{"gene":"CCP110","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2002,"finding":"CP110 is phosphorylated by CDKs (CDK2) in vitro and in vivo, localizes to centrosomes, and is required for centrosome duplication; RNAi-mediated depletion inhibits centrosome duplication, and long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and polyploidy.","method":"CDK substrate screen, in vitro kinase assay, immunofluorescence localization, RNAi knockdown with centrosome phenotype readout","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro kinase assay, in vivo phosphorylation, RNAi, centrosome phenotype), foundational paper replicated by subsequent studies","pmids":["12361598"],"is_preprint":false},{"year":2006,"finding":"CP110 directly interacts with calmodulin (CaM) and centrin in vivo; CP110 exists in large complexes (~300 kDa to 3 MDa) containing both centrin and CaM; CP110 depletion or expression of a CaM-binding-deficient CP110 mutant causes failure at a late stage of cytokinesis and binucleate cell formation.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro binding assay, RNAi knockdown, expression of dominant-negative mutant","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro binding, mutagenesis, and functional RNAi with specific cytokinesis phenotype in one study","pmids":["16760425"],"is_preprint":false},{"year":2007,"finding":"CP110 forms a complex with Cep97, which recruits CP110 to centrosomes; depletion of Cep97 causes CP110 disappearance from centrosomes, spindle defects, and polyploidy. Loss of Cep97 or CP110 promotes primary cilia formation in growing cells, and enforced CP110 expression in quiescent cells suppresses cilia assembly, demonstrating that Cep97 and CP110 collaborate to inhibit ciliogenesis.","method":"Biochemical complex purification, RNAi knockdown, dominant-negative expression, immunofluorescence, cilia formation assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex purification, RNAi, dominant-negative with multiple phenotypic readouts; replicated by subsequent studies","pmids":["17719545"],"is_preprint":false},{"year":2008,"finding":"CP110 interacts with CEP290 in a discrete complex separable from other CP110 complexes; interaction with CEP290 is required for CP110's ability to suppress primary cilia formation. CEP290 and CP110 also interact with Rab8a; depletion of CEP290 prevents ciliogenesis and mislocalizes Rab8a at centrosomes and cilia.","method":"Co-immunoprecipitation, RNAi knockdown, immunofluorescence, ciliogenesis assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi rescue epistasis, multiple orthogonal assays in one study; foundational finding replicated by later work","pmids":["18694559"],"is_preprint":false},{"year":2009,"finding":"CP110 acts as a distal end-capping protein of centrioles; depletion of CP110 leads to elongated microtubule structures extending from centrioles. CP110 and CPAP play antagonistic roles in controlling the length of newly formed centrioles, with CPAP promoting tubulin addition and CP110 restraining it.","method":"siRNA knockdown, overexpression, immunofluorescence, electron microscopy of centriole ultrastructure","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with EM-level phenotypic validation; replicated in multiple studies","pmids":["19481458"],"is_preprint":false},{"year":2010,"finding":"Cyclin F (Fbxo1) is the substrate recognition subunit of SCF(Cyclin F) ubiquitin ligase complex that physically associates with CP110 at centrioles during G2 and ubiquitylates CP110, leading to its proteasomal degradation. SCF(Cyclin F)-mediated CP110 degradation is required for mitotic fidelity; stable CP110 causes multipolar spindles and chromosome instability.","method":"Unbiased protein interaction screen, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, expression of stable CP110 mutant, cell biology phenotype readouts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay, Co-IP, epistasis (co-silencing rescues phenotype), stable mutant, multiple orthogonal methods; published in Nature","pmids":["20596027"],"is_preprint":false},{"year":2011,"finding":"Kif24, a kinesin-13 subfamily motor protein, specifically interacts with CP110 and Cep97 at mother centrioles; loss of Kif24 causes disappearance of CP110 from mother centrioles in cycling cells and leads to aberrant cilia assembly. Kif24 depolymerizes microtubules in vitro and specifically remodels centriolar microtubules in cells.","method":"Co-immunoprecipitation, RNAi knockdown, in vitro microtubule depolymerization assay, immunofluorescence, ciliogenesis assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP, in vitro motor activity assay, RNAi with defined phenotype, multiple orthogonal methods","pmids":["21620453"],"is_preprint":false},{"year":2012,"finding":"In Drosophila, CP110 depletion results in centriole length diminution (in contrast to mammalian cells where depletion causes elongation); co-depletion of CP110 and Klp10A (kinesin-13) gives longer centrioles than usual, indicating functional interaction between these two proteins in controlling centriole length.","method":"RNAi in Drosophila cultured cells and testes, electron microscopy of centriole ultrastructure, co-depletion epistasis","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila epistasis with EM phenotype, single lab, orthologous system but divergent result from mammalian cells","pmids":["22365849"],"is_preprint":false},{"year":2013,"finding":"USP33, a deubiquitinating enzyme, interacts with CP110 and localizes to centrioles primarily in S and G2/M phases; USP33 potently and specifically deubiquitinates CP110 (but not other cyclin-F substrates), counteracting SCF(cyclin F)-mediated ubiquitination. USP33 overactivity promotes supernumerary centrioles; USP33 ablation destabilizes CP110 and inhibits centrosome amplification.","method":"Co-immunoprecipitation, in vitro deubiquitination assay, RNAi knockdown, overexpression, centrosome number assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deubiquitination assay, Co-IP, RNAi epistasis, specific substrate specificity demonstrated; published in Nature","pmids":["23486064"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, CP110 subtly influences centriole length by counteracting centriole-elongating activity of duplication proteins; CP110 ensures centriolar microtubules do not extend beyond the distal centriole end; CP110 suppresses centriole overduplication induced by overexpression of duplication proteins.","method":"CP110 null mutant fly analysis, overexpression, immunofluorescence and electron microscopy of centrioles","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null mutant with multiple phenotypic readouts in vivo (Drosophila), single lab, orthologous