Guo Y, Virshup DM, Patel K, Khorkova O, Styren S, Morse B, Yao Z, Keesler GA.; ''Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2.''; PubMed Europe PMC Scholia
  49. Keesler GA, Camacho F, Guo Y, Virshup D, Mondadori C, Yao Z.; ''Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon.''; PubMed Europe PMC Scholia
  50. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ.; ''Role of the CLOCK protein in the mammalian circadian mechanism.''; PubMed Europe PMC Scholia
  51. Miyazaki K, Nagase T, Mesaki M, Narukawa J, Ohara O, Ishida N.; ''Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts.''; PubMed Europe PMC Scholia
  52. Phelan CA, Gampe RT, Lambert MH, Parks DJ, Montana V, Bynum J, Broderick TM, Hu X, Williams SP, Nolte RT, Lazar MA.; ''Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction.''; PubMed Europe PMC Scholia
  53. Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, McKnight SL.; ''Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system.''; PubMed Europe PMC Scholia
  54. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA.; ''Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.''; PubMed Europe PMC Scholia
  55. Shirogane T, Jin J, Ang XL, Harper JW.; ''SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein.''; PubMed Europe PMC Scholia
  56. Knutti D, Kaul A, Kralli A.; ''A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.''; PubMed Europe PMC Scholia
  57. Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada RG, Masumoto KH, Kiuchi R, Ishida M, Ukai-Tadenuma M, Minami Y, Kito R, Nakao K, Kishimoto W, Yoo SH, Shimomura K, Takao T, Takano A, Kojima T, Nagai K, Sakaki Y, Takahashi JS, Ueda HR.; ''CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock.''; PubMed Europe PMC Scholia
  58. Griffin EA, Staknis D, Weitz CJ.; ''Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115092view17:04, 25 January 2021ReactomeTeamReactome version 75
113534view12:01, 2 November 2020ReactomeTeamReactome version 74
112732view16:13, 9 October 2020ReactomeTeamReactome version 73
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

DataNodes

View all...
NameTypeDatabase referenceComment
AA MetaboliteCHEBI:15843 (ChEBI)
ALA MetaboliteCHEBI:27432 (ChEBI)
ARNTL ProteinO00327 (Uniprot-TrEMBL)
ARNTL2 ProteinQ8WYA1 (Uniprot-TrEMBL)
ARNTLProteinO00327 (Uniprot-TrEMBL)
AVPProteinP01185 (Uniprot-TrEMBL)
BHLHE40ProteinO14503 (Uniprot-TrEMBL)
BHLHE41ProteinQ9C0J9 (Uniprot-TrEMBL)
BMAL1

CLOCK/NPAS2 CRY

PER		ComplexREACT_26318 (Reactome)
BMAL1

CLOCK/NPAS2

CRY		ComplexREACT_25684 (Reactome)
BMAL1 CLOCK/NPAS2ComplexREACT_26547 (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.
BMAL2 CLOCKComplexREACT_26482 (Reactome)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
BTRCProteinQ9Y297 (Uniprot-TrEMBL)
Beta-TrCP1 PERComplexREACT_27062 (Reactome)
CARM1ProteinQ86X55 (Uniprot-TrEMBL)
CCRN4LProteinQ9UK39 (Uniprot-TrEMBL)
CHD9 ProteinQ3L8U1 (Uniprot-TrEMBL)
CLOCK ProteinO15516 (Uniprot-TrEMBL)
CLOCK/NPAS2ProteinREACT_26942 (Reactome)
CLOCKProteinO15516 (Uniprot-TrEMBL)
CPT1AProteinP50416 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CRY

