Casein kinase I isoform delta (CK1delta) is a constitutively active, monomeric serine/threonine protein kinase of the casein kinase 1 (CK1) family. It uses ATP and is magnesium-dependent, and is operationally defined as a "casein kinase" by its preference for acidic substrates; it performs both primed (phospho-directed) and unprimed phosphorylation. Its activity is autoinhibited by C-terminal autophosphorylation and reactivated by phosphatase (PP1)-mediated dephosphorylation. CK1delta is a central component of the circadian clock, phosphorylating PERIOD proteins PER1 and PER2 to control their stability and nuclear entry and thereby set circadian period; missense variants (e.g. T44A, H46R) reduce kinase activity and cause familial advanced sleep phase syndrome and familial migraine. CK1delta also phosphorylates Dishevelled (DVL2/DVL3) and other components to modulate Wnt/beta-catenin signaling, acts at the centrosome and Golgi to promote microtubule nucleation, Golgi organization and primary (non-motile) ciliogenesis, and regulates the mitotic spindle. It phosphorylates a large and diverse set of additional substrates including p53/TP53, MDM2, YAP1, HIF1A, TOP2A, connexin-43/GJA1, PKD2, eIF6, DCK and tau/MAPT, linking it to DNA-damage responses, Hippo signaling, vesicle trafficking and (via tau hyperphosphorylation) neurodegeneration. It localizes to the cytoplasm/cytosol, nucleus, centrosome, perinuclear region, spindle and spindle microtubules, Golgi apparatus, ciliary basal body and plasma membrane, with correct localization dependent on kinase activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005876 spindle microtubule | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) transfer of spindle microtubule localization. CK1delta does localize to spindle microtubules upon DNA damage by direct experimental evidence, so this CC term is supported. Reason: Consistent with experimental IDA evidence (PMID:10826492) showing CK1delta localization at spindle microtubules; a genuine, if context-dependent (DNA-damage), location. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA transfer of a role in promoting proteasomal degradation. CK1delta phosphorylates phosphodegrons that prime substrates (YAP1, MDM2) for SCF(beta-TRCP)-mediated ubiquitination and degradation, so the process is real but is a downstream, substrate-driven consequence of kinase activity rather than a core function. Reason: Supported by experimental data on YAP1 and MDM2 degron phosphorylation, but this is one of many substrate-specific downstream effects rather than the gene's core function. Supporting Evidence: PMID:20048001 A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). PMID:20708156 Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. |
| GO:0042752 regulation of circadian rhythm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of regulation of circadian rhythm. This is a hallmark, well-established physiological role of CK1delta via PER1/PER2 phosphorylation; disease variants cause familial advanced sleep phase. Reason: Core biological process; strongly supported by direct interaction with and phosphorylation of PER1/PER2 and by FASPS2/migraine disease variants. Supporting Evidence: PMID:23636092 Casein kinase idelta mutations in familial migraine and advanced sleep phase. |
| GO:0051225 spindle assembly | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA transfer of a spindle assembly role. CK1delta is recruited to the spindle/centrosome and its inhibition alters mitotic spindle formation, so the process has direct experimental support. Reason: Supported experimentally (PMID:10826492, PMID:16027726) but represents a context-specific (mitotic/trophoblast) role rather than the core kinase/circadian function. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of positive regulation of canonical Wnt signaling. CK1delta/CK1 phosphorylates DVL2/DVL3 and other Wnt components; a well-supported signaling role of the gene. Reason: Core signaling process supported by experimental data on DVL phosphorylation and Wnt-3a-dependent neurite outgrowth. Supporting Evidence: PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. |
| GO:1905515 non-motile cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of a primary (non-motile) cilium assembly role, also directly demonstrated by loss-of-function in human RPE cells and Csnk1d-null mouse cells. Reason: Supported by direct IMP evidence (PMID:24648492) that CK1delta is required for primary ciliogenesis; a well-established cell-biological role. Supporting Evidence: PMID:24648492 Casein kinase 1delta functions at the centrosome and Golgi to promote ciliogenesis. |
