id: P48730 gene_symbol: CSNK1D product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. alternative_products: - name: '1' id: P48730-1 - name: '2' id: P48730-2 sequence_note: VSP_010253 existing_annotations: - term: id: GO:0005876 label: spindle microtubule evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: 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. action: ACCEPT reason: Consistent with experimental IDA evidence (PMID:10826492) showing CK1delta localization at spindle microtubules; a genuine, if context-dependent (DNA-damage), location. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:20048001 supporting_text: A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). - reference_id: PMID:20708156 supporting_text: Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: Core biological process; strongly supported by direct interaction with and phosphorylation of PER1/PER2 and by FASPS2/migraine disease variants. supported_by: - reference_id: PMID:23636092 supporting_text: Casein kinase idelta mutations in familial migraine and advanced sleep phase. - term: id: GO:0051225 label: spindle assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE reason: Supported experimentally (PMID:10826492, PMID:16027726) but represents a context-specific (mitotic/trophoblast) role rather than the core kinase/circadian function. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0090263 label: positive regulation of canonical Wnt signaling pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: Core signaling process supported by experimental data on DVL phosphorylation and Wnt-3a-dependent neurite outgrowth. supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. - term: id: GO:1905515 label: non-motile cilium assembly evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT reason: Supported by direct IMP evidence (PMID:24648492) that CK1delta is required for primary ciliogenesis; a well-established cell-biological role. supported_by: - reference_id: PMID:24648492 supporting_text: Casein kinase 1delta functions at the centrosome and Golgi to promote ciliogenesis. - term: id: GO:0006897 label: endocytosis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: MARK_AS_OVER_ANNOTATED 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. - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic annotation of generic protein kinase activity. Correct but superseded by the more specific protein serine/threonine kinase activity, which is experimentally established. action: MODIFY reason: Term is correct but too general; CK1delta is specifically a serine/threonine kinase. proposed_replacement_terms: - id: GO:0004674 label: protein serine/threonine kinase activity - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000003 qualifier: enables review: summary: Electronic (EC-based) annotation of protein serine/threonine kinase activity. This is the core molecular function, directly demonstrated for many substrates. action: ACCEPT reason: Core molecular function, abundantly supported by experimental (EXP/IDA) evidence and structural data. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 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}; - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: 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. action: ACCEPT reason: Essential for catalysis; supported by InterPro kinase domain signatures and over 30 PDB structures of the ATP-binding site. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: Belongs to the protein kinase superfamily. CK1 Ser/Thr protein kinase family. Casein kinase I subfamily. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: 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). action: ACCEPT reason: Consistent with documented nuclear localization in UniProt and nuclear substrate biology. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus.' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cytoplasmic localization from UniProt mapping; CK1delta is predominantly cytoplasmic. action: ACCEPT reason: Well-supported primary location of this kinase. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus.' - term: id: GO:0005794 label: Golgi apparatus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Golgi localization from UniProt mapping, also directly demonstrated; CK1delta acts at the Golgi (with AKAP450) for microtubule nucleation and ciliogenesis. action: ACCEPT reason: Supported by experimental IDA (PMID:10826492) and functional ciliogenesis data (PMID:24648492). supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Centrosome localization from UniProt mapping, directly demonstrated and functionally important; CK1delta is anchored at the centrosome via AKAP9/AKAP450. action: ACCEPT reason: Strongly supported by experimental IDA evidence and a defined centrosomal localization signal required for ciliogenesis. supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. - term: id: GO:0005819 label: spindle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Spindle localization from UniProt mapping, also directly demonstrated (recruited to the spindle apparatus upon DNA damage). action: ACCEPT reason: Consistent with experimental IDA evidence (PMID:10826492). supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Plasma membrane localization from UniProt mapping; CK1delta is reported at the cell membrane, also supported by IDA and HPA. action: ACCEPT reason: Consistent with UniProt subcellular location and experimental evidence. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: Cell membrane. - term: id: GO:0030111 label: regulation of Wnt signaling pathway evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning annotation of Wnt signaling regulation. Generic but correct; captured more specifically by the canonical Wnt annotations. action: ACCEPT reason: A genuine, well-supported role of CK1delta in Wnt signaling (DVL phosphorylation). supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Perinuclear region localization from UniProt mapping, also directly demonstrated. action: ACCEPT reason: Consistent with experimental IDA evidence (PMID:16027726). supported_by: - reference_id: PMID:16027726 supporting_text: Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. - term: id: GO:0050321 label: tau-protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Tau-protein kinase activity (EC 2.7.11.26), a specific molecular function of CK1delta directly demonstrated in vitro. action: ACCEPT reason: Experimentally established specific MF; CK1delta phosphorylates tau and disrupts microtubule binding. supported_by: - reference_id: PMID:14761950 supporting_text: Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 qualifier: enables review: summary: Rhea/EC-based electronic annotation of protein serine kinase activity, a core CK1delta function. action: ACCEPT reason: Core molecular function abundantly supported by experimental evidence. supported_by: - reference_id: PMID:14761950 supporting_text: Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 qualifier: enables review: summary: Generic protein binding from a high-throughput interactome (with DVL3). The term is uninformative about molecular function. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" conveys no specific function; relevant interactions (e.g. DVL3) are captured by the Wnt-signaling and kinase annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20708156 qualifier: enables review: summary: Protein binding evidenced by interaction with MDM2 (Q00987). The MDM2 interaction is functionally meaningful (phosphodegron priming) but the bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Uninformative MF term; the functional MDM2 relationship is captured by the proteasomal degradation BP annotation. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21179498 qualifier: enables review: summary: Protein binding evidenced by interaction with PER2 (O15055). Functionally central to circadian biology but the bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Uninformative MF term; the PER2 interaction is captured by circadian regulation and kinase annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22609948 qualifier: enables review: summary: Protein binding evidenced by interaction with mouse Dvl2 (Q60838). The bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Uninformative MF term; the DVL2 relationship is captured by Wnt-signaling and cilium annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Generic protein binding from a proteome-scale interactome map (DVL3, LURAP1, TRIM9). Uninformative about function. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput interactome; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Generic protein binding from a binary interactome reference map (multiple partners). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32707033 qualifier: enables review: summary: Generic protein binding from a kinase interaction network (GAPVD1). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Generic protein binding from a neurodegenerative-disease interactome (APP). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Generic protein binding from a cell-specific interactome remodeling study (PER2, GAPVD1, ZNF618). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: Generic protein binding from OpenCell endogenous-tagging interactome (GAPVD1). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36931259 qualifier: enables review: summary: Protein binding evidenced by interaction with 14-3-3 epsilon/YWHAE (P62258). Uninformative bare term. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding"; no specific molecular function conveyed. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Generic protein binding from a multimodal cell-map study (PER2, GAPVD1). Uninformative. action: MARK_AS_OVER_ANNOTATED reason: Bare "protein binding" from high-throughput screen; no specific function conveyed. - term: id: GO:0048208 label: COPII vesicle coat assembly evidence_type: TAS original_reference_id: Reactome:R-HSA-204005 qualifier: involved_in review: summary: Reactome annotation linking CK1delta to COPII vesicle formation via SEC23 phosphorylation. A narrow substrate-driven role. action: KEEP_AS_NON_CORE reason: Real but specialized substrate-driven role (CSNK1D phosphorylates SEC23, Reactome R-HSA-5694441); not a core function. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: Golgi apparatus. - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5694441 qualifier: enables review: summary: Reactome (TAS) annotation of protein serine/threonine kinase activity in the context of SEC23 phosphorylation. Core MF. action: ACCEPT reason: Core molecular function, consistent with all experimental evidence. supported_by: - reference_id: PMID:10606744 supporting_text: Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Cytosol localization from immunofluorescence (HPA). CK1delta is a predominantly cytosolic kinase. action: ACCEPT reason: Direct IDA evidence for a genuine cytosolic location. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.' - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Plasma membrane localization from immunofluorescence (HPA), concordant with UniProt cell membrane annotation. action: ACCEPT reason: Direct IDA evidence consistent with documented cell membrane location. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: Cell membrane. - term: id: GO:0050321 label: tau-protein kinase activity evidence_type: EXP original_reference_id: PMID:14761950 qualifier: enables review: summary: Direct experimental demonstration that CK1delta phosphorylates tau, a specific molecular function (EC 2.7.11.26). action: ACCEPT reason: Strong EXP evidence; CK1delta phosphorylates tau and disrupts its microtubule binding. supported_by: - reference_id: PMID:14761950 supporting_text: Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. - term: id: GO:0050321 label: tau-protein kinase activity evidence_type: EXP original_reference_id: PMID:17562708 qualifier: enables review: summary: Experimental support for tau-protein kinase activity; CK1 phosphorylates novel tau sites found in Alzheimer brain. action: ACCEPT reason: EXP evidence corroborating the specific tau-kinase MF. supported_by: - reference_id: PMID:17562708 supporting_text: Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:14761950 qualifier: enables review: summary: Experimental support for protein serine kinase activity (tau phosphorylation). action: ACCEPT reason: Core MF; strong EXP evidence. supported_by: - reference_id: PMID:14761950 supporting_text: Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:17562708 qualifier: enables review: summary: Experimental support for protein serine kinase activity (tau phosphorylation at novel sites). action: ACCEPT reason: Core MF; EXP evidence. supported_by: - reference_id: PMID:17562708 supporting_text: Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:17962809 qualifier: enables review: summary: Experimental support for protein serine kinase activity via PKD2 Ser244 phosphorylation. action: ACCEPT reason: Core MF; EXP evidence (PKD2 substrate). supported_by: - reference_id: PMID:17962809 supporting_text: Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:19591487 qualifier: enables review: summary: Experimental support for protein serine kinase activity in an inhibitor characterization study of CK1delta. action: ACCEPT reason: Core MF; EXP/inhibitor-based evidence of catalytic activity. supported_by: - reference_id: PMID:19591487 supporting_text: 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:20041275 qualifier: enables review: summary: Experimental support for protein serine kinase activity via isoform-specific p53 phosphorylation. action: ACCEPT reason: Core MF; EXP evidence (p53 substrate). supported_by: - reference_id: PMID:20041275 supporting_text: Isoform specific phosphorylation of p53 by protein kinase CK1. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:20048001 qualifier: enables review: summary: Experimental support for protein serine kinase activity via YAP1 phosphodegron phosphorylation. action: ACCEPT reason: Core MF; EXP evidence (YAP1 substrate). supported_by: - reference_id: PMID:20048001 supporting_text: A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:20637175 qualifier: enables review: summary: Experimental support for protein serine kinase activity via DCK Ser-74 phosphorylation (in vitro; per UniProt CAUTION, probably not physiological in vivo). action: ACCEPT reason: The MF is directly demonstrated in vitro; the caveat applies to the in vivo DCK regulation, not to the kinase activity itself. supported_by: - reference_id: PMID:20637175 supporting_text: Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:20699359 qualifier: enables review: summary: Experimental support for protein serine kinase activity via HIF-1alpha phosphorylation. action: ACCEPT reason: Core MF; EXP evidence (HIF-1 substrate). supported_by: - reference_id: PMID:20699359 supporting_text: Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:21422228 qualifier: enables review: summary: Experimental support for protein serine kinase activity via DVL2/DVL3 phosphorylation. action: ACCEPT reason: Core MF; EXP evidence (DVL substrates, Wnt signaling). supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: EXP original_reference_id: PMID:23636092 qualifier: enables review: summary: Experimental support for protein serine kinase activity via PER2 peptide phosphorylation; FASPS2/migraine variants reduce activity. action: ACCEPT reason: Core MF; EXP evidence directly tied to circadian biology and disease. supported_by: - reference_id: PMID:23636092 supporting_text: Casein kinase idelta mutations in familial migraine and advanced sleep phase. - term: id: GO:1904948 label: midbrain dopaminergic neuron differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE reason: Inferred by sequence similarity from mouse; a pleiotropic developmental role, not a core function. - term: id: GO:2000052 label: positive regulation of non-canonical Wnt signaling pathway evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: ISS transfer from mouse ortholog of a non-canonical Wnt role. CK1delta acts in Wnt signaling broadly; the non-canonical specificity is inferred. action: KEEP_AS_NON_CORE reason: Sequence-similarity-based; Wnt signaling involvement is supported overall, but the non-canonical-specific role is inferred rather than directly shown in human. - term: id: GO:0050321 label: tau-protein kinase activity evidence_type: IDA original_reference_id: PMID:16618118 qualifier: enables review: summary: Direct assay (IDA) of CK1delta catalytic activity (tau/casein kinase activity) in the context of DBNDD2 binding. action: ACCEPT reason: Supports the specific tau-protein kinase MF with direct evidence. supported_by: - reference_id: PMID:16618118 supporting_text: Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IDA original_reference_id: PMID:16618118 qualifier: enables review: summary: Direct assay (IDA) of CK1delta protein serine kinase activity. action: ACCEPT reason: Core MF; direct evidence. supported_by: - reference_id: PMID:16618118 supporting_text: Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. - term: id: GO:0004672 label: protein kinase activity evidence_type: IMP original_reference_id: PMID:19591487 qualifier: enables review: summary: Generic protein kinase activity from inhibitor characterization. Correct but superseded by the specific serine/threonine kinase term. action: MODIFY reason: Too general; CK1delta is specifically a serine/threonine kinase. proposed_replacement_terms: - id: GO:0004674 label: protein serine/threonine kinase activity - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:10606744 qualifier: enables review: summary: Direct demonstration that CK1 phosphorylates p53 at Thr18, a serine/threonine kinase activity. action: ACCEPT reason: Core MF; direct experimental evidence (p53 Thr18 kinase). supported_by: - reference_id: PMID:10606744 supporting_text: Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:20041275 qualifier: enables review: summary: Direct demonstration of isoform-specific p53 phosphorylation by CK1. action: ACCEPT reason: Core MF; direct experimental evidence. supported_by: - reference_id: PMID:20041275 supporting_text: Isoform specific phosphorylation of p53 by protein kinase CK1. - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:20637175 qualifier: enables review: summary: Direct demonstration of CK1delta serine/threonine kinase activity (DCK Ser-74 phosphorylation in vitro). action: ACCEPT reason: Core MF; direct in vitro kinase assay. supported_by: - reference_id: PMID:20637175 supporting_text: Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IDA original_reference_id: PMID:12270943 qualifier: enables review: summary: Direct demonstration that CK1 phosphorylates connexin-43/GJA1 (serine kinase activity). action: ACCEPT reason: Core MF; direct experimental evidence (connexin-43 substrate). supported_by: - reference_id: PMID:12270943 supporting_text: Casein kinase 1 regulates connexin-43 gap junction assembly. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IMP original_reference_id: PMID:19043076 qualifier: enables review: summary: CK1delta/epsilon phosphorylates TOP2A at Ser-1106, supporting protein serine kinase activity. action: ACCEPT reason: Core MF; supported by substrate phosphorylation evidence (TOP2A). supported_by: - reference_id: PMID:19043076 supporting_text: Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IDA original_reference_id: PMID:21084295 qualifier: enables review: summary: Direct demonstration of eIF6 phosphorylation by CK1, supporting protein serine kinase activity. action: ACCEPT reason: Core MF; direct experimental evidence (eIF6 substrate). supported_by: - reference_id: PMID:21084295 supporting_text: Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. - term: id: GO:0036064 label: ciliary basal body evidence_type: IDA original_reference_id: PMID:29257953 qualifier: located_in review: summary: Direct localization to the ciliary basal body, consistent with CK1delta's established centrosome/basal-body role in ciliogenesis. action: ACCEPT reason: Direct IDA evidence; concordant with the functional ciliogenesis data. supported_by: - reference_id: PMID:29257953 supporting_text: Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. - term: id: GO:0045296 label: cadherin binding evidence_type: HDA original_reference_id: PMID:25468996 qualifier: enables review: summary: Cadherin binding from a high-throughput E-cadherin interactome proximity dataset. CK1delta is not an established cadherin-binding adaptor. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proximity-based annotation; no specific cadherin-binding function is established for CK1delta and it is not supported by focused studies. - term: id: GO:0004672 label: protein kinase activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Generic protein kinase activity inferred by sequence similarity from mouse ortholog. Superseded by the specific serine/threonine kinase term. action: MODIFY reason: Too general; CK1delta is specifically a serine/threonine kinase. proposed_replacement_terms: - id: GO:0004674 label: protein serine/threonine kinase activity - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IDA original_reference_id: PMID:25500533 qualifier: enables review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:25500533 supporting_text: we found that CK1δ/ε and CK1γ isoforms could moderately phosphorylate S955 and S935 in vitro, respectively - term: id: GO:0033116 label: endoplasmic reticulum-Golgi intermediate compartment membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5694441 qualifier: located_in review: summary: Reactome localization to the ERGIC membrane in the context of SEC23 phosphorylation during COPII vesicle formation. Plausible given the Golgi/secretory role. action: KEEP_AS_NON_CORE reason: Pathway-specific Reactome localization tied to the SEC23/COPII substrate role; consistent with Golgi association but specialized. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: Golgi apparatus. - term: id: GO:0007020 label: microtubule nucleation evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: Loss-of-function evidence that CK1delta is required for microtubule nucleation at the Golgi (via AKAP450), part of its ciliogenesis function. action: ACCEPT reason: Direct IMP evidence; a well-supported cell-biological role. supported_by: - reference_id: PMID:24648492 supporting_text: CK1δ was required for microtubule nucleation at the Golgi and maintenance of Golgi integrity. - term: id: GO:0034067 label: protein localization to Golgi apparatus evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: CK1delta loss disperses Golgi/centrosomal proteins (AKAP450, IFT20), supporting a role in protein localization to the Golgi. action: KEEP_AS_NON_CORE reason: Supported by IMP evidence but a downstream component of the broader Golgi-organization/ciliogenesis function. supported_by: - reference_id: PMID:24648492 supporting_text: the Golgi distribution of its binding partner, A-kinase anchor protein 450 (AKAP450) - term: id: GO:0007030 label: Golgi organization evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: CK1delta is required for maintenance of Golgi integrity and the polarized Golgi ribbon, supporting Golgi organization. action: ACCEPT reason: Direct IMP evidence; CK1delta inhibition disrupts cis-Golgi organization. supported_by: - reference_id: PMID:24648492 supporting_text: where it is important for maintaining Golgi organization and polarized trafficking - term: id: GO:0061512 label: protein localization to cilium evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: CK1delta is required for correct ciliary distribution of transport proteins (Rab8a, polycystin-2), supporting protein localization to cilium. action: KEEP_AS_NON_CORE reason: Supported by IMP evidence; a component of the ciliogenesis function rather than an independent core role. supported_by: - reference_id: PMID:24648492 supporting_text: alters pericentrosomal or ciliary distribution of several proteins involved in ciliary transport - term: id: GO:0071539 label: protein localization to centrosome evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: CK1delta is required for pericentrosomal positioning of CEP290/PCM1, supporting protein localization to the centrosome. action: KEEP_AS_NON_CORE reason: Supported by IMP evidence; part of the centrosome/ciliogenesis function. supported_by: - reference_id: PMID:24648492 supporting_text: CK1δ is required for proper positioning of these centriolar satellite proteins - term: id: GO:1905515 label: non-motile cilium assembly evidence_type: IMP original_reference_id: PMID:24648492 qualifier: acts_upstream_of_or_within review: summary: Direct loss-of-function evidence (siRNA, kinase inhibitor, Csnk1d-null cells) that CK1delta is required for primary (non-motile) ciliogenesis. action: ACCEPT reason: Strong IMP evidence across multiple models; a well-established role. supported_by: - reference_id: PMID:24648492 supporting_text: Casein kinase 1δ functions at the centrosome and Golgi to promote ciliogenesis. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2574840 qualifier: located_in review: summary: Cytosol localization from Reactome (AURKA pathway reaction). Cytosol is a genuine CK1delta location; one of many redundant Reactome citations. action: ACCEPT reason: The cytosol CC term is correct; redundant with other cytosol annotations differing only by Reactome reference. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-2574845 qualifier: located_in review: summary: Cytosol localization from Reactome (AURKA pathway reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3000310 qualifier: located_in review: summary: Cytosol localization from Reactome (AURKA/PLK1 reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3000319 qualifier: located_in review: summary: Cytosol localization from Reactome (BORA/PLK1/AURKA reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380272 qualifier: located_in review: summary: Cytosol localization from Reactome (centrosome maturation reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380283 qualifier: located_in review: summary: Cytosol localization from Reactome (gamma-TuRC recruitment reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380294 qualifier: located_in review: summary: Cytosol localization from Reactome (centrosome reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380303 qualifier: located_in review: summary: Cytosol localization from Reactome (Nlp dissociation reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380311 qualifier: located_in review: summary: Cytosol localization from Reactome (Plk1 recruitment reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380316 qualifier: located_in review: summary: Cytosol localization from Reactome (NuMA/microtubule reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380455 qualifier: located_in review: summary: Cytosol localization from Reactome (CDK11p58 recruitment reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-380508 qualifier: located_in review: summary: Cytosol localization from Reactome (NuMA translocation reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5617816 qualifier: located_in review: summary: Cytosol localization from Reactome (RAB3IP/RAB8A reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626220 qualifier: located_in review: summary: Cytosol localization from Reactome (C2CD3 centriole reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626223 qualifier: located_in review: summary: Cytosol localization from Reactome (distal appendage protein reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626227 qualifier: located_in review: summary: Cytosol localization from Reactome (CP110/CEP97 dissociation reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626228 qualifier: located_in review: summary: Cytosol localization from Reactome (TTBK2 recruitment reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626681 qualifier: located_in review: summary: Cytosol localization from Reactome (transition zone protein reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5626699 qualifier: located_in review: summary: Cytosol localization from Reactome (MARK4/ODF2 reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5638009 qualifier: located_in review: summary: Cytosol localization from Reactome (CEP164/RAB3IP vesicle reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-6791223 qualifier: located_in review: summary: Cytosol localization from Reactome (pre-40S rRNA processing reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8853405 qualifier: located_in review: summary: Cytosol localization from Reactome (TPX2/AURKA reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8853419 qualifier: located_in review: summary: Cytosol localization from Reactome (TPX2/AURKA autophosphorylation reaction). Redundant but correct CC term. action: ACCEPT reason: Cytosol is a genuine location; redundant Reactome citation. - term: id: GO:0005794 label: Golgi apparatus evidence_type: IDA original_reference_id: PMID:10826492 qualifier: located_in review: summary: Direct demonstration of CK1delta association with post-Golgi structures. action: ACCEPT reason: Direct IDA evidence; concordant with the Golgi/secretory role. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:21422228 qualifier: located_in review: summary: Direct demonstration of centrosomal localization, functionally required for Wnt-3a-dependent neurite outgrowth. action: ACCEPT reason: Direct IDA evidence; a functionally important location. supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. - term: id: GO:0005819 label: spindle evidence_type: IDA original_reference_id: PMID:10826492 qualifier: located_in review: summary: Direct demonstration of CK1delta localization at the spindle apparatus. action: ACCEPT reason: Direct IDA evidence. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005876 label: spindle microtubule evidence_type: IDA original_reference_id: PMID:10826492 qualifier: located_in review: summary: Direct demonstration of CK1delta localization at spindle microtubules. action: ACCEPT reason: Direct IDA evidence. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:16027726 qualifier: located_in review: summary: Direct demonstration of plasma membrane localization in trophoblast cells. action: ACCEPT reason: Direct IDA evidence consistent with the cell membrane annotation. supported_by: - reference_id: PMID:16027726 supporting_text: Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IDA original_reference_id: PMID:16027726 qualifier: located_in review: summary: Direct demonstration of perinuclear localization. action: ACCEPT reason: Direct IDA evidence. supported_by: - reference_id: PMID:16027726 supporting_text: Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. - term: id: GO:0051225 label: spindle assembly evidence_type: IDA original_reference_id: PMID:10826492 qualifier: involved_in review: summary: CK1delta associates with the spindle apparatus; functional involvement in spindle formation is supported by inhibitor studies in trophoblasts. action: KEEP_AS_NON_CORE reason: Supported experimentally but a context-specific (mitotic) role, not the core function. supported_by: - reference_id: PMID:10826492 supporting_text: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-6791223 qualifier: located_in review: summary: Nucleoplasm localization from Reactome (pre-rRNA processing reaction); consistent with documented nuclear localization. action: ACCEPT reason: Consistent with nuclear localization of CK1delta. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus.' - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:21399614 qualifier: located_in review: summary: Centrosome localization from a proteomic study of asymmetrically localizing centrosome components. action: ACCEPT reason: Direct evidence corroborating the well-established centrosomal location. supported_by: - reference_id: PMID:21399614 supporting_text: Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. - term: id: GO:0090263 label: positive regulation of canonical Wnt signaling pathway evidence_type: IMP original_reference_id: PMID:20412773 qualifier: involved_in review: 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). action: ACCEPT reason: Supported by IMP evidence; a core signaling role of CK1delta. supported_by: - reference_id: PMID:20412773 supporting_text: The Hippo pathway regulates Wnt/beta-catenin signaling. - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Nuclear localization inferred by sequence similarity from mouse ortholog; concordant with the experimentally and UniProt-documented nuclear location. action: ACCEPT reason: Consistent with documented nuclear localization. supported_by: - reference_id: file:human/CSNK1D/CSNK1D-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus.' - term: id: GO:0004672 label: protein kinase activity evidence_type: IDA original_reference_id: PMID:16618118 qualifier: enables review: summary: Generic protein kinase activity from a direct assay. Correct but superseded by the specific serine/threonine kinase term. action: MODIFY reason: Too general; CK1delta is specifically a serine/threonine kinase. proposed_replacement_terms: - id: GO:0004674 label: protein serine/threonine kinase activity - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16618118 qualifier: enables review: summary: Protein binding evidenced by interaction with DBNDD2/CK1BP (Q9BQY9), an isoform-selective binding partner. Bare term is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Uninformative MF term; the specific DBNDD2 interaction is documented in UniProt but the bare "protein binding" conveys no function. - term: id: GO:0006468 label: protein phosphorylation evidence_type: IDA original_reference_id: PMID:16618118 qualifier: involved_in review: summary: Protein phosphorylation as a biological process, directly demonstrated; this is the core enzymatic activity of CK1delta expressed as a BP. action: ACCEPT reason: Core process directly supported; CK1delta phosphorylates numerous protein substrates. supported_by: - reference_id: PMID:16618118 supporting_text: Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. - term: id: GO:0032436 label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: ISS transfer (from mouse ortholog) of a role in promoting proteasomal degradation; supported in human by YAP1/MDM2 degron phosphorylation. action: KEEP_AS_NON_CORE reason: A genuine substrate-driven downstream effect (degron priming), not a core function. supported_by: - reference_id: PMID:20708156 supporting_text: Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. - term: id: GO:0032922 label: circadian regulation of gene expression evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: ISS transfer of circadian regulation of gene expression. CK1delta controls PER stability/nuclear entry and thus the transcriptional clock; a core role. action: ACCEPT reason: Core circadian function; CK1delta regulates PER-mediated transcriptional feedback. supported_by: - reference_id: PMID:23636092 supporting_text: Casein kinase idelta mutations in familial migraine and advanced sleep phase. - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: ISS transfer of regulation of circadian rhythm; a hallmark, disease-linked role of CK1delta. action: ACCEPT reason: Core biological process supported by PER phosphorylation and FASPS2/migraine variants. supported_by: - reference_id: PMID:23636092 supporting_text: Casein kinase idelta mutations in familial migraine and advanced sleep phase. - term: id: GO:0004672 label: protein kinase activity evidence_type: TAS original_reference_id: PMID:8786104 qualifier: enables review: summary: Generic protein kinase activity from the original CSNK1D cDNA characterization. Correct but superseded by the specific serine/threonine kinase term. action: MODIFY reason: Too general; CK1delta is specifically a serine/threonine kinase. proposed_replacement_terms: - id: GO:0004674 label: protein serine/threonine kinase activity core_functions: - description: Constitutively active protein serine/threonine kinase (ATP- and Mg2+-dependent) that phosphorylates a broad range of substrates, including via primed (phospho-directed) and unprimed mechanisms. supported_by: - reference_id: PMID:10606744 supporting_text: Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity - description: Phosphorylates PER1 and PER2 to control their stability and nuclear transport, acting as a central component of the circadian clock that sets period length; loss-of-function variants cause familial advanced sleep phase syndrome and migraine. supported_by: - reference_id: PMID:23636092 supporting_text: Casein kinase idelta mutations in familial migraine and advanced sleep phase. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:0042752 label: regulation of circadian rhythm - id: GO:0032922 label: circadian regulation of gene expression - description: Phosphorylates Dishevelled (DVL2/DVL3) and other components to regulate canonical Wnt/beta-catenin signaling and Wnt-3a-dependent neurite outgrowth. supported_by: - reference_id: PMID:21422228 supporting_text: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:0090263 label: positive regulation of canonical Wnt signaling pathway - description: Acts at the centrosome and Golgi (anchored via AKAP9/AKAP450) to promote microtubule nucleation, Golgi organization and primary (non-motile) ciliogenesis. supported_by: - reference_id: PMID:24648492 supporting_text: Casein kinase 1δ functions at the centrosome and Golgi to promote ciliogenesis. molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:1905515 label: non-motile cilium assembly - id: GO:0007030 label: Golgi organization - id: GO:0007020 label: microtubule nucleation proposed_new_terms: [] suggested_questions: - question: Which CK1delta substrates and biological roles are truly delta-specific versus shared with the highly similar CK1epsilon, given their frequent co-redundancy? - question: 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? suggested_experiments: - description: 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. - description: 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. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000003 title: Gene Ontology annotation based on Enzyme Commission mapping findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10606744 title: Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. findings: [] - id: PMID:10826492 title: Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. findings: [] - id: PMID:12270943 title: Casein kinase 1 regulates connexin-43 gap junction assembly. findings: [] - id: PMID:14761950 title: Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules. findings: [] - id: PMID:16027726 title: Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. findings: [] - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: [] - id: PMID:16618118 title: Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1. findings: [] - id: PMID:17562708 title: Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. findings: [] - id: PMID:17962809 title: Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2. findings: [] - id: PMID:19043076 title: Casein kinase I delta/epsilon phosphorylates topoisomerase IIalpha at serine-1106 and modulates DNA cleavage activity. findings: [] - id: PMID:19591487 title: 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta. findings: [] - id: PMID:20041275 title: Isoform specific phosphorylation of p53 by protein kinase CK1. findings: [] - id: PMID:20048001 title: A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). findings: [] - id: PMID:20412773 title: The Hippo pathway regulates Wnt/beta-catenin signaling. findings: [] - id: PMID:20637175 title: Casein kinase 1delta activates human recombinant deoxycytidine kinase by Ser-74 phosphorylation, but is not involved in the in vivo regulation of its activity. findings: [] - id: PMID:20699359 title: Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. findings: [] - id: PMID:20708156 title: Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. findings: [] - id: PMID:21084295 title: Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. findings: [] - id: PMID:21179498 title: High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. findings: [] - id: PMID:21399614 title: Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. findings: [] - id: PMID:21422228 title: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth. findings: [] - id: PMID:22609948 title: Identification of a novel Wnt5a-CK1ɛ-Dvl2-Plk1-mediated primary cilia disassembly pathway. findings: [] - id: PMID:23636092 title: Casein kinase iδ mutations in familial migraine and advanced sleep phase. findings: [] - id: PMID:24648492 title: Casein kinase 1δ functions at the centrosome and Golgi to promote ciliogenesis. findings: [] - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] - id: PMID:25468996 title: E-cadherin interactome complexity and robustness resolved by quantitative proteomics. findings: [] - id: PMID:25500533 title: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. findings: [] - id: PMID:29257953 title: Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32707033 title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:36931259 title: A central chaperone-like role for 14-3-3 proteins in human cells. findings: [] - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: PMID:8786104 title: Sequence analysis of the cDNA for the human casein kinase I delta (CSNK1D) gene and its chromosomal localization. findings: [] - id: Reactome:R-HSA-204005 title: COPII-mediated vesicle transport findings: [] - id: Reactome:R-HSA-2574840 title: AJUBA facilitates AURKA autophosphorylation findings: [] - id: Reactome:R-HSA-2574845 title: AJUBA binds centrosome-associated AURKA findings: [] - id: Reactome:R-HSA-3000310 title: AURKA phosphorylates PLK1 findings: [] - id: Reactome:R-HSA-3000319 title: BORA binds PLK1 and AURKA findings: [] - id: Reactome:R-HSA-380272 title: Plk1-mediated phosphorylation of Nlp findings: [] - id: Reactome:R-HSA-380283 title: Recruitment of additional gamma tubulin/ gamma TuRC to the centrosome findings: [] - id: Reactome:R-HSA-380294 title: Loss of C-Nap-1 from centrosomes findings: [] - id: Reactome:R-HSA-380303 title: Dissociation of Phospho-Nlp from the centrosome findings: [] - id: Reactome:R-HSA-380311 title: Recruitment of Plk1 to centrosomes findings: [] - id: Reactome:R-HSA-380316 title: Association of NuMA with microtubules findings: [] - id: Reactome:R-HSA-380455 title: Recruitment of CDK11p58 to the centrosomes findings: [] - id: Reactome:R-HSA-380508 title: Translocation of NuMA to the centrosomes findings: [] - id: Reactome:R-HSA-5617816 title: RAB3IP stimulates nucleotide exchange on RAB8A findings: [] - id: Reactome:R-HSA-5626220 title: C2CD3 binds the mother centriole findings: [] - id: Reactome:R-HSA-5626223 title: C2CD3 and OFD1 recruit 5 distal appendage proteins to the centriole findings: [] - id: Reactome:R-HSA-5626227 title: CP110 and CEP97 dissociate from the centriole findings: [] - id: Reactome:R-HSA-5626228 title: The distal appendage proteins recruit TTBK2 findings: [] - id: Reactome:R-HSA-5626681 title: Recruitment of transition zone proteins findings: [] - id: Reactome:R-HSA-5626699 title: MARK4 binds ODF2 in the centriole findings: [] - id: Reactome:R-HSA-5638009 title: CEP164 recruits RAB3IP-carrying Golgi-derived vesicles to the basal body findings: [] - id: Reactome:R-HSA-5694441 title: CSNK1D phosphorylates SEC23 findings: [] - id: Reactome:R-HSA-6791223 title: 18SE pre-rRNA in pre-40S particles is nucleolytically processed during translocation from the nucleus to the cytosol findings: [] - id: Reactome:R-HSA-8853405 title: TPX2 binds AURKA at centrosomes findings: [] - id: Reactome:R-HSA-8853419 title: TPX2 promotes AURKA autophosphorylation findings: []