BioPAX pathway converted from "CSNK1E,CSNK1D phosphorylate CRY and PER proteins" in the Reactome database. LEFT-TO-RIGHT 2.7.11.1 CSNK1E,CSNK1D phosphorylate CRY and PER proteins 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.<br>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.<br>A mutation at Serine662 of PER2 is responsible for familial advanced phase sleep syndrome, however the particular kinase responsible for phosphorylating Serine662 is unknown. Authored: May, B, 2009-05-17 22:04:50 Reviewed: D'Eustachio, P, 2009-05-26 22:13:22 Reviewed: Albrecht, Urs, 2010-06-23 Reviewed: Kay, SA, 2010-06-23 Reviewed: Hirota, T, 2010-06-23 Reviewed: Delaunay, F, 2010-06-23 Edited: May, B, 2009-06-02 00:51:49 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 82 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 Reactome http://www.reactome.org COMPOUND C00002 additional information MI MI:0361 2 CRY:PER:Kinase Reactome DB_ID: 421287 Converted from EntitySet in Reactome CSNK1E,CSNK1D Casein kinase I delta or Casein kinase I epsilon Reactome DB_ID: 421289 CSNK1E CKIepsilon Casein kinase I isoform epsilon Reactome DB_ID: 205877 UniProt:P49674 CSNK1E CSNK1E FUNCTION Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates DVL1 and DVL2. Central component of the circadian clock. In balance with PP1, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. Inhibits cytokine-induced granuloytic differentiation.ACTIVITY REGULATION Phosphorylation leads to a decrease of the catalytic activity.SUBUNIT Monomer (PubMed:23106386). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with PER1 (PubMed:10790862). Interacts with ANKRD6 (By similarity). Interacts with DBNDD2 (PubMed:16618118). Interacts with LRP5 and LRP6 (PubMed:16513652). Interacts with SOCS3 (PubMed:15070676). Interacts with SNAI1 (via zinc fingers) (PubMed:20305697). Interacts with DDX3X; this interaction greatly enhances CSNK1E affinity for ATP and DVL2 phosphorylation, but inhibits DDX3X ATPase/helicase activity. In the presence of RNA, the interaction is decreased (PubMed:23413191, PubMed:29222110).TISSUE SPECIFICITY Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. Expressed in monocytes and lymphocytes but not in granulocytes.INDUCTION Down-regulated during granulocytic differentiation.PTM Autophosphorylated. Partially dephosphorylated by PPP5C. May be dephosphorylated by PP1.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily. Homo sapiens NCBI Taxonomy 9606 UniProt P49674 1 EQUAL 416 EQUAL Reactome Database ID Release 82 205877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=205877 Reactome R-HSA-205877 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-205877.1 CSNK1D Casein kinase I, delta Reactome DB_ID: 380315 UniProt:P48730 CSNK1D CSNK1D HCKID FUNCTION Essential serine/threonine-protein kinase that regulates diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. It can phosphorylate a large number of proteins. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. Phosphorylates connexin-43/GJA1, MAP1A, SNAPIN, MAPT/TAU, TOP2A, DCK, HIF1A, EIF6, p53/TP53, DVL2, DVL3, ESR1, AIB1/NCOA3, DNMT1, PKD2, YAP1, PER1 and PER2. Central component of the circadian clock. In balance with PP1, determines the circadian period length through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. Controls PER1 and PER2 nuclear transport and degradation. YAP1 phosphorylation promotes its SCF(beta-TRCP) E3 ubiquitin ligase-mediated ubiquitination and subsequent degradation. DNMT1 phosphorylation reduces its DNA-binding activity. Phosphorylation of ESR1 and AIB1/NCOA3 stimulates their activity and coactivation. Phosphorylation of DVL2 and DVL3 regulates WNT3A signaling pathway that controls neurite outgrowth. EIF6 phosphorylation promotes its nuclear export. Triggers down-regulation of dopamine receptors in the forebrain. Activates DCK in vitro by phosphorylation. TOP2A phosphorylation favors DNA cleavable complex formation. May regulate the formation of the mitotic spindle apparatus in extravillous trophoblast. Modulates connexin-43/GJA1 gap junction assembly by phosphorylation. Probably involved in lymphocyte physiology. Regulates fast synaptic transmission mediated by glutamate.ACTIVITY REGULATION Exhibits substrate-dependent heparin activation. Drug-mediated inhibition leads to a delay of the oscillations with the magnitude of this effect dependent upon the timing of drug administration. Inhibited by phosphorylation. Repressed by 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide (CKI-7), 4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzamide (D4476), 3,4-diaryl-isoxazoles and -imidazoles, and 4-(3-cyclohexyl-5-(4-fluoro-phenyl)-3H-imidazol-4-yl) pyrimidin-2-ylamine (PF670462, PF670).SUBUNIT Monomer (PubMed:22168824, PubMed:23106386). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins (By similarity). Interacts with DNMT1 and MAP1A (By similarity). Interacts directly with PER1 and PER2 which may lead to their degradation (PubMed:11165242). Interacts with MAPT/TAU (PubMed:14761950). Interacts with SNAPIN (By similarity). Interacts with DBNDD2 (PubMed:16618118). Interacts with AKAP9/AKAP450; this interaction promotes centrosomal subcellular location (PubMed:12270714). Binds to tubulins in mitotic cells upon DNA damage (PubMed:10826492). Interacts with GJA1 (PubMed:12270943). Interacts with DDX3X; this interaction enhances CSNK1D kinase activity in vitro, but it is unclear whether this interaction is physiologically relevant (PubMed:29222110).TISSUE SPECIFICITY Expressed in all tissues examined, including brain, heart, lung, liver, pancreas, kidney, placenta and skeletal muscle. However, kinase activity is not uniform, with highest kinase activity in splenocytes. In blood, highly expressed in hemopoietic cells and mature granulocytes. Also found in monocytes and lymphocytes.DEVELOPMENTAL STAGE Highly present in extravillous trophoblast cells, which are present at the placenta implantation site and invade the decidua and decidual vessels.PTM Autophosphorylated on serine and threonine residues; this autophosphorylation represses activity. Reactivated by phosphatase-mediated dephosphorylation. May be dephosphorylated by PP1.MISCELLANEOUS May be involved in Alzheimer disease by phosphorylating MAPT/TAU.SIMILARITY Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily.CAUTION Was shown to phosphorylate and activate DCK in vitro but probably not in vivo. UniProt P48730 1 EQUAL 415 EQUAL Reactome Database ID Release 82 380315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380315 Reactome R-HSA-380315 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380315.1 Reactome Database ID Release 82 421289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421289 Reactome R-HSA-421289 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421289.2 1 Converted from EntitySet in Reactome CRY1,2 Reactome DB_ID: 400223 CRY1 Cryptochrome-1 CRY1_HUMAN Reactome DB_ID: 400247 UniProt:Q16526 CRY1 CRY1 PHLL1 FUNCTION Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression (By similarity). Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4 (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Plays an essential role in the generation of circadian rhythms in the retina (By similarity). Represses the transcriptional activity of NR1I2 (By similarity).ACTIVITY REGULATION KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.SUBUNIT Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS (By similarity). Interacts directly with PER1 and PER3 (By similarity). Interacts directly with PER2; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:21613214). Interacts with FBXL21 (By similarity). Interacts with FBXL3 (PubMed:17463251). Interacts with PPP5C (via TPR repeats) (PubMed:16790549). Interacts with CLOCK-ARNTL/BMAL1 independently of PER2 and DNA (PubMed:28388406). Interacts with HDAC1, HDAC2 and SIN3B. Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (PubMed:22170608). Interacts with PRKDC (By similarity). Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (PubMed:20852621). Interacts with PRMT5 (PubMed:23133559). Interacts with EZH2 (By similarity). Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (By similarity). Interacts with MAP1LC3B (By similarity). Interacts with CLOCK (By similarity). Interacts with ARNTL/BMAL1 (By similarity). Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with TRIM28, KCTD5 and DDB1 (By similarity). Interacts with FOXO1 (By similarity). Interacts with DTL and DDB1-CUL4A complex (PubMed:26431207). Interacts with HNF4A (PubMed:30530698). Interacts with PSMD2 in a KDM8-dependent manner (By similarity). Interacts with KDM8 in a FBXL3-dependent manner (By similarity). Interacts with PPARG in a ligand-dependent manner (By similarity). Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity). Interacts with PPARA, NR1I3 and VDR (By similarity).INDUCTION Expression is regulated by light and circadian rhythms and osicllates diurnally. Peak expression in the suprachiasma nucleus (SCN) and eye at the day/night transition (CT12). Levels decrease with ARNTL/BMAL1-CLOCK inhibition as part of the autoregulatory feedback loop.DOMAIN The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation.PTM Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-568 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC.PTM Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2 (PubMed:17463251, PubMed:22798407, PubMed:27565346). Deubiquitinated by USP7 (By similarity).PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels.SIMILARITY Belongs to the DNA photolyase class-1 family. UniProt Q16526 1 EQUAL 586 EQUAL Reactome Database ID Release 82 400247 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400247 Reactome R-HSA-400247 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400247.1 CRY2 Cryptochrome-2 CRY2_HUMAN Reactome DB_ID: 400255 UniProt:Q49AN0 CRY2 CRY2 KIAA0658 FUNCTION Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/BMAL1 induced transcription of NAMPT (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Represses the transcriptional activity of NR1I2 (By similarity).ACTIVITY REGULATION KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods.SUBUNIT Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts with TIMELESS (By similarity). Interacts directly with PER1, PER2 and PER3; interaction with PER2 inhibits its ubiquitination and vice versa (By similarity). Interacts with CLOCK-ARNTL/BMAL1 (By similarity). Interacts with CLOCK (By similarity). Interacts with ARNTL/BMAL1 (By similarity). Interacts with NFIL3 (By similarity). Interacts with FBXL3 (PubMed:17463251). Interacts with FBXL21 (By similarity). FBXL3, PER2 and the cofactor FAD compete for overlapping binding sites (By similarity). FBXL3 cannot bind CRY2 that interacts already with PER2 or that contains bound FAD (By similarity). Interacts with PPP5C (via TPR repeats); the interaction down-regulates the PPP5C phosphatase activity on CSNK1E (PubMed:16790549). Interacts with nuclear receptors AR and NR3C1/GR; the interaction is ligand dependent (By similarity). Interacts with PRKDC and CIART (By similarity). Interacts with ISCA1 (in vitro) (PubMed:26569474). Interacts with DDB1, USP7 and TARDBP (By similarity). Interacts with HNF4A (PubMed:30530698). Interacts with PPARA (By similarity). Interacts with PPARD (via domain NR LBD) and NR1I2 (via domain NR LBD) in a ligand-dependent manner (By similarity). Interacts with PPARG, NR1I3 and VDR in a ligand-dependent manner (By similarity).TISSUE SPECIFICITY Expressed in all tissues examined including fetal brain, fibroblasts, heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and leukocytes. Highest levels in heart and skeletal muscle.PTM Phosphorylation on Ser-266 by MAPK is important for the inhibition of CLOCK-ARNTL-mediated transcriptional activity. Phosphorylation by CSKNE requires interaction with PER1 or PER2. Phosphorylated in a circadian manner at Ser-554 and Ser-558 in the suprachiasmatic nucleus (SCN) and liver. Phosphorylation at Ser-558 by DYRK1A promotes subsequent phosphorylation at Ser-554 by GSK3-beta: the two-step phosphorylation at the neighboring Ser residues leads to its proteasomal degradation.PTM Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY2. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY2 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. The SCF(FBXL3) complex recognizes and binds CRY2 phosphorylated at Ser-554 and Ser-558. Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7 (By similarity).SIMILARITY Belongs to the DNA photolyase class-1 family. UniProt Q49AN0 1 EQUAL 593 EQUAL Reactome Database ID Release 82 400255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400255 Reactome R-HSA-400255 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400255.1 Reactome Database ID Release 82 400223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400223 Reactome R-HSA-400223 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400223.1 1 Converted from EntitySet in Reactome PER1,PER2 Reactome DB_ID: 400344 PER1 Period circadian protein homolog 1 PER1_HUMAN Reactome DB_ID: 400373 UniProt:O15534 PER1 PER1 KIAA0482 PER RIGUI FUNCTION Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. Regulates circadian target genes expression at post-transcriptional levels, but may not be required for the repression at transcriptional level. Controls PER2 protein decay. Represses CRY2 preventing its repression on CLOCK/ARNTL target genes such as FXYD5 and SCNN1A in kidney and PPARA in liver. Besides its involvement