| GO:0006897 endocytosis | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA transfer of an endocytosis role, derived largely from distant yeast CK1 paralogs (Yck1/Yck2, SGD). Human CK1delta has no direct experimental support for a role in endocytosis. Reason: Over-transfer from divergent fungal paralogs; the WITH/FROM evidence (SGD:S000001177, SGD:S000005098) is from yeast CK1 enzymes whose endocytic role is not established for human CK1delta. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: Electronic annotation of generic protein kinase activity. Correct but superseded by the more specific protein serine/threonine kinase activity, which is experimentally established. Reason: Term is correct but too general; CK1delta is specifically a serine/threonine kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Electronic (EC-based) annotation of protein serine/threonine kinase activity. This is the core molecular function, directly demonstrated for many substrates. Reason: Core molecular function, abundantly supported by experimental (EXP/IDA) evidence and structural data. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt EC=2.7.11.1 {ECO:0000269|PubMed:14761950, ECO:0000269|PubMed:17562708, ECO:0000269|PubMed:20041275, ECO:0000269|PubMed:20637175, ECO:0000269|PubMed:21422228, ECO:0000269|PubMed:23636092}; |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is a core feature of this ATP-dependent kinase, supported by numerous co-crystal structures with ATP-competitive inhibitors bound in the ATP pocket. Reason: Essential for catalysis; supported by InterPro kinase domain signatures and over 30 PDB structures of the ATP-binding site. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization from UniProt subcellular location mapping. CK1delta shuttles to the nucleus where it acts on nuclear substrates (e.g. p53, PER nuclear transport). Reason: Consistent with documented nuclear localization in UniProt and nuclear substrate biology. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization from UniProt mapping; CK1delta is predominantly cytoplasmic. Reason: Well-supported primary location of this kinase. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi localization from UniProt mapping, also directly demonstrated; CK1delta acts at the Golgi (with AKAP450) for microtubule nucleation and ciliogenesis. Reason: Supported by experimental IDA (PMID:10826492) and functional ciliogenesis data (PMID:24648492). Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosome localization from UniProt mapping, directly demonstrated and functionally important; CK1delta is anchored at the centrosome via AKAP9/AKAP450. Reason: Strongly supported by experimental IDA evidence and a defined centrosomal localization signal required for ciliogenesis. Supporting Evidence: PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. |
| GO:0005819 spindle | IEA GO_REF:0000044 | ACCEPT | Summary: Spindle localization from UniProt mapping, also directly demonstrated (recruited to the spindle apparatus upon DNA damage). Reason: Consistent with experimental IDA evidence (PMID:10826492). Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization from UniProt mapping; CK1delta is reported at the cell membrane, also supported by IDA and HPA. Reason: Consistent with UniProt subcellular location and experimental evidence. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt Cell membrane. |
| GO:0030111 regulation of Wnt signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning annotation of Wnt signaling regulation. Generic but correct; captured more specifically by the canonical Wnt annotations. Reason: A genuine, well-supported role of CK1delta in Wnt signaling (DVL phosphorylation). Supporting Evidence: PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Perinuclear region localization from UniProt mapping, also directly demonstrated. Reason: Consistent with experimental IDA evidence (PMID:16027726). Supporting Evidence: PMID:16027726 Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. |
| GO:0050321 tau-protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Tau-protein kinase activity (EC 2.7.11.26), a specific molecular function of CK1delta directly demonstrated in vitro. Reason: Experimentally established specific MF; CK1delta phosphorylates tau and disrupts microtubule binding. Supporting Evidence: PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea/EC-based electronic annotation of protein serine kinase activity, a core CK1delta function. Reason: Core molecular function abundantly supported by experimental evidence. Supporting Evidence: PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a high-throughput interactome (with DVL3). The term is uninformative about molecular function. Reason: Bare "protein binding" conveys no specific function; relevant interactions (e.g. DVL3) are captured by the Wnt-signaling and kinase annotations. |
| GO:0005515 protein binding | IPI PMID:20708156 Phosphorylation by casein kinase I promotes the turnover of ... | MARK AS OVER ANNOTATED | Summary: Protein binding evidenced by interaction with MDM2 (Q00987). The MDM2 interaction is functionally meaningful (phosphodegron priming) but the bare term is uninformative. Reason: Uninformative MF term; the functional MDM2 relationship is captured by the proteasomal degradation BP annotation. |
| GO:0005515 protein binding | IPI PMID:21179498 High-throughput chemical screen identifies a novel potent mo... | MARK AS OVER ANNOTATED | Summary: Protein binding evidenced by interaction with PER2 (O15055). Functionally central to circadian biology but the bare term is uninformative. Reason: Uninformative MF term; the PER2 interaction is captured by circadian regulation and kinase annotations. |
| GO:0005515 protein binding | IPI PMID:22609948 Identification of a novel Wnt5a-CK1Ι-Dvl2-Plk1-mediated prim... | MARK AS OVER ANNOTATED | Summary: Protein binding evidenced by interaction with mouse Dvl2 (Q60838). The bare term is uninformative. Reason: Uninformative MF term; the DVL2 relationship is captured by Wnt-signaling and cilium annotations. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a proteome-scale interactome map (DVL3, LURAP1, TRIM9). Uninformative about function. Reason: Bare "protein binding" from high-throughput interactome; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a binary interactome reference map (multiple partners). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a kinase interaction network (GAPVD1). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a neurodegenerative-disease interactome (APP). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a cell-specific interactome remodeling study (PER2, GAPVD1, ZNF618). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from OpenCell endogenous-tagging interactome (GAPVD1). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MARK AS OVER ANNOTATED | Summary: Protein binding evidenced by interaction with 14-3-3 epsilon/YWHAE (P62258). Uninformative bare term. Reason: Bare "protein binding"; no specific molecular function conveyed. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a multimodal cell-map study (PER2, GAPVD1). Uninformative. Reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. |
| GO:0048208 COPII vesicle coat assembly | TAS Reactome:R-HSA-204005 | KEEP AS NON CORE | Summary: Reactome annotation linking CK1delta to COPII vesicle formation via SEC23 phosphorylation. A narrow substrate-driven role. Reason: Real but specialized substrate-driven role (CSNK1D phosphorylates SEC23, Reactome R-HSA-5694441); not a core function. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt Golgi apparatus. |
| GO:0004674 protein serine/threonine kinase activity | TAS Reactome:R-HSA-5694441 | ACCEPT | Summary: Reactome (TAS) annotation of protein serine/threonine kinase activity in the context of SEC23 phosphorylation. Core MF. Reason: Core molecular function, consistent with all experimental evidence. Supporting Evidence: PMID:10606744 Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol localization from immunofluorescence (HPA). CK1delta is a predominantly cytosolic kinase. Reason: Direct IDA evidence for a genuine cytosolic location. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Plasma membrane localization from immunofluorescence (HPA), concordant with UniProt cell membrane annotation. Reason: Direct IDA evidence consistent with documented cell membrane location. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt Cell membrane. |
| GO:0050321 tau-protein kinase activity | EXP PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its bi... | ACCEPT | Summary: Direct experimental demonstration that CK1delta phosphorylates tau, a specific molecular function (EC 2.7.11.26). Reason: Strong EXP evidence; CK1delta phosphorylates tau and disrupts its microtubule binding. Supporting Evidence: PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. |
| GO:0050321 tau-protein kinase activity | EXP PMID:17562708 Novel phosphorylation sites in tau from Alzheimer brain supp... | ACCEPT | Summary: Experimental support for tau-protein kinase activity; CK1 phosphorylates novel tau sites found in Alzheimer brain. Reason: EXP evidence corroborating the specific tau-kinase MF. Supporting Evidence: PMID:17562708 Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. |
| GO:0106310 protein serine kinase activity | EXP PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its bi... | ACCEPT | Summary: Experimental support for protein serine kinase activity (tau phosphorylation). Reason: Core MF; strong EXP evidence. Supporting Evidence: PMID:14761950 Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. |
| GO:0106310 protein serine kinase activity | EXP PMID:17562708 Novel phosphorylation sites in tau from Alzheimer brain supp... | ACCEPT | Summary: Experimental support for protein serine kinase activity (tau phosphorylation at novel sites). Reason: Core MF; EXP evidence. Supporting Evidence: PMID:17562708 Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. |
| GO:0106310 protein serine kinase activity | EXP PMID:17962809 Phosphorylation at Ser244 by CK1 determines nuclear localiza... | ACCEPT | Summary: Experimental support for protein serine kinase activity via PKD2 Ser244 phosphorylation. Reason: Core MF; EXP evidence (PKD2 substrate). Supporting Evidence: PMID:17962809 Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. |
| GO:0106310 protein serine kinase activity | EXP PMID:19591487 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibit... | ACCEPT | Summary: Experimental support for protein serine kinase activity in an inhibitor characterization study of CK1delta. Reason: Core MF; EXP/inhibitor-based evidence of catalytic activity. Supporting Evidence: PMID:19591487 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta. |
| GO:0106310 protein serine kinase activity | EXP PMID:20041275 Isoform specific phosphorylation of p53 by protein kinase CK... | ACCEPT | Summary: Experimental support for protein serine kinase activity via isoform-specific p53 phosphorylation. Reason: Core MF; EXP evidence (p53 substrate). Supporting Evidence: PMID:20041275 Isoform specific phosphorylation of p53 by protein kinase CK1. |
| GO:0106310 protein serine kinase activity | EXP PMID:20048001 A coordinated phosphorylation by Lats and CK1 regulates YAP ... | ACCEPT | Summary: Experimental support for protein serine kinase activity via YAP1 phosphodegron phosphorylation. Reason: Core MF; EXP evidence (YAP1 substrate). Supporting Evidence: PMID:20048001 A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). |
| GO:0106310 protein serine kinase activity | EXP PMID:20637175 Casein kinase 1delta activates human recombinant deoxycytidi... | ACCEPT | Summary: Experimental support for protein serine kinase activity via DCK Ser-74 phosphorylation (in vitro; per UniProt CAUTION, probably not physiological in vivo). Reason: The MF is directly demonstrated in vitro; the caveat applies to the in vivo DCK regulation, not to the kinase activity itself. Supporting Evidence: PMID:20637175 Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. |
| GO:0106310 protein serine kinase activity | EXP PMID:20699359 Casein kinase 1 regulates human hypoxia-inducible factor HIF... | ACCEPT | Summary: Experimental support for protein serine kinase activity via HIF-1alpha phosphorylation. Reason: Core MF; EXP evidence (HIF-1 substrate). Supporting Evidence: PMID:20699359 Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. |
| GO:0106310 protein serine kinase activity | EXP PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate... | ACCEPT | Summary: Experimental support for protein serine kinase activity via DVL2/DVL3 phosphorylation. Reason: Core MF; EXP evidence (DVL substrates, Wnt signaling). Supporting Evidence: PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. |
| GO:0106310 protein serine kinase activity | EXP PMID:23636092 Casein kinase iΞ΄ mutations in familial migraine and advanced... | ACCEPT | Summary: Experimental support for protein serine kinase activity via PER2 peptide phosphorylation; FASPS2/migraine variants reduce activity. Reason: Core MF; EXP evidence directly tied to circadian biology and disease. Supporting Evidence: PMID:23636092 Casein kinase idelta mutations in familial migraine and advanced sleep phase. |
| GO:1904948 midbrain dopaminergic neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from the mouse ortholog (Q9DC28) of a role in midbrain dopaminergic neuron differentiation. Plausible developmental/pleiotropic role but not core and without direct human evidence. Reason: Inferred by sequence similarity from mouse; a pleiotropic developmental role, not a core function. |
| GO:2000052 positive regulation of non-canonical Wnt signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer from mouse ortholog of a non-canonical Wnt role. CK1delta acts in Wnt signaling broadly; the non-canonical specificity is inferred. Reason: Sequence-similarity-based; Wnt signaling involvement is supported overall, but the non-canonical-specific role is inferred rather than directly shown in human. |
| GO:0050321 tau-protein kinase activity | IDA PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective... | ACCEPT | Summary: Direct assay (IDA) of CK1delta catalytic activity (tau/casein kinase activity) in the context of DBNDD2 binding. Reason: Supports the specific tau-protein kinase MF with direct evidence. Supporting Evidence: PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. |
| GO:0106310 protein serine kinase activity | IDA PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective... | ACCEPT | Summary: Direct assay (IDA) of CK1delta protein serine kinase activity. Reason: Core MF; direct evidence. Supporting Evidence: PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. |
| GO:0004672 protein kinase activity | IMP PMID:19591487 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibit... | MODIFY | Summary: Generic protein kinase activity from inhibitor characterization. Correct but superseded by the specific serine/threonine kinase term. Reason: Too general; CK1delta is specifically a serine/threonine kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:10606744 Protein kinase CK1 is a p53-threonine 18 kinase which requir... | ACCEPT | Summary: Direct demonstration that CK1 phosphorylates p53 at Thr18, a serine/threonine kinase activity. Reason: Core MF; direct experimental evidence (p53 Thr18 kinase). Supporting Evidence: PMID:10606744 Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:20041275 Isoform specific phosphorylation of p53 by protein kinase CK... | ACCEPT | Summary: Direct demonstration of isoform-specific p53 phosphorylation by CK1. Reason: Core MF; direct experimental evidence. Supporting Evidence: PMID:20041275 Isoform specific phosphorylation of p53 by protein kinase CK1. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:20637175 Casein kinase 1delta activates human recombinant deoxycytidi... | ACCEPT | Summary: Direct demonstration of CK1delta serine/threonine kinase activity (DCK Ser-74 phosphorylation in vitro). Reason: Core MF; direct in vitro kinase assay. Supporting Evidence: PMID:20637175 Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. |
| GO:0106310 protein serine kinase activity | IDA PMID:12270943 Casein kinase 1 regulates connexin-43 gap junction assembly. | ACCEPT | Summary: Direct demonstration that CK1 phosphorylates connexin-43/GJA1 (serine kinase activity). Reason: Core MF; direct experimental evidence (connexin-43 substrate). Supporting Evidence: PMID:12270943 Casein kinase 1 regulates connexin-43 gap junction assembly. |
| GO:0106310 protein serine kinase activity | IMP PMID:19043076 Casein kinase I delta/epsilon phosphorylates topoisomerase I... | ACCEPT | Summary: CK1delta/epsilon phosphorylates TOP2A at Ser-1106, supporting protein serine kinase activity. Reason: Core MF; supported by substrate phosphorylation evidence (TOP2A). Supporting Evidence: PMID:19043076 Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. |
| GO:0106310 protein serine kinase activity | IDA PMID:21084295 Opposing action of casein kinase 1 and calcineurin in nucleo... | ACCEPT | Summary: Direct demonstration of eIF6 phosphorylation by CK1, supporting protein serine kinase activity. Reason: Core MF; direct experimental evidence (eIF6 substrate). Supporting Evidence: PMID:21084295 Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. |
| GO:0036064 ciliary basal body | IDA PMID:29257953 Evolutionary Proteomics Uncovers Ancient Associations of Cil... | ACCEPT | Summary: Direct localization to the ciliary basal body, consistent with CK1delta's established centrosome/basal-body role in ciliogenesis. Reason: Direct IDA evidence; concordant with the functional ciliogenesis data. Supporting Evidence: PMID:29257953 Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. |
| GO:0045296 cadherin binding | HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: Cadherin binding from a high-throughput E-cadherin interactome proximity dataset. CK1delta is not an established cadherin-binding adaptor. Reason: High-throughput proximity-based annotation; no specific cadherin-binding function is established for CK1delta and it is not supported by focused studies. |
| GO:0004672 protein kinase activity | ISS GO_REF:0000024 | MODIFY | Summary: Generic protein kinase activity inferred by sequence similarity from mouse ortholog. Superseded by the specific serine/threonine kinase term. Reason: Too general; CK1delta is specifically a serine/threonine kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:25500533 Phosphorylation of LRRK2 by casein kinase 1Ξ± regulates trans... | ACCEPT | Summary: This paper is primarily about CK1alpha/CSNK1A1 as the LRRK2 kinase; for CK1delta it shows only moderate in vitro phosphorylation of LRRK2 at S955. It nonetheless documents CK1delta serine/threonine kinase activity in vitro. Reason: Supports the generic Ser/Thr kinase MF in vitro; the LRRK2-specific physiological role belongs to CK1alpha and should not be over-transferred to CK1delta. Supporting Evidence: PMID:25500533 we found that CK1Ξ΄/Ξ΅ and CK1Ξ³ isoforms could moderately phosphorylate S955 and S935 in vitro, respectively |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | TAS Reactome:R-HSA-5694441 | KEEP AS NON CORE | Summary: Reactome localization to the ERGIC membrane in the context of SEC23 phosphorylation during COPII vesicle formation. Plausible given the Golgi/secretory role. Reason: Pathway-specific Reactome localization tied to the SEC23/COPII substrate role; consistent with Golgi association but specialized. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt Golgi apparatus. |
| GO:0007020 microtubule nucleation | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | ACCEPT | Summary: Loss-of-function evidence that CK1delta is required for microtubule nucleation at the Golgi (via AKAP450), part of its ciliogenesis function. Reason: Direct IMP evidence; a well-supported cell-biological role. Supporting Evidence: PMID:24648492 CK1Ξ΄ was required for microtubule nucleation at the Golgi and maintenance of Golgi integrity. |
| GO:0034067 protein localization to Golgi apparatus | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | KEEP AS NON CORE | Summary: CK1delta loss disperses Golgi/centrosomal proteins (AKAP450, IFT20), supporting a role in protein localization to the Golgi. Reason: Supported by IMP evidence but a downstream component of the broader Golgi-organization/ciliogenesis function. Supporting Evidence: PMID:24648492 the Golgi distribution of its binding partner, A-kinase anchor protein 450 (AKAP450) |
| GO:0007030 Golgi organization | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | ACCEPT | Summary: CK1delta is required for maintenance of Golgi integrity and the polarized Golgi ribbon, supporting Golgi organization. Reason: Direct IMP evidence; CK1delta inhibition disrupts cis-Golgi organization. Supporting Evidence: PMID:24648492 where it is important for maintaining Golgi organization and polarized trafficking |
| GO:0061512 protein localization to cilium | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | KEEP AS NON CORE | Summary: CK1delta is required for correct ciliary distribution of transport proteins (Rab8a, polycystin-2), supporting protein localization to cilium. Reason: Supported by IMP evidence; a component of the ciliogenesis function rather than an independent core role. Supporting Evidence: PMID:24648492 alters pericentrosomal or ciliary distribution of several proteins involved in ciliary transport |
| GO:0071539 protein localization to centrosome | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | KEEP AS NON CORE | Summary: CK1delta is required for pericentrosomal positioning of CEP290/PCM1, supporting protein localization to the centrosome. Reason: Supported by IMP evidence; part of the centrosome/ciliogenesis function. Supporting Evidence: PMID:24648492 CK1Ξ΄ is required for proper positioning of these centriolar satellite proteins |
| GO:1905515 non-motile cilium assembly | IMP PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to pr... | ACCEPT | Summary: Direct loss-of-function evidence (siRNA, kinase inhibitor, Csnk1d-null cells) that CK1delta is required for primary (non-motile) ciliogenesis. Reason: Strong IMP evidence across multiple models; a well-established role. Supporting Evidence: PMID:24648492 Casein kinase 1Ξ΄ functions at the centrosome and Golgi to promote ciliogenesis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2574840 | ACCEPT | Summary: Cytosol localization from Reactome (AURKA pathway reaction). Cytosol is a genuine CK1delta location; one of many redundant Reactome citations. Reason: The cytosol CC term is correct; redundant with other cytosol annotations differing only by Reactome reference. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2574845 | ACCEPT | Summary: Cytosol localization from Reactome (AURKA pathway reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3000310 | ACCEPT | Summary: Cytosol localization from Reactome (AURKA/PLK1 reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3000319 | ACCEPT | Summary: Cytosol localization from Reactome (BORA/PLK1/AURKA reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380272 | ACCEPT | Summary: Cytosol localization from Reactome (centrosome maturation reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380283 | ACCEPT | Summary: Cytosol localization from Reactome (gamma-TuRC recruitment reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380294 | ACCEPT | Summary: Cytosol localization from Reactome (centrosome reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380303 | ACCEPT | Summary: Cytosol localization from Reactome (Nlp dissociation reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380311 | ACCEPT | Summary: Cytosol localization from Reactome (Plk1 recruitment reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380316 | ACCEPT | Summary: Cytosol localization from Reactome (NuMA/microtubule reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380455 | ACCEPT | Summary: Cytosol localization from Reactome (CDK11p58 recruitment reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380508 | ACCEPT | Summary: Cytosol localization from Reactome (NuMA translocation reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5617816 | ACCEPT | Summary: Cytosol localization from Reactome (RAB3IP/RAB8A reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626220 | ACCEPT | Summary: Cytosol localization from Reactome (C2CD3 centriole reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626223 | ACCEPT | Summary: Cytosol localization from Reactome (distal appendage protein reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626227 | ACCEPT | Summary: Cytosol localization from Reactome (CP110/CEP97 dissociation reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626228 | ACCEPT | Summary: Cytosol localization from Reactome (TTBK2 recruitment reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626681 | ACCEPT | Summary: Cytosol localization from Reactome (transition zone protein reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5626699 | ACCEPT | Summary: Cytosol localization from Reactome (MARK4/ODF2 reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5638009 | ACCEPT | Summary: Cytosol localization from Reactome (CEP164/RAB3IP vesicle reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6791223 | ACCEPT | Summary: Cytosol localization from Reactome (pre-40S rRNA processing reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8853405 | ACCEPT | Summary: Cytosol localization from Reactome (TPX2/AURKA reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8853419 | ACCEPT | Summary: Cytosol localization from Reactome (TPX2/AURKA autophosphorylation reaction). Redundant but correct CC term. Reason: Cytosol is a genuine location; redundant Reactome citation. |
| GO:0005794 Golgi apparatus | IDA PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Go... | ACCEPT | Summary: Direct demonstration of CK1delta association with post-Golgi structures. Reason: Direct IDA evidence; concordant with the Golgi/secretory role. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005813 centrosome | IDA PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate... | ACCEPT | Summary: Direct demonstration of centrosomal localization, functionally required for Wnt-3a-dependent neurite outgrowth. Reason: Direct IDA evidence; a functionally important location. Supporting Evidence: PMID:21422228 Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. |
| GO:0005819 spindle | IDA PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Go... | ACCEPT | Summary: Direct demonstration of CK1delta localization at the spindle apparatus. Reason: Direct IDA evidence. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005876 spindle microtubule | IDA PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Go... | ACCEPT | Summary: Direct demonstration of CK1delta localization at spindle microtubules. Reason: Direct IDA evidence. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005886 plasma membrane | IDA PMID:16027726 Inhibition of casein kinase I delta alters mitotic spindle f... | ACCEPT | Summary: Direct demonstration of plasma membrane localization in trophoblast cells. Reason: Direct IDA evidence consistent with the cell membrane annotation. Supporting Evidence: PMID:16027726 Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16027726 Inhibition of casein kinase I delta alters mitotic spindle f... | ACCEPT | Summary: Direct demonstration of perinuclear localization. Reason: Direct IDA evidence. Supporting Evidence: PMID:16027726 Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. |
| GO:0051225 spindle assembly | IDA PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Go... | KEEP AS NON CORE | Summary: CK1delta associates with the spindle apparatus; functional involvement in spindle formation is supported by inhibitor studies in trophoblasts. Reason: Supported experimentally but a context-specific (mitotic) role, not the core function. Supporting Evidence: PMID:10826492 Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-6791223 | ACCEPT | Summary: Nucleoplasm localization from Reactome (pre-rRNA processing reaction); consistent with documented nuclear localization. Reason: Consistent with nuclear localization of CK1delta. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005813 centrosome | IDA PMID:21399614 Novel asymmetrically localizing components of human centroso... | ACCEPT | Summary: Centrosome localization from a proteomic study of asymmetrically localizing centrosome components. Reason: Direct evidence corroborating the well-established centrosomal location. Supporting Evidence: PMID:21399614 Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IMP PMID:20412773 The Hippo pathway regulates Wnt/beta-catenin signaling. | ACCEPT | Summary: Loss/gain-of-function evidence linking CK1 to canonical Wnt/beta-catenin signaling in the context of Hippo-Wnt crosstalk (CK1delta/epsilon-mediated DVL phosphorylation). Reason: Supported by IMP evidence; a core signaling role of CK1delta. Supporting Evidence: PMID:20412773 The Hippo pathway regulates Wnt/beta-catenin signaling. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear localization inferred by sequence similarity from mouse ortholog; concordant with the experimentally and UniProt-documented nuclear location. Reason: Consistent with documented nuclear localization. Supporting Evidence: file:human/CSNK1D/CSNK1D-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0004672 protein kinase activity | IDA PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective... | MODIFY | Summary: Generic protein kinase activity from a direct assay. Correct but superseded by the specific serine/threonine kinase term. Reason: Too general; CK1delta is specifically a serine/threonine kinase. Proposed replacements: protein serine/threonine kinase activity |
| GO:0005515 protein binding | IPI PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective... | MARK AS OVER ANNOTATED | Summary: Protein binding evidenced by interaction with DBNDD2/CK1BP (Q9BQY9), an isoform-selective binding partner. Bare term is uninformative. Reason: Uninformative MF term; the specific DBNDD2 interaction is documented in UniProt but the bare "protein binding" conveys no function. |
| GO:0006468 protein phosphorylation | IDA PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective... | ACCEPT | Summary: Protein phosphorylation as a biological process, directly demonstrated; this is the core enzymatic activity of CK1delta expressed as a BP. Reason: Core process directly supported; CK1delta phosphorylates numerous protein substrates. Supporting Evidence: PMID:16618118 Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from mouse ortholog) of a role in promoting proteasomal degradation; supported in human by YAP1/MDM2 degron phosphorylation. Reason: A genuine substrate-driven downstream effect (degron priming), not a core function. Supporting Evidence: PMID:20708156 Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. |
| GO:0032922 circadian regulation of gene expression | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of circadian regulation of gene expression. CK1delta controls PER stability/nuclear entry and thus the transcriptional clock; a core role. Reason: Core circadian function; CK1delta regulates PER-mediated transcriptional feedback. Supporting Evidence: PMID:23636092 Casein kinase idelta mutations in familial migraine and advanced sleep phase. |
| GO:0042752 regulation of circadian rhythm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer of regulation of circadian rhythm; a hallmark, disease-linked role of CK1delta. Reason: Core biological process supported by PER phosphorylation and FASPS2/migraine variants. Supporting Evidence: PMID:23636092 Casein kinase idelta mutations in familial migraine and advanced sleep phase. |
| GO:0004672 protein kinase activity | TAS PMID:8786104 Sequence analysis of the cDNA for the human casein kinase I ... | MODIFY | Summary: Generic protein kinase activity from the original CSNK1D cDNA characterization. Correct but superseded by the specific serine/threonine kinase term. Reason: Too general; CK1delta is specifically a serine/threonine kinase. Proposed replacements: protein serine/threonine kinase activity |
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Download this section (compressed HTML)Q: Which CK1delta substrates and biological roles are truly delta-specific versus shared with the highly similar CK1epsilon, given their frequent co-redundancy?
Q: To what extent are the many in vitro substrate phosphorylations (e.g. DCK, eIF6, TOP2A) physiologically relevant in vivo, as opposed to reflecting CK1delta's broad acidic-substrate preference?
Experiment: Acute, isoform-selective degradation (e.g. dTAG/AID) of CK1delta versus CK1epsilon followed by phosphoproteomics to define the delta-specific substrate repertoire and disentangle redundancy.
Experiment: Structure-guided separation-of-function CSNK1D alleles (catalytic-dead vs centrosomal-localization-deficient) in human cells and mice to dissect the kinase-dependent versus scaffolding contributions to ciliogenesis and circadian period.
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