PER

Kinase		ComplexREACT_26725 (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).
CRY1 ProteinQ16526 (Uniprot-TrEMBL)
CRY1/2ProteinREACT_26101 (Reactome)
CRY1ProteinQ16526 (Uniprot-TrEMBL)
CRY2 ProteinQ49AN0 (Uniprot-TrEMBL)
CRY2ProteinQ49AN0 (Uniprot-TrEMBL)
CSNK1E/CSNK1DREACT_26408 (Reactome)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
DBPProteinQ10586 (Uniprot-TrEMBL)
DEXA MetaboliteCHEBI:41879 (ChEBI)
E-box REACT_25457 (Reactome) The consensus sequence of the E-box is CACGTG.
ELOVL3ProteinQ9HB03 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPA MetaboliteCHEBI:28364 (ChEBI)
FBXL3 CRYComplexREACT_25657 (Reactome)
FBXL3 ProteinQ9UKT7 (Uniprot-TrEMBL)
FBXL3ProteinQ9UKT7 (Uniprot-TrEMBL)
Glucocorticoid receptor Dexamethasone ComplexComplexREACT_26089 (Reactome)
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 PPARGC1AComplexREACT_120029 (Reactome)
MEF2D ProteinQ14814 (Uniprot-TrEMBL)
NAMPTProteinP43490 (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)
NPAS2ProteinQ99743 (Uniprot-TrEMBL)
NR1D1 ProteinP20393 (Uniprot-TrEMBL)
NR1D1 ComplexREACT_111441 (Reactome)
NR1D1ProteinP20393 (Uniprot-TrEMBL)
NR3C1 ProteinP04150 (Uniprot-TrEMBL)
PER1 ProteinO15534 (Uniprot-TrEMBL)
PER1/2ProteinREACT_25978 (Reactome)
PER1ProteinO15534 (Uniprot-TrEMBL)
PER2 ProteinO15055 (Uniprot-TrEMBL)
PER2ProteinO15055 (Uniprot-TrEMBL)
PPARA RXRA Coactivator ComplexComplexREACT_20439 (Reactome)
PPARA ProteinQ07869 (Uniprot-TrEMBL)
PPARAProteinQ07869 (Uniprot-TrEMBL)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1AProteinQ9UBK2 (Uniprot-TrEMBL)
Palm MetaboliteCHEBI:15756 (ChEBI)
ROR-alpha CoactivatorComplexREACT_111748 (Reactome)
RORA ProteinP35398 (Uniprot-TrEMBL)
RORAProteinP35398 (Uniprot-TrEMBL)
RORE REACT_111419 (Reactome)
RXRA ProteinP19793 (Uniprot-TrEMBL)
SCF-beta-TrCP1 complexComplexREACT_6992 (Reactome)
SERPINE1ProteinP05121 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SMARCD3 ProteinQ6STE5 (Uniprot-TrEMBL)
SREBF1ProteinP36956 (Uniprot-TrEMBL)
TBL1X ProteinO60907 (Uniprot-TrEMBL)
TBL1XR1 ProteinQ9BZK7 (Uniprot-TrEMBL)
TGS1 ProteinQ96RS0 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
ferriheme b MetaboliteCHEBI:36144 (ChEBI)
ferriheme bMetaboliteCHEBI:36144 (ChEBI)
p-BMAL1