in the maintenance of the circadian clock, has an important function in the regulation of several processes. Participates in the repression of glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) by ARNTL:CLOCK. Plays a role in the modulation of the neuroinflammatory state via the regulation of inflammatory mediators release, such as CCL2 and IL6. In spinal astrocytes, negatively regulates the MAPK14/p38 and MAPK8/JNK MAPK cascades as well as the subsequent activation of NFkappaB. Coordinately regulates the expression of multiple genes that are involved in the regulation of renal sodium reabsorption. Can act as gene expression activator in a gene and tissue specific manner, in kidney enhances WNK1 and SLC12A3 expression in collaboration with CLOCK. Modulates hair follicle cycling. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1.SUBUNIT Homodimer (By similarity). Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (By similarity). Interacts directly with TIMELESS, PER2, PER3, CRY1 and CRY2 (By similarity). Interacts with ARNTL/BMAL1 and CLOCK (By similarity). Interacts with GPRASP1 (By similarity). Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation (PubMed:15917222). Interacts with NONO, WDR5 and SFPQ (By similarity). Interacts with USP2 (By similarity). Interacts with HNF4A (PubMed:30530698).TISSUE SPECIFICITY Widely expressed. Expressed in hair follicles (at protein level).Found in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, kidney, spleen, thymus, prostate, testis, ovary and small intestine. Highest level in skeletal muscle.INDUCTION Serum-induced levels in fibroblasts show circadian oscillations. Maximum levels after 1 hour stimulation, minimum levels after 12 hours. Another peak is then observed after 20 hours. Protein levels show maximum levels at 6 hours, decrease to reach minimum levels at 20 hours, and increase again to reach a second peak after 26 hours. Levels then decrease slightly and then increase to maximum levels at 32 hours. Levels of phosphorylated form increase between 3 hours and 12 hours.PTM Phosphorylated on serine residues by CSNK1D, CSNK1E and probably also by CSNK1G2. Phosphorylation by CSNK1D or CSNK1E promotes nuclear location of PER proteins as well as ubiquitination and subsequent degradation. May be dephosphorylated by PP1.PTM Ubiquitinated; requires phosphorylation by CSNK1E and interaction with BTRC and FBXW11. Deubiquitinated by USP2 (By similarity). UniProt O15534 1 EQUAL 1290 EQUAL Reactome Database ID Release 82 400373 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400373 Reactome R-HSA-400373 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400373.1 PER2 Period circadian protein homolog 2 PER2_HUMAN Reactome DB_ID: 400399 UniProt:O15055 PER2 PER2 KIAA0347 FUNCTION Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndrome and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. PER1 and PER2 proteins transport CRY1 and CRY2 into the nucleus with appropriate circadian timing, but also contribute directly to repression of clock-controlled target genes through interaction with several classes of RNA-binding proteins, helicases and others transcriptional repressors. PER appears to regulate circadian control of transcription by at least three different modes. First, interacts directly with the CLOCK-ARTNL/BMAL1 at the tail end of the nascent transcript peak to recruit complexes containing the SIN3-HDAC that remodel chromatin to repress transcription. Second, brings H3K9 methyltransferases such as SUV39H1 and SUV39H2 to the E-box elements of the circadian target genes, like PER2 itself or PER1. The recruitment of each repressive modifier to the DNA seems to be very precisely temporally orchestrated by the large PER complex, the deacetylases acting before than the methyltransferases. Additionally, large PER complexes are also recruited to the target genes 3' termination site through interactions with RNA-binding proteins and helicases that may play a role in transcription termination to regulate transcription independently of CLOCK-ARTNL/BMAL1 interactions. Recruitment of large PER complexes to the elongating polymerase at PER and CRY termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. May propagate clock information to metabolic pathways via the interaction with nuclear receptors. Coactivator of PPARA and corepressor of NR1D1, binds rhythmically at the promoter of nuclear receptors target genes like ARNTL or G6PC1. Directly and specifically represses PPARG proadipogenic activity by blocking PPARG recruitment to target promoters and thereby inhibiting transcriptional activation. Required for fatty acid and lipid metabolism, is involved as well in the regulation of circulating insulin levels. Plays an important role in the maintenance of cardiovascular functions through the regulation of NO and vasodilatatory prostaglandins production in aortas. Controls circadian glutamate uptake in synaptic vesicles through the regulation of VGLUT1 expression. May also be involved in the regulation of inflammatory processes. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1 and ATF4. Negatively regulates the formation of the TIMELESS-CRY1 complex by competing with TIMELESS for binding to CRY1.SUBUNIT Homodimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with CLOCK-ARNTL/BMAL1 (off DNA).Interacts with ARNTL2/BMAL2. Interacts directly with PER1 and PER3, and through a C-terminal domain, with CRY1 and CRY2. Interacts, via its second PAS domain, with TIMELESS in vitro. Interacts with NFIL3. Different large complexes have been identified with different repressive functions. The core of PER complexes is composed of at least PER1, PER2, PER3, CRY1, CRY2, CSNK1D and/or CSNK1E. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with SETX; the interaction inhibits termination of circadian target genes. Interacts with the nuclear receptors HNF4A, NR1D1, NR4A2, RORA, PPARA, PPARG and THRA; the interaction with at least PPARG is ligand dependent. Interacts with PML. Interacts (phosphorylated) with BTRC and FBXW11; the interactions trigger proteasomal degradation. Interacts with NONO and SFPQ. Interacts with CAVIN3 (By similarity). Interacts with MAGEL2 (By similarity). Interacts with MAP1LC3B (By similarity). Interacts with HNF4A (PubMed:30530698).TISSUE SPECIFICITY Widely expressed. Found in heart, brain, placenta, lung, liver, skeleatal muscle, kidney and pancreas. High levels in skeletal muscle and pancreas. Low levels in lung. Isoform 2 is expressed in keratinocytes (at protein level).INDUCTION Oscillates diurnally. Rhythmic levels are critical for the generation of circadian rhythms in central as well as peripheral clocks. Targeted degradation of PER and CRY proteins enables the reactivation of CLOCK-ARTNL/BMAL1, thus initiating a new circadian transcriptional cycle with an intrinsic period of 24 hours.PTM Acetylated. Deacetylated by SIRT1, resulting in decreased protein stability. Deacetylated by SIRT6, preventing its degradation by the proteasome, resulting in increased protein stability.PTM Phosphorylated by CSNK1E and CSNK1D. Phosphorylation results in PER2 protein degradation. May be dephosphorylated by PP1.PTM Ubiquitinated, leading to its proteasomal degradation. Ubiquitination may be inhibited by CRY1. UniProt O15055 1 EQUAL 1255 EQUAL Reactome Database ID Release 82 400399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400399 Reactome R-HSA-400399 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400399.1 Reactome Database ID Release 82 400344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400344 Reactome R-HSA-400344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400344.1 1 Reactome Database ID Release 82 421287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421287 Reactome R-HSA-421287 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421287.2 p-CRY:p-PER:Kinase Reactome DB_ID: 421296 Converted from EntitySet in Reactome p-CRY1,p-CRY2 Reactome DB_ID: 400287 p-CRY1 p-S-CRY1 Phosphorylated Cryptochrome-1 CRY1_HUMAN Reactome DB_ID: 400270 O-phospho-L-serine MOD MOD:00046 1 EQUAL 586 EQUAL Reactome Database ID Release 82 400270 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400270 Reactome R-HSA-400270 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400270.1 p-CRY2 p-S-CRY2 Phosphorylated Cryptochrome-2 CRY2_HUMAN Reactome DB_ID: 400305 1 EQUAL 593 EQUAL Reactome Database ID Release 82 400305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400305 Reactome R-HSA-400305 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400305.1 Reactome Database ID Release 82 400287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400287 Reactome R-HSA-400287 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400287.1 1 1 Converted from EntitySet in Reactome p-PER1,p-PER2 Reactome DB_ID: 400346 p-PER1 p-S-PER1 Phosphorylated Period circadian protein homolog 1 PER1_HUMAN Reactome DB_ID: 400310 1 EQUAL 1290 EQUAL Reactome Database ID Release 82 400310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400310 Reactome R-HSA-400310 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400310.1 p-PER2 p-S-PER2 Phosphorylated Period circadian protein homolog 2 PER2_HUMAN Reactome DB_ID: 400331 1 EQUAL 1255 EQUAL Reactome Database ID Release 82 400331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400331 Reactome R-HSA-400331 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400331.1 Reactome Database ID Release 82 400346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400346 Reactome R-HSA-400346 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400346.1 1 Reactome Database ID Release 82 421296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421296 Reactome R-HSA-421296 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-421296.2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 82 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 2 ACTIVATION activeUnit: #Protein1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 421295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=421295 Reactome Database ID Release 82 400382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400382 Reactome R-HSA-400382 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400382.4 15800623 Pubmed 2005 Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome Xu, Y Padiath, QS Shapiro, RE Jones, CR Wu, SC Saigoh, N Saigoh, K Ptácek, LJ Fu, YH Nature 434:640-4 15917222 Pubmed 2005 SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein Shirogane, T Jin, J Ang, XL Harper, JW J Biol Chem 280:26863-72 14750904 Pubmed 2004 Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts Miyazaki, K Nagase, T Mesaki, M Narukawa, J Ohara, O Ishida, N Biochem J 380:95-103 11165242 Pubmed 2001 Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2 Camacho, F Cilio, M Guo, Y Virshup, DM Patel, K Khorkova, O Styren, S Morse, B Yao, Z Keesler, GA FEBS Lett 489:159-65 10790862 Pubmed 2000 Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon Keesler, GA Camacho, F Guo, Y Virshup, D Mondadori, C Yao, Z Neuroreport 11:951-5 17218255 Pubmed 2007 Modeling of a human circadian mutation yields insights into clock regulation by PER2 Xu, Y Toh, KL Jones, CR Shin, JY Fu, YH Ptácek, LJ Cell 128:59-70 11232563 Pubmed 2001 An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome Toh, KL Jones, CR He, Y Eide, EJ Hinz, WA Virshup, DM Ptácek, LJ Fu, YH Science 291:1040-3 19805222 Pubmed 2009 CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock 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 Proc Natl Acad Sci U S A 106:15744-9 INHIBITION Reactome Database ID Release 82 5656529 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5656529 Reactome R-HSA-5656529 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5656529.1 Converted from EntitySet in Reactome PP1 catalytic subunit Reactome DB_ID: 163538 PP1CA PPP1CA Serine/threonine protein phosphatase PP1-alpha 1 catalytic subunit PP-1A Reactome DB_ID: 163525 UniProt:P62136 PPP1CA PPP1CA PPP1A FUNCTION Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. Regulates NEK2 function in terms of kinase activity and centrosome number and splitting, both in the presence and absence of radiation-induced DNA damage. Regulator of neural tube and optic fissure closure, and enteric neural crest cell (ENCCs) migration during development. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Dephosphorylates CENPA (PubMed:25556658). Dephosphorylates the 'Ser-139' residue of ATG16L1 causing dissociation of ATG12-ATG5-ATG16L1 complex, thereby inhibiting autophagy (PubMed:26083323).FUNCTION (Microbial infection) Necessary for alphaviruses replication.ACTIVITY REGULATION The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SUBUNIT PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Interacts with PPP1R39 (By similarity). Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts with PPP1R9A and PPP1R9B. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with PHACTR4; which acts as an activator of PP1 activity (By similarity). Interacts with PPP1R15A and PPP1R15B; the interactions mediate binding to EIF2S1 (PubMed:26095357). Interacts with PPP1R7. Interacts with YLPM1. Forms a complex with ILF2, ILF3, YLPM1, KHDRBS1, RBMX and NCOA5. Interacts with NOM1 and PPP1R8. Interacts with PPP1R16B. Interacts with RPSA only in the presence of PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R10/PNUTS and PPP1R8. Interacts with WDR82 in the presence of PPP1R10/PNUTS. Interacts with TRIM28; the interaction dephosphorylates TRIM28 on 'Ser-824' and forms a complex at the p21 promoter site. Interacts with isoform 1 and isoform 4 of NEK2. Interacts with FER; this promotes phosphorylation at Thr-320. Interacts with DAB2; the interaction is mutually exclusive with the AXIN1:PPP1CA interaction. Interacts with FOXP3 (PubMed:23396208). Interacts with CENPA (PubMed:25556658). Interacts with ATG16L1 (PubMed:26083323). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654).SUBUNIT (Microbial infection) Interacts with HHV-1 ICP34.5.SUBUNIT (Microbial infection) Interacts with Venezuelan equine encephalitis virus (VEEV) capsid protein; this interaction dephosphorylates the capsid protein, which increases its ability to bind to the viral genome.INDUCTION Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.PTM Phosphorylated. Dephosphorylated at Thr-320 in the presence of ionizing radiation.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). UniProt P62136 2 EQUAL 330 EQUAL Reactome Database ID Release 82 163525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163525 Reactome R-HSA-163525 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163525.1 PP1CB PPP1CB Serine/threonine protein phosphatase PP1-beta catalytic subunit PP-1B Reactome DB_ID: 163405 UniProt:P62140 PPP1CB PPP1CB FUNCTION Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase (PP1) is essential for cell division, it participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Involved in regulation of ionic conductances and long-term synaptic plasticity. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).ACTIVITY REGULATION Inhibited by the toxins okadaic acid, tautomycin and microcystin Leu-Arg (By similarity). The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SUBUNIT PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. The targeting or regulatory subunits determine the substrate specificity of PP1. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Part of a complex containing PPP1R15B, PP1 and NCK1/2 (By similarity). Interacts with PPP1R7 and PPP1R12C. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Interacts with PPP1R16B. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with TRIM28; the interaction is weak. Interacts with PPP1R12A and NUAK1; the interaction is direct. Interacts with FOXP3. Interacts with RRP1B (PubMed:20926688). Interacts with SERPINE1 (PubMed:28296156). Interacts with LZTR1 (PubMed:30368668).INDUCTION Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). UniProt P62140 2 EQUAL 327 EQUAL Reactome Database ID Release 82 163405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163405 Reactome R-HSA-163405 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163405.1 PP1CC PPP1CC Serine/threonine protein phosphatase PP1-gamma catalytic subunit PP-1G Reactome DB_ID: 163443 UniProt:P36873 PPP1CC PPP1CC FUNCTION Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).ACTIVITY REGULATION Inactivated by binding to URI1. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SUBUNIT PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Interacts with cyanobacterial toxin microcystin; disulfide-linked. Interacts with PPP1R3B and PPP1R7. Isoform 2 interacts with SPZ1 (By similarity). Interacts with CDCA2. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with IKFZ1; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. Interacts with PPP1R42; the interaction is direct (By similarity). Interacts with NOM1 and PPP1R8. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with isoform 1 and isoform 4 NEK2. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner. Interacts with FOXP3. Interacts with TMEM225 (via RVxF motif) (By similarity). Interacts with MKI67 (PubMed:24867636). Interacts with RRP1B; this targets PPP1CC to the nucleolus (PubMed:20926688). Interacts with PPP1R2B (PubMed:23506001). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654). Interacts with DYNLT4 (PubMed:23789093).INDUCTION Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.PTM Phosphorylated by NEK2.MISCELLANEOUS Microcystin toxin is bound to Cys-273 through a thioether bond.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). UniProt P36873 2 EQUAL 323 EQUAL Reactome Database ID Release 82 163443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163443 Reactome R-HSA-163443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163443.1 Reactome Database ID Release 82 163538 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163538 Reactome R-HSA-163538 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163538.1