system","pmids":["24297749"],"is_preprint":false},{"year":2014,"finding":"Talpid3/KIAA0586 is a component of a CP110-containing protein complex; Talpid3 assembles a ring-like structure at the extreme distal end of centrioles. Depletion of Talpid3 causes abnormal centriolar satellite distribution and cilia assembly defects reminiscent of Cep290 loss, including mislocalization of Rab8a; activated Rab8a suppresses cilia defects caused by Talpid3 depletion.","method":"Co-immunoprecipitation, RNAi, immunofluorescence, activated GTPase rescue epistasis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi epistasis, rescue experiment, single lab with multiple orthogonal methods","pmids":["24421332"],"is_preprint":false},{"year":2014,"finding":"miR-34/449 miRNAs promote motile ciliogenesis in part by post-transcriptionally repressing Cp110; cp110 knockdown in miR-34/449-deficient multiciliated cells (mouse and Xenopus) restored ciliogenesis by rescuing basal body maturation and docking.","method":"miRNA knockout mice, Xenopus model, morpholino knockdown, cp110 knockdown rescue epistasis, basal body imaging","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo (mouse), Xenopus validation, cp110 knockdown rescue epistasis, two independent model organisms","pmids":["24899310"],"is_preprint":false},{"year":2015,"finding":"Centrin2 controls CP110 removal from the mother centriole during ciliogenesis; CETN2-deficient human RPE cells fail to remove CP110 and show abnormal distal appendage protein localization; knockdown of CP110 in CETN2-deficient cells rescues ciliation, placing centrin2 upstream of CP110 removal.","method":"CETN2 gene disruption (reverse genetics), immunofluorescence, CP110 knockdown epistasis, ciliogenesis assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene disruption in human cells, epistasis rescue experiment, two orthogonal methods","pmids":["25753040"],"is_preprint":false},{"year":2015,"finding":"CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe; siRNA-mediated repression of CP110 induced anaphase catastrophe in lung cancer cells, while CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Site-directed mutagenesis identified CDK phosphorylation sites Ser170 and Thr194 as critical for conferring anaphase catastrophe by altering centrosome clustering in mitosis.","method":"siRNA knockdown, overexpression, site-directed mutagenesis, live-cell imaging, CDK2 inhibitor treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotype, site-directed mutagenesis, single lab","pmids":["25808870","26304236"],"is_preprint":false},{"year":2016,"finding":"CP110 is required for anchoring basal bodies to the membrane during cilia formation in vivo; Cp110-/- mice die shortly after birth with organogenesis defects including impaired Shh signaling and reduced primary cilia. CP110 loss results in abnormal distribution of subdistal appendage (SDA) core components and recycling endosomes, implicating CP110 in SDA assembly and ciliary vesicle docking.","method":"Cp110 knockout mouse, immunofluorescence, ciliogenesis assay in multiple tissues, Shh signaling readout","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in vivo, multiple tissues, multiple phenotypic readouts including signaling pathway assay","pmids":["26965371"],"is_preprint":false},{"year":2016,"finding":"In Xenopus multiciliated cells, Cp110 at optimal levels promotes ciliogenesis by localizing to cilia-forming basal bodies and rootlets and being required for ciliary adhesion complexes that facilitate actin interactions; coiled-coil domains mediate preferential binding to centrioles over rootlets. Cp110 levels are precisely controlled by both ciliary transcription factors and miRNAs.","method":"Xenopus in vivo experiments, domain mutagenesis, immunofluorescence, knockdown/overexpression of transcription factors and miRNAs","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Xenopus model, domain mutagenesis, multiple readouts, single lab","pmids":["27623009"],"is_preprint":false},{"year":2017,"finding":"PLK4 specifically phosphorylates CP110 at Ser98; phospho-resistant CP110 (S98A) inhibits centriole assembly while phospho-mimetic CP110 (S98D) induces centriole assembly even under PLK4-limiting conditions. Phosphorylated CP110 augments centrosomal SAS6 levels, suggesting involvement in cartwheel stabilization.","method":"In vitro kinase assay, site-directed mutagenesis, overexpression of phospho-mutants, immunofluorescence, SAS6 quantification","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, gain-of-function phenotype, single lab","pmids":["28562169"],"is_preprint":false},{"year":2018,"finding":"MPP9 is recruited by KIF24 to the distal end of the mother centriole where it forms a ring-like structure that recruits the CP110-CEP97 complex by directly binding CEP97. Phosphorylation of MPP9 by TTBK2 at the onset of ciliogenesis targets MPP9 for ubiquitin-proteasome degradation, which facilitates removal of CP110 and CEP97 from the mother centriole.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, super-resolution microscopy, TTBK2 kinase assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, kinase substrate identification, siRNA epistasis, super-resolution imaging, multiple orthogonal methods","pmids":["30375385"],"is_preprint":false},{"year":2021,"finding":"NudCL2 acts as a selective autophagy receptor at mother centrioles, containing an LIR motif that mediates association of CP110 with the autophagosome marker LC3. Knockout of NudCL2 induces defective CP110 removal from mother centrioles and ciliogenesis defects rescued by wild-type NudCL2 but not its LIR mutant; CP110 knockdown attenuates ciliogenesis defects in NudCL2-deficient cells.","method":"NudCL2 knockout, LIR motif mutagenesis, Co-IP, autophagy/LC3 interaction assay, RNAi epistasis, zebrafish morphant analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with domain-specific rescue, autophagy receptor mechanism, epistasis, two model systems (MEF cells and zebrafish)","pmids":["34480124"],"is_preprint":false},{"year":2021,"finding":"CEP78 promotes ciliogenesis by negatively regulating CP110 levels via the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex involved in CP110 ubiquitination and degradation. CEP78 interacts with CEP350, which promotes centrosomal recruitment and stability of CEP78, leading to EDD1 centrosomal recruitment. Cells lacking CEP78 display significantly increased CP110 levels, and depletion of CP110 in CEP78-deficient cells restores ciliation frequency.","method":"Disease-based interactome screen, Co-IP, CEP78 knockout, RNAi epistasis, ciliogenesis assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells, multiple Co-IPs, CP110 depletion epistasis rescue, pathway ordering established","pmids":["34259627"],"is_preprint":false},{"year":2021,"finding":"LUBAC (linear ubiquitin chain assembly complex) specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole during ciliogenesis. PRPF8, located at the distal end of the mother centriole, acts as a receptor for linear ubiquitin chains on CP110 to facilitate its removal at the initial stage of ciliogenesis.