p-CLOCK/NPAS2

DNA		ComplexREACT_25790 (Reactome)
p-CRY

p-PER

Kinase		ComplexREACT_25528 (Reactome)
p-CRY

p-PER

Kinase		ComplexREACT_26285 (Reactome)
p-CRY1/2ProteinREACT_26910 (Reactome)
p-PER1/2ProteinREACT_25419 (Reactome)
p-PPARGC1AREACT_119064 (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-CREB1ProteinP16220 (Uniprot-TrEMBL)
p-T69,T71-ATF2ProteinP15336 (Uniprot-TrEMBL)
pro-factor VIIProteinP08709 (Uniprot-TrEMBL)
ub-p-CRY1/2ProteinREACT_26499 (Reactome)
ub-p-PER1/2ProteinREACT_25524 (Reactome)
ubiquitinProteinREACT_3995 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ARNTLREACT_25402 (Reactome)
BMAL1 CLOCK/NPAS2REACT_25029 (Reactome)
BMAL1 CLOCK/NPAS2REACT_25234 (Reactome)
BMAL2 CLOCKArrowREACT_25123 (Reactome)
BTRCArrowREACT_25143 (Reactome)
BTRCREACT_25088 (Reactome)
Beta-TrCP1 PERREACT_25143 (Reactome)
CLOCK/NPAS2REACT_25402 (Reactome)
CRY1/2REACT_115943 (Reactome)
CRY1/2REACT_25234 (Reactome)
CSNK1E/CSNK1DREACT_115943 (Reactome)
CSNK1E/CSNK1Dmim-catalysisREACT_25125 (Reactome)
E-box REACT_25029 (Reactome)
EP300REACT_118616 (Reactome)
FBXL3 CRYREACT_25378 (Reactome)
FBXL3ArrowREACT_25378 (Reactome)
FBXL3REACT_25106 (Reactome)
Glucocorticoid receptor Dexamethasone ComplexArrowREACT_25321 (Reactome)
HDAC3REACT_118766 (Reactome)
HIF1AArrowREACT_118635 (Reactome)
MEF2C/D PPARGC1AArrowREACT_118642 (Reactome)
NCOR1REACT_118766 (Reactome)
NR1D1 TBarREACT_116112 (Reactome)
NR1D1 TBarREACT_118642 (Reactome)
NR1D1 TBarREACT_118691 (Reactome)
NR1D1 TBarREACT_118740 (Reactome)
NR1D1 TBarREACT_25225 (Reactome)
NR1D1 TBarREACT_25233 (Reactome)
NR1D1REACT_118766 (Reactome)
PER1/2REACT_115943 (Reactome)
PPARA RXRA Coactivator ComplexArrowREACT_115644 (Reactome)
PPARA RXRA Coactivator ComplexArrowREACT_116112 (Reactome)
PPARA RXRA Coactivator ComplexArrowREACT_25084 (Reactome)
PPARGC1AREACT_118616 (Reactome)
REACT_115644 (Reactome) The CPT1A gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_115943 (Reactome) CRYPTOCHROME, PERIOD, and a kinase (CKIepsilon or CKIdelta) form a ternary complex in the cytosol.
REACT_115946 (Reactome) The NAMPT (NamPRT) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer enhances transcription of NAMPT.
REACT_116112 (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.
REACT_118616 (Reactome) As inferred from mouse, RORA binds DNA and recruits the coactivators PGC-1alpha (PPARGC1A) and p300 (EP300, a histone acetylase).
REACT_118635 (Reactome) The RORA gene is transcribed to yield mRNA and the mRNA is transcribed to yield protein.
REACT_118642 (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.
REACT_118691 (Reactome) The ELOVL3 gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_118734 (Reactome) The SREBF1 (SREBP1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein.
REACT_118740 (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.
REACT_118766 (Reactome) NR1D1 (REV-ERBA) binds heme. The REV-ERBA:heme complex is then able to recruit the corepressors NCoR and HDAC3. Corepressors do not bind REV-ERBA in the absence of heme.
REACT_24929 (Reactome) The AVP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind an E-box enhancer in the promoter of the AVP gene and activate transcription of AVP.
REACT_24956 (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.
REACT_25029 (Reactome) In mouse, BMAL1, 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.
REACT_25049 (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.
REACT_25061 (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 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.
REACT_25084 (Reactome) The PPARA gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind the scond intron of the PPARA gene and activate transcription of PPARA.
REACT_25088 (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.
REACT_25092 (Reactome) The FACTOR VII (F7) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mouse the F7 gene shows circadian expression due to activation by the Bmal1:Clock heterodimer.
REACT_25106 (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.
REACT_25123 (Reactome) The PAI-1 gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The PAI-1 gene shows circadian expression due to direct transcriptional activation by the BMAL1:CLOCK heterodimer and the BMAL2(CLIF, ARNTL2):CLOCK heterodimer.
REACT_25125 (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.
REACT_25132 (Reactome) The DEC1 (BHLHE40, BHLHB2) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The DEC1 gene contains E-box elements in its promoter which bind the BMAL:CLOCK heterodimer and confer circadian rhythm on its expression.
REACT_25143 (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 targets in the morning during the circadian cycle.
REACT_25212 (Reactome) The DEC2 (BHLHE41, BHLHB3) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, the BMAL1:CLOCK heterodimer binds E-box elements in the DEC2 promoter and activates transcription of DEC2.
REACT_25225 (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 heterodimer. REV-ERBA binds the promoter of its own gene and represses its own expression (Adelmont et al. 1996).
REACT_25233 (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.
REACT_25234 (Reactome) CRY1 and CRY2 bind the unphosphorylated BMAL1:CLOCK heterodimer (and by homology the BMAL1: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.
REACT_25237 (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 heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER1.
REACT_25278 (Reactome) The DBP gene is transcribed to yield mRNA and the mRNA is translated to yield protein. As inferred from mouse, BMAL1:CLOCK heterodimers bind E-boxes in the DBP promoter and activate transcription of DBP.
REACT_25321 (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 heterodimer (and probably also the BMAL1:NPAS2 heterodimer). The BMAL1:CLOCK heterodimer activates transcription of PER2.
REACT_25365 (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 heterodimer (and probably also the BMAL1:NPAS2 heterodimer), which activates transcription of CRY1.
REACT_25378 (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 targets in the morning during the circadian cycle.
REACT_25395 (Reactome) The NOCTURNIN gene is transcribed to yield mRNA and the mRNA is translated to yield protein. The NOCTURNIN gene shows circadian expression because the BMAL1:CLOCK heterodimer binds an E-box element in the NOCTURNIN promoter and activates transcription.
REACT_25402 (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.
ROR-alpha CoactivatorArrowREACT_115644 (Reactome)
ROR-alpha CoactivatorArrowREACT_116112 (Reactome)
ROR-alpha CoactivatorArrowREACT_118734 (Reactome)
ROR-alpha CoactivatorArrowREACT_25225 (Reactome)
ROR-alpha CoactivatorArrowREACT_25233 (Reactome)
RORAREACT_118616 (Reactome)
RORE REACT_118616 (Reactome)
RORE REACT_118766 (Reactome)
SCF-beta-TrCP1 complexmim-catalysisREACT_25143 (Reactome)
UbREACT_25143 (Reactome)
ferriheme bREACT_118766 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_115946 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_24929 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25084 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25092 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25123 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25132 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25212 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25225 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25237 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25278 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25321 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25365 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		ArrowREACT_25395 (Reactome)
p-BMAL1

p-CLOCK/NPAS2

DNA		REACT_25061 (Reactome)
p-CRY

p-PER

Kinase		REACT_25061 (Reactome)
p-CRY1/2REACT_25106 (Reactome)
p-PER1/2REACT_25088 (Reactome)
p-PPARGC1AArrowREACT_118642 (Reactome)
p-S133-CREB1ArrowREACT_118642 (Reactome)
p-T69,T71-ATF2ArrowREACT_118642 (Reactome)
ub-p-CRY1/2ArrowREACT_25378 (Reactome)
ub-p-PER1/2ArrowREACT_25143 (Reactome)
ubiquitinREACT_25378 (Reactome)
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