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UniProt functional annotation for P48730 | ||
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| UniProt code: P48730. |
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| Organism: | |
Homo sapiens (Human). |
| Taxonomy: | |
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. |
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| 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. {ECO:0000269|PubMed:10606744, ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:17962809, ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19339517, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20048001, ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}. |
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| Catalytic activity: | |
Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; |
| Catalytic activity: | |
Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; |
| Catalytic activity: | |
Reaction=ATP + L-seryl-[tau protein] = ADP + H(+) + O-phospho-L-seryl- [tau protein]; Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA- COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26; |
| Catalytic activity: | |
Reaction=ATP + L-threonyl-[tau protein] = ADP + H(+) + O-phospho-L- threonyl-[tau protein]; Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703, Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.26; |
| 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). {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16027726, ECO:0000269|PubMed:19043076, ECO:0000269|PubMed:19591487, ECO:0000269|PubMed:20407760, ECO:0000269|PubMed:20696890, ECO:0000269|PubMed:21084295, ECO:0000269|PubMed:21258417, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:9632646}. |
| Biophysicochemical properties: | |
Kinetic parameters: KM=36.5 uM for alpha-casein {ECO:0000269|PubMed:23636092}; KM=635.8 uM for PER2 peptide {ECO:0000269|PubMed:23636092}; KM=180.6 uM for ATP {ECO:0000269|PubMed:23636092}; Note=Maximal velocity nearly identical for the reactions with alpha- casein and PER2 peptide.; |
| 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 AIB1/NCOA3 and ESR1 (PubMed:19339517). 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). {ECO:0000250|UniProtKB:Q06486, ECO:0000250|UniProtKB:Q9DC28, ECO:0000269|PubMed:10826492, ECO:0000269|PubMed:11165242, ECO:0000269|PubMed:12270714, ECO:0000269|PubMed:12270943, ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:16618118, ECO:0000269|PubMed:19339517, ECO:0000269|PubMed:22168824, ECO:0000269|PubMed:23106386, ECO:0000269|PubMed:29222110}. |
| Subcellular location: | |
Cytoplasm. Nucleus. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:14654843}. Cytoplasm, perinuclear region. Cell membrane. Cytoplasm, cytoskeleton, spindle. Golgi apparatus. Note=Localized at mitotic spindle microtubules, and at the centrosomes and interphase in interphase cells. Recruited to the spindle apparatus and the centrosomes in response to DNA-damage. Correct subcellular localization requires kinase activity. |
| 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. {ECO:0000269|PubMed:15070676, ECO:0000269|PubMed:16027726}. |
| Developmental stage: | |
Highly present in extravillous trophoblast cells, which are present at the placenta implantation site and invade the decidua and decidual vessels. {ECO:0000269|PubMed:16027726}. |
| Ptm: | |
Autophosphorylated on serine and threonine residues; this autophosphorylation represses activity. Reactivated by phosphatase- mediated dephosphorylation. May be dephosphorylated by PP1. |
| Disease: | |
Advanced sleep phase syndrome, familial, 2 (FASPS2) [MIM:615224]: A disorder characterized by very early sleep onset and offset. Individuals are 'morning larks' with a 4 hours advance of the sleep, temperature and melatonin rhythms. {ECO:0000269|PubMed:15800623, ECO:0000269|PubMed:23636092}. Note=The disease is caused by variants affecting the gene represented in this entry. |
| Miscellaneous: | |
May be involved in Alzheimer disease by phosphorylating MAPT/TAU. {ECO:0000305|PubMed:17562708}. |
| Similarity: | |
Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily. {ECO:0000305}. |
Annotations taken from UniProtKB at the EBI.