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, immunofluorescence, ciliogenesis assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay demonstrating linear chain specificity, receptor identification, multiple orthogonal methods","pmids":["34813648"],"is_preprint":false},{"year":2022,"finding":"Aggresome assembly at the centrosome depends on CP110, CEP97, and CEP290; the seeding of a phosphorylated HSP27 ring around centrioles (the initial aggresome structure) requires these proteins. In senescent cells, reduced CP110 levels impair aggresome formation.","method":"siRNA knockdown, quantitative immunofluorescence, aggresome formation assay, mutant huntingtin aggregation assay","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with specific phenotypic readout, multiple proteins tested, single lab","pmids":["35411088"],"is_preprint":false},{"year":2022,"finding":"CP110 and Cep97 form a complex at the distal end of centrioles in Drosophila embryos whose levels rise and fall entrained by the Cdk-Cyclin oscillator; altering CP110 and Cep97 levels changes Plk4 oscillation and cartwheel growth at the proximal end, revealing unexpected crosstalk between distal-end factors and proximal centriole assembly.","method":"Live imaging in Drosophila embryos, quantitative fluorescence analysis, overexpression and knockdown of CP110/Cep97","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging in vivo with quantitative analysis, multiple perturbations, single lab","pmids":["35707992"],"is_preprint":false},{"year":2022,"finding":"ENKD1 competes with CEP97 for binding to CP110; depletion of ENKD1 enhances the CP110-CEP97 interaction and retains CP110 at the mother centriole. Co-knockdown of ENKD1 and CP110 reverses ciliogenesis defects caused by ENKD1 depletion. Enkd1 knockout mice have ciliogenesis defects in multiple organs.","method":"Co-immunoprecipitation, competitive binding assay, siRNA knockdown, knockout mice, super-resolution microscopy, ciliogenesis assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — competition binding assay, in vivo knockout, epistasis rescue, super-resolution microscopy, multiple orthogonal methods","pmids":["35301795"],"is_preprint":false},{"year":2023,"finding":"EHD1 regulates CP110 ubiquitination during ciliogenesis; EHD1 controls centriolar satellite movement to the mother centriole, delivering the E3 ubiquitin ligase HERC2, which interacts with and ubiquitinates CP110. MIB1 also ubiquitinates CP110. HERC2 is required for ciliogenesis and localizes to centriolar satellites.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, immunofluorescence, centriolar satellite trafficking assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ubiquitination assay, Co-IP, loss-of-function with ciliogenesis readout, trafficking mechanism established, multiple methods","pmids":["37074924"],"is_preprint":false},{"year":2023,"finding":"CCP5 and CCP6 interact with CP110 (CCP5 through its N-terminus) and retain CP110 at the mother centriole to suppress cilia formation in cycling cells. Loss of CCP5 or CCP6 causes disappearance of CP110 from the mother centriole and increased ciliation; these effects are independent of their enzymatic deglutamylation activity.","method":"CoIP-MS, co-immunoprecipitation, RNAi knockdown, immunofluorescence, ciliogenesis assay, domain mapping","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS, RNAi with functional readout, enzyme-activity-independent mechanism, single lab","pmids":["37226238"],"is_preprint":false},{"year":2023,"finding":"ODF2 controls CP110 levels at centrioles; ODF2 knockdown leads to decreased CP110 levels, while ODF2 most likely acts as a scaffold for NEURL4 or HYLS1 binding to mediate CP110 degradation via the ubiquitin-dependent proteasome pathway.","method":"siRNA knockdown, rapamycin-mediated dimerization recruitment assay, immunofluorescence, ciliogenesis assay","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (RNAi + overexpression), scaffold role proposed but not directly demonstrated by reconstitution","pmids":["37681926"],"is_preprint":false},{"year":2025,"finding":"p97/VCP (valosin-containing protein), an AAA-ATPase, is responsible for removal of CP110 from the mother centriole; p97 knockdown or inhibition impairs ciliogenesis in a mechanism dependent on CP110. p97 is proposed to unfold and extract polyubiquitinated CP110 from the mother centriole.","method":"siRNA knockdown, p97 chemical inhibition, ciliogenesis assay, immunofluorescence, epistasis with CP110","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis, two orthogonal approaches (knockdown and inhibitor), single lab","pmids":["39785673"],"is_preprint":false},{"year":2025,"finding":"EHD1 promotes CP110/CEP97 removal from the mother centriole cap through its membrane tubulation function during formation of tubular ciliogenesis intermediates; EHD1 and RAB8 orchestrate formation of tubular C-shaped and toroidal membrane intermediates upstream of the ciliary vesicle.","method":"3D electron microscopy (isotropic ultrastructure imaging), EHD1 depletion/inhibition, immunofluorescence, quantitative analysis of membrane structures","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-resolution EM with loss-of-function, novel mechanistic insight, single lab preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"CP110 (CCP110) is a distal-end capping protein of centrioles that is phosphorylated by CDK2 and PLK4, recruited to centrosomes by CEP97, and positively regulates centriole duplication while restraining centriole elongation; it suppresses primary ciliogenesis by capping the mother centriole, an inhibitory function relieved by its proteasomal degradation (mediated by SCF(Cyclin F)/EDD1/LUBAC/HERC2 ubiquitin ligases and p97-dependent extraction) or autophagy (via NudCL2), with these degradation pathways counterbalanced by the deubiquitinase USP33, and further controlled by interacting proteins including Cep97, CEP290, Kif24, MPP9, ENKD1, centrin2, CCP5/6, and EHD1 that collectively gate the timing of CP110 removal and cilia assembly."},"narrative":{"mechanistic_narrative":"CP110 (CCP110) is a centriolar distal-end capping protein that governs both centriole biogenesis and the licensing of ciliogenesis [PMID:12361598, PMID:19481458]. It localizes to the distal end of centrioles where it restrains centriolar microtubule extension, acting antagonistically to the elongation-promoting factor CPAP, such that CP110 loss yields aberrantly elongated microtubule structures [PMID:19481458]. CP110 is recruited to centrosomes within a complex with CEP97 [PMID:17719545], and together this complex caps the mother centriole to suppress primary cilium assembly; a separable CP110–CEP290 complex is additionally required for ciliogenesis suppression and couples to Rab8a-dependent membrane trafficking [PMID:17719545, PMID:18694559]. Its capping activity is reinforced by interactions with Kif24, MPP9, ENKD1, CCP5/CCP6, and centrin2, which collectively retain CP110 at the mother centriole until ciliogenesis is triggered [PMID:21620453, PMID:25753040, PMID:30375385, PMID:35301795, PMID:37226238]. CP110 is required for centriole/centrosome duplication and its activity is controlled by phosphorylation: CDK2 phosphorylation supports duplication and mitotic fidelity, and PLK4 phosphorylation at Ser98 promotes centriole assembly in part by augmenting centrosomal SAS6 [PMID:12361598, PMID:28562169]. The timing of cilia assembly is set by regulated CP110 destruction — proteasomal degradation through SCF(Cyclin F) and additional ubiquitin ligases (EDD1/DDB1–VPRBP, LUBAC-generated linear chains read by PRPF8, HERC2 delivered via EHD1-controlled centriolar satellites), p97/VCP-dependent extraction, and selective autophagy via the LIR-containing receptor NudCL2 — counterbalanced by the deubiquitinase USP33 [PMID:20596027, PMID:23486064, PMID:34480124, PMID:34259627, PMID:34813648, PMID:37074924, PMID:39785673]. CP110 is essential in vivo: Cp110-null mice die after birth with organogenesis defects, impaired Shh signaling, and basal-body docking failures, establishing CP110's role in subdistal appendage assembly and ciliary vesicle anchoring [PMID:26965371].","teleology":[{"year":2002,"claim":"Established CP110 as a CDK2 substrate at centrosomes required for centrosome duplication, defining its entry point into the centriole cycle.","evidence":"CDK substrate screen, in vitro kinase assay, and RNAi with centrosome phenotype readout","pmids":["12361598"],"confidence":"High","gaps":["Did not define the structural target of capping","Mechanism linking phosphorylation to duplication not resolved"]},{"year":2006,"claim":"Showed CP110 assembles into large centrin/calmodulin-containing complexes and functions in late cytokinesis, broadening its role beyond duplication.","evidence":"Yeast two-hybrid, reciprocal Co-IP, in vitro binding, and RNAi/dominant-negative with cytokinesis readout","pmids":["16760425"],"confidence":"High","gaps":["Composition of the megadalton complexes not fully resolved","Link between cytokinesis role and centriolar capping unclear"]},{"year":2007,"claim":"Identified CEP97 as the recruiter of CP110 to centrosomes and demonstrated the CP110–CEP97 module suppresses ciliogenesis, the central regulatory axis of the gene.","evidence":"Biochemical complex purification, RNAi, dominant-negative, and cilia-formation assays","pmids":["17719545"],"confidence":"High","gaps":["How the cap physically blocks cilium initiation not shown","Signals removing the cap unknown at this point"]},{"year":2008,"claim":"Resolved a distinct CP110–CEP290 complex required for ciliogenesis suppression and linked CP110 to Rab8a-dependent ciliary membrane trafficking.","evidence":"Reciprocal Co-IP, RNAi epistasis, and ciliogenesis assays","pmids":["18694559"],"confidence":"High","gaps":["How CEP290 and CEP97 complexes are coordinated unclear","Direct CP110–Rab8a connection not defined"]},{"year":2009,"claim":"Defined CP110 mechanistically as a distal-end cap restraining centriolar microtubule elongation, antagonistic to CPAP.","evidence":"siRNA/overexpression with immunofluorescence and electron microscopy of centriole ultrastructure","pmids":["19481458"],"confidence":"High","gaps":["Molecular basis of microtubule-end capping not structurally defined","How antagonism with CPAP is balanced unknown"]},{"year":2010,"claim":"Identified SCF(Cyclin F) as the ubiquitin ligase that degrades CP110 in G2, establishing that timed CP110 destruction enforces mitotic fidelity.","evidence":"Interaction screen, Co-IP, in vitro ubiquitination, siRNA, and stable-mutant phenotype","pmids":["20596027"],"confidence":"High","gaps":["Did not address ciliogenesis-coupled degradation","Other degradation routes not yet known"]},{"year":2011,"claim":"Showed the kinesin-13 Kif24 acts with the CP110–CEP97 cap at mother centrioles to remodel centriolar microtubules and restrain cilia assembly.","evidence":"Co-IP, in vitro microtubule depolymerization, RNAi, and ciliogenesis assay","pmids":["21620453"],"confidence":"High","gaps":["How Kif24 recruitment is regulated not resolved","Coupling of depolymerization to capping unclear"]},{"year":2013,"claim":"Identified USP33 as the deubiquitinase that stabilizes CP110, defining a ubiquitin/deubiquitin balance controlling centriole number.","evidence":"Co-IP, in vitro deubiquitination with substrate specificity, RNAi, and centrosome-number assay","pmids":["23486064"],"confidence":"High","gaps":["What sets the USP33/Cyclin F balance temporally unknown","Role in ciliogenesis-coupled removal not addressed"]},{"year":2014,"claim":"Connected CP110 to vertebrate motile ciliogenesis through miR-34/449-mediated repression and to a distal-cap complex with Talpid3, showing CP110 levels gate basal body maturation.","evidence":"miRNA knockout mice, Xenopus and morpholino models, Co-IP, and rescue epistasis","pmids":["24899310","24421332"],"confidence":"High","gaps":["How transcriptional/miRNA control integrates with degradation unclear","Talpid3 ring assembly mechanism not defined"]},{"year":2015,"claim":"Placed centrin2 upstream of CP110 removal during ciliogenesis and identified CP110 as a mediator of CDK2-inhibition-driven anaphase catastrophe in cancer cells.","evidence":"CETN2 gene disruption with epistasis rescue; siRNA/overexpression, site-directed mutagenesis (Ser170/Thr194), and live imaging","pmids":["25753040","25808870","26304236"],"confidence":"High","gaps":["How centrin2 triggers cap removal mechanistically unknown","Anaphase catastrophe link is correlative at the centrosome-clustering level"]},{"year":2016,"claim":"Demonstrated CP110 is required in vivo for basal body membrane docking, subdistal appendage assembly, and Shh signaling, and that optimal CP110 levels can promote ciliogenesis context-dependently.","evidence":"Cp110 knockout mouse with multi-tissue ciliogenesis and signaling readouts; Xenopus domain mutagenesis","pmids":["26965371","27623009"],"confidence":"High","gaps":["Dual inhibitory/promoting roles not mechanistically reconciled","Direct CP110 role in SDA assembly versus indirect effect unclear"]},{"year":2017,"claim":"Identified PLK4 phosphorylation of CP110 at Ser98 as a positive regulator of centriole assembly linked to SAS6 levels.","evidence":"In vitro kinase assay, phospho-mutant overexpression, and SAS6 quantification","pmids":["28562169"],"confidence":"Medium","gaps":["Single-lab; in vivo relevance of Ser98 not tested in animals","Direct effect on cartwheel stabilization inferred, not shown"]},{"year":2018,"claim":"Defined a KIF24–MPP9 ring that recruits the CP110–CEP97 cap and showed TTBK2-driven MPP9 degradation licenses cap removal at ciliogenesis onset.","evidence":"Co-IP, direct binding, super-resolution microscopy, siRNA, and TTBK2 kinase assay","pmids":["30375385"],"confidence":"High","gaps":["How TTBK2 activation is timed not resolved","Quantitative stoichiometry of the cap assembly unknown"]},{"year":2021,"claim":"Expanded CP110 removal mechanisms to selective autophagy (NudCL2/LC3), the CEP78–EDD1 ubiquitin pathway, and LUBAC linear ubiquitination read by PRPF8, showing redundant degradation routes converge on cap clearance.","evidence":"Knockouts with domain/LIR mutagenesis, Co-IP, in vitro ubiquitination, epistasis rescue, and zebrafish models","pmids":["34480124","34259627","34813648"],"confidence":"High","gaps":["How proteasomal, autophagic, and linear-ubiquitin routes are prioritized unknown","Spatial coordination of multiple ligases at the mother centriole unclear"]},{"year":2022,"claim":"Revealed additional regulators of CP110 retention/removal (ENKD1 competing with CEP97) and a non-ciliary role in centrosomal aggresome seeding, plus Cdk–Cyclin-entrained crosstalk with proximal centriole assembly.","evidence":"Competitive binding, knockout mice, super-resolution microscopy, aggresome assays, and Drosophila live imaging","pmids":["35301795","35411088","35707992"],"confidence":"Medium","gaps":["Aggresome role mechanistically separable from capping unclear","Distal-to-proximal crosstalk mechanism not molecularly defined"]},{"year":2023,"claim":"Identified satellite-delivered HERC2 (via EHD1) and MIB1 as CP110 ligases, CCP5/CCP6 as enzymatic-activity-independent retention factors, and ODF2 as a scaffold influencing CP110 levels.","evidence":"Co-IP/CoIP-MS, ubiquitination assays, RNAi, satellite trafficking assays, and dimerization recruitment","pmids":["37074924","37226238","37681926"],"confidence":"Medium","gaps":["ODF2 scaffold role not directly reconstituted (Low confidence)","How many parallel ligases are physiologically rate-limiting unknown"]},{"year":2025,"claim":"Established p97/VCP as the AAA-ATPase that extracts polyubiquitinated CP110 from the mother centriole and linked CP110/CEP97 removal to EHD1-driven tubular ciliary membrane intermediates.","evidence":"siRNA/chemical inhibition with CP110 epistasis; 3D electron microscopy of membrane intermediates (preprint)","pmids":["39785673"],"confidence":"Medium","gaps":["Direct demonstration of p97 unfolding CP110 not shown","Coupling of membrane tubulation to ubiquitin-dependent extraction not resolved"]},{"year":null,"claim":"How the cell integrates multiple parallel CP110-removal pathways (proteasome, autophagy, p97 extraction) with membrane remodeling and the diverse retention factors into a single deterministic ciliogenesis switch remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of pathway hierarchy or redundancy","Structural basis of CP110 microtubule-end capping unknown","Quantitative dynamics of cap assembly/disassembly at the mother centriole undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,6]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8,20,24]}],"complexes":["CP110-CEP97 complex","CP110-CEP290 complex"],"partners":["CEP97","CEP290","KIF24","MPP9","ENKD1","USP33","CYCLIN F","CETN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43303","full_name":"Centriolar coiled-coil protein of 110 kDa","aliases":["Centrosomal protein of 110 kDa","CP110","Cep110"],"length_aa":1012,"mass_kda":113.4,"function":"Necessary for centrosome duplication at different stages of procentriole formation. Acts as a key negative regulator of ciliogenesis in collaboration with CEP97 by capping the mother centriole thereby preventing cilia formation (PubMed:17681131, PubMed:17719545, PubMed:23486064, PubMed:30375385, PubMed:35301795). Also involved in promoting ciliogenesis. May play a role in the assembly of the mother centriole subdistal appendages (SDA) thereby effecting the fusion of recycling endosomes to basal bodies during cilia formation (By similarity). Required for correct spindle formation and has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CETN2 (PubMed:16760425)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/O43303/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCP110","classification":"Not Classified","n_dependent_lines":239,"n_total_lines":1208,"dependency_fraction":0.1978476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CYP51A1","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCP110","total_profiled":1310},"omim":[{"mim_id":"621119","title":"ENKURIN DOMAIN-CONTAINING PROTEIN 1; ENKD1","url":"https://www.omim.org/entry/621119"},{"mim_id":"620791","title":"CENTROSOMAL PROTEIN, 76-KD; CEP76","url":"https://www.omim.org/entry/620791"},{"mim_id":"615944","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 3; C2CD3","url":"https://www.omim.org/entry/615944"},{"mim_id":"611695","title":"TAU TUBULIN KINASE 2; TTBK2","url":"https://www.omim.org/entry/611695"},{"mim_id":"609544","title":"CENTRIOLAR COILED-COIL PROTEIN, 110-KD; CCP110","url":"https://www.omim.org/entry/609544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centriolar satellite","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":33.2}],"url":"https://www.proteinatlas.org/search/CCP110"},"hgnc":{"alias_symbol":["KIAA0419","CP110"],"prev_symbol":[]},"alphafold":{"accession":"O43303","domains":[{"cath_id":"-","chopping":"2-21_32-48","consensus_level":"medium","plddt":77.3789,"start":2,"end":48},{"cath_id":"-","chopping":"818-843_850-903","consensus_level":"medium","plddt":90.966,"start":818,"end":903}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43303","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43303-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43303-F1-predicted_aligned_error_v6.png","plddt_mean":54.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCP110","jax_strain_url":"https://www.jax.org/strain/search?query=CCP110"},"sequence":{"accession":"O43303","fasta_url":"https://rest.uniprot.org/uniprotkb/O43303.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43303/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43303"}},"corpus_meta":[{"pmid":"17719545","id":"PMC_17719545","title":"Cep97 and CP110 suppress a cilia assembly program.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17719545","citation_count":388,"is_preprint":false},{"pmid":"19481458","id":"PMC_19481458","title":"Control of centriole length by CPAP and CP110.","date":"2009","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/19481458","citation_count":282,"is_preprint":false},{"pmid":"12361598","id":"PMC_12361598","title":"CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells.","date":"2002","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12361598","citation_count":258,"is_preprint":false},{"pmid":"20596027","id":"PMC_20596027","title":"SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20596027","citation_count":229,"is_preprint":false},{"pmid":"18694559","id":"PMC_18694559","title":"CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease.","date":"2008","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/18694559","citation_count":220,"is_preprint":false},{"pmid":"24899310","id":"PMC_24899310","title":"miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24899310","citation_count":182,"is_preprint":false},{"pmid":"21620453","id":"PMC_21620453","title":"Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21620453","citation_count":165,"is_preprint":false},{"pmid":"22684256","id":"PMC_22684256","title":"miR-129-3p controls cilia assembly by regulating CP110 and actin dynamics.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22684256","citation_count":132,"is_preprint":false},{"pmid":"23486064","id":"PMC_23486064","title":"USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23486064","citation_count":111,"is_preprint":false},{"pmid":"24421332","id":"PMC_24421332","title":"The CP110-interacting proteins Talpid3 and Cep290 play overlapping and distinct roles in cilia assembly.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24421332","citation_count":98,"is_preprint":false},{"pmid":"16760425","id":"PMC_16760425","title":"CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16760425","citation_count":80,"is_preprint":false},{"pmid":"24053599","id":"PMC_24053599","title":"CP110 and its network of partners coordinately regulate cilia assembly.","date":"2013","source":"Cilia","url":"https://pubmed.ncbi.nlm.nih.gov/24053599","citation_count":70,"is_preprint":false},{"pmid":"26965371","id":"PMC_26965371","title":"Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis.","date":"2016","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26965371","citation_count":68,"is_preprint":false},{"pmid":"30375385","id":"PMC_30375385","title":"M-Phase Phosphoprotein 9 regulates ciliogenesis by modulating CP110-CEP97 complex localization at the mother centriole.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30375385","citation_count":68,"is_preprint":false},{"pmid":"27623009","id":"PMC_27623009","title":"Ciliary transcription factors and miRNAs precisely regulate Cp110 levels required for ciliary adhesions and ciliogenesis.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27623009","citation_count":61,"is_preprint":false},{"pmid":"25753040","id":"PMC_25753040","title":"Centrin2 regulates CP110 removal in primary cilium formation.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25753040","citation_count":61,"is_preprint":false},{"pmid":"22365849","id":"PMC_22365849","title":"Klp10A, a microtubule-depolymerizing kinesin-13, cooperates with CP110 to control Drosophila centriole length.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22365849","citation_count":52,"is_preprint":false},{"pmid":"24297749","id":"PMC_24297749","title":"CP110 exhibits novel regulatory activities during centriole assembly in Drosophila.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24297749","citation_count":47,"is_preprint":false},{"pmid":"25808870","id":"PMC_25808870","title":"CDK2 Inhibition Causes Anaphase Catastrophe in Lung Cancer through the Centrosomal Protein CP110.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25808870","citation_count":42,"is_preprint":false},{"pmid":"26487539","id":"PMC_26487539","title":"MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26487539","citation_count":40,"is_preprint":false},{"pmid":"35411088","id":"PMC_35411088","title":"Aggresome assembly at the centrosome is driven by CP110-CEP97-CEP290 and centriolar satellites.","date":"2022","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35411088","citation_count":36,"is_preprint":false},{"pmid":"34259627","id":"PMC_34259627","title":"CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34259627","citation_count":33,"is_preprint":false},{"pmid":"35301795","id":"PMC_35301795","title":"ENKD1 promotes CP110 removal through competing with CEP97 to initiate ciliogenesis.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35301795","citation_count":26,"is_preprint":false},{"pmid":"34480124","id":"PMC_34480124","title":"NudCL2 is an autophagy receptor that mediates selective autophagic degradation of CP110 at mother centrioles to promote ciliogenesis.","date":"2021","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34480124","citation_count":23,"is_preprint":false},{"pmid":"34813648","id":"PMC_34813648","title":"LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34813648","citation_count":21,"is_preprint":false},{"pmid":"26918338","id":"PMC_26918338","title":"miR-129-3p controls centrosome number in metastatic prostate cancer cells by repressing CP110.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26918338","citation_count":21,"is_preprint":false},{"pmid":"26304236","id":"PMC_26304236","title":"Specific CP110 Phosphorylation Sites Mediate Anaphase Catastrophe after CDK2 Inhibition: Evidence for Cooperation with USP33 Knockdown.","date":"2015","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26304236","citation_count":20,"is_preprint":false},{"pmid":"28562169","id":"PMC_28562169","title":"PLK4 phosphorylation of CP110 is required for efficient centriole assembly.","date":"2017","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28562169","citation_count":20,"is_preprint":false},{"pmid":"37074924","id":"PMC_37074924","title":"EHD1 promotes CP110 ubiquitination by centriolar satellite delivery of HERC2 to the mother centriole.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37074924","citation_count":16,"is_preprint":false},{"pmid":"38415788","id":"PMC_38415788","title":"Emerging insights into CP110 removal during early steps of ciliogenesis.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/38415788","citation_count":13,"is_preprint":false},{"pmid":"35707992","id":"PMC_35707992","title":"Centriole distal-end proteins CP110 and Cep97 influence centriole cartwheel growth at the proximal end.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/35707992","citation_count":11,"is_preprint":false},{"pmid":"36911384","id":"PMC_36911384","title":"lncRNA XIST/miR‑129‑2‑3p axis targets CCP110 to regulate the proliferation, invasion and migration of endometrial cancer cells.","date":"2023","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36911384","citation_count":9,"is_preprint":false},{"pmid":"37681926","id":"PMC_37681926","title":"ODF2 Negatively Regulates CP110 Levels at the Centrioles/Basal Bodies to Control the Biogenesis of Primary Cilia.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37681926","citation_count":7,"is_preprint":false},{"pmid":"37226238","id":"PMC_37226238","title":"CCP5 and CCP6 retain CP110 and negatively regulate ciliogenesis.","date":"2023","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/37226238","citation_count":6,"is_preprint":false},{"pmid":"37822686","id":"PMC_37822686","title":"CP110 and CEP135 localize near the proximal and distal centrioles of cattle and human spermatozoa.","date":"2023","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/37822686","citation_count":5,"is_preprint":false},{"pmid":"23701692","id":"PMC_23701692","title":"Cell biology: DUBing CP110 controls centrosome numbers.","date":"2013","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/23701692","citation_count":4,"is_preprint":false},{"pmid":"38351906","id":"PMC_38351906","title":"CP110 and CEP135 Localize Near the Proximal Centriolar Remnants of Mice Spermatozoa.","date":"2024","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/38351906","citation_count":3,"is_preprint":false},{"pmid":"39785673","id":"PMC_39785673","title":"Valosin-containing protein p97 extracts capping protein CP110 from the mother centriole to promote ciliogenesis.","date":"2025","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/39785673","citation_count":2,"is_preprint":false},{"pmid":"38857829","id":"PMC_38857829","title":"Biallelic loss-of-function variants in the centriolar protein CCP110 leads to a ciliopathy-like phenotype.","date":"2024","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38857829","citation_count":1,"is_preprint":false},{"pmid":"41102520","id":"PMC_41102520","title":"BICD2 promotes ciliogenesis by facilitating CP110 removal from the mother centriole.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/41102520","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.670930","title":"Characterization of membrane structures regulating primary ciliogenesis by quantitative isotropic ultrastructure imaging","date":"2025-08-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.670930","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.10.632335","title":"Wnt/LRP6 signaling imbalance impairs ciliogenesis in human retina epithelial cells","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.632335","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.28.648957","title":"SSNA1 organizes the distal luminal centriolar network and promotes ciliogenesis without microtubule association","date":"2025-04-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.648957","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20739,"output_tokens":7230,"usd":0.085334,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16339,"output_tokens":5177,"usd":0.10556,"stage2_stop_reason":"end_turn"},"total_usd":0.190894,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CP110 is phosphorylated by CDKs (CDK2) in vitro and in vivo, localizes to centrosomes, and is required for centrosome duplication; RNAi-mediated depletion inhibits centrosome duplication, and long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and polyploidy.\",\n      \"method\": \"CDK substrate screen, in vitro kinase assay, immunofluorescence localization, RNAi knockdown with centrosome phenotype readout\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro kinase assay, in vivo phosphorylation, RNAi, centrosome phenotype), foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"12361598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CP110 directly interacts with calmodulin (CaM) and centrin in vivo; CP110 exists in large complexes (~300 kDa to 3 MDa) containing both centrin and CaM; CP110 depletion or expression of a CaM-binding-deficient CP110 mutant causes failure at a late stage of cytokinesis and binucleate cell formation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro binding assay, RNAi knockdown, expression of dominant-negative mutant\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro binding, mutagenesis, and functional RNAi with specific cytokinesis phenotype in one study\",\n      \"pmids\": [\"16760425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CP110 forms a complex with Cep97, which recruits CP110 to centrosomes; depletion of Cep97 causes CP110 disappearance from centrosomes, spindle defects, and polyploidy. Loss of Cep97 or CP110 promotes primary cilia formation in growing cells, and enforced CP110 expression in quiescent cells suppresses cilia assembly, demonstrating that Cep97 and CP110 collaborate to inhibit ciliogenesis.\",\n      \"method\": \"Biochemical complex purification, RNAi knockdown, dominant-negative expression, immunofluorescence, cilia formation assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex purification, RNAi, dominant-negative with multiple phenotypic readouts; replicated by subsequent studies\",\n      \"pmids\": [\"17719545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CP110 interacts with CEP290 in a discrete complex separable from other CP110 complexes; interaction with CEP290 is required for CP110's ability to suppress primary cilia formation. CEP290 and CP110 also interact with Rab8a; depletion of CEP290 prevents ciliogenesis and mislocalizes Rab8a at centrosomes and cilia.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, immunofluorescence, ciliogenesis assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi rescue epistasis, multiple orthogonal assays in one study; foundational finding replicated by later work\",\n      \"pmids\": [\"18694559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CP110 acts as a distal end-capping protein of centrioles; depletion of CP110 leads to elongated microtubule structures extending from centrioles. CP110 and CPAP play antagonistic roles in controlling the length of newly formed centrioles, with CPAP promoting tubulin addition and CP110 restraining it.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence, electron microscopy of centriole ultrastructure\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with EM-level phenotypic validation; replicated in multiple studies\",\n      \"pmids\": [\"19481458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cyclin F (Fbxo1) is the substrate recognition subunit of SCF(Cyclin F) ubiquitin ligase complex that physically associates with CP110 at centrioles during G2 and ubiquitylates CP110, leading to its proteasomal degradation. SCF(Cyclin F)-mediated CP110 degradation is required for mitotic fidelity; stable CP110 causes multipolar spindles and chromosome instability.\",\n      \"method\": \"Unbiased protein interaction screen, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, expression of stable CP110 mutant, cell biology phenotype readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay, Co-IP, epistasis (co-silencing rescues phenotype), stable mutant, multiple orthogonal methods; published in Nature\",\n      \"pmids\": [\"20596027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kif24, a kinesin-13 subfamily motor protein, specifically interacts with CP110 and Cep97 at mother centrioles; loss of Kif24 causes disappearance of CP110 from mother centrioles in cycling cells and leads to aberrant cilia assembly. Kif24 depolymerizes microtubules in vitro and specifically remodels centriolar microtubules in cells.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, in vitro microtubule depolymerization assay, immunofluorescence, ciliogenesis assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP, in vitro motor activity assay, RNAi with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"21620453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Drosophila, CP110 depletion results in centriole length diminution (in contrast to mammalian cells where depletion causes elongation); co-depletion of CP110 and Klp10A (kinesin-13) gives longer centrioles than usual, indicating functional interaction between these two proteins in controlling centriole length.\",\n      \"method\": \"RNAi in Drosophila cultured cells and testes, electron microscopy of centriole ultrastructure, co-depletion epistasis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila epistasis with EM phenotype, single lab, orthologous system but divergent result from mammalian cells\",\n      \"pmids\": [\"22365849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"USP33, a deubiquitinating enzyme, interacts with CP110 and localizes to centrioles primarily in S and G2/M phases; USP33 potently and specifically deubiquitinates CP110 (but not other cyclin-F substrates), counteracting SCF(cyclin F)-mediated ubiquitination. USP33 overactivity promotes supernumerary centrioles; USP33 ablation destabilizes CP110 and inhibits centrosome amplification.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deubiquitination assay, RNAi knockdown, overexpression, centrosome number assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deubiquitination assay, Co-IP, RNAi epistasis, specific substrate specificity demonstrated; published in Nature\",\n      \"pmids\": [\"23486064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, CP110 subtly influences centriole length by counteracting centriole-elongating activity of duplication proteins; CP110 ensures centriolar microtubules do not extend beyond the distal centriole end; CP110 suppresses centriole overduplication induced by overexpression of duplication proteins.\",\n      \"method\": \"CP110 null mutant fly analysis, overexpression, immunofluorescence and electron microscopy of centrioles\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null mutant with multiple phenotypic readouts in vivo (Drosophila), single lab, orthologous system\",\n      \"pmids\": [\"24297749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Talpid3/KIAA0586 is a component of a CP110-containing protein complex; Talpid3 assembles a ring-like structure at the extreme distal end of centrioles. Depletion of Talpid3 causes abnormal centriolar satellite distribution and cilia assembly defects reminiscent of Cep290 loss, including mislocalization of Rab8a; activated Rab8a suppresses cilia defects caused by Talpid3 depletion.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, immunofluorescence, activated GTPase rescue epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi epistasis, rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24421332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-34/449 miRNAs promote motile ciliogenesis in part by post-transcriptionally repressing Cp110; cp110 knockdown in miR-34/449-deficient multiciliated cells (mouse and Xenopus) restored ciliogenesis by rescuing basal body maturation and docking.\",\n      \"method\": \"miRNA knockout mice, Xenopus model, morpholino knockdown, cp110 knockdown rescue epistasis, basal body imaging\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo (mouse), Xenopus validation, cp110 knockdown rescue epistasis, two independent model organisms\",\n      \"pmids\": [\"24899310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Centrin2 controls CP110 removal from the mother centriole during ciliogenesis; CETN2-deficient human RPE cells fail to remove CP110 and show abnormal distal appendage protein localization; knockdown of CP110 in CETN2-deficient cells rescues ciliation, placing centrin2 upstream of CP110 removal.\",\n      \"method\": \"CETN2 gene disruption (reverse genetics), immunofluorescence, CP110 knockdown epistasis, ciliogenesis assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene disruption in human cells, epistasis rescue experiment, two orthogonal methods\",\n      \"pmids\": [\"25753040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CP110 is a critical mediator of CDK2 inhibition-driven anaphase catastrophe; siRNA-mediated repression of CP110 induced anaphase catastrophe in lung cancer cells, while CP110 overexpression antagonized CDK2 inhibitor-mediated anaphase catastrophe. Site-directed mutagenesis identified CDK phosphorylation sites Ser170 and Thr194 as critical for conferring anaphase catastrophe by altering centrosome clustering in mitosis.\",\n      \"method\": \"siRNA knockdown, overexpression, site-directed mutagenesis, live-cell imaging, CDK2 inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined phenotype, site-directed mutagenesis, single lab\",\n      \"pmids\": [\"25808870\", \"26304236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CP110 is required for anchoring basal bodies to the membrane during cilia formation in vivo; Cp110-/- mice die shortly after birth with organogenesis defects including impaired Shh signaling and reduced primary cilia. CP110 loss results in abnormal distribution of subdistal appendage (SDA) core components and recycling endosomes, implicating CP110 in SDA assembly and ciliary vesicle docking.\",\n      \"method\": \"Cp110 knockout mouse, immunofluorescence, ciliogenesis assay in multiple tissues, Shh signaling readout\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in vivo, multiple tissues, multiple phenotypic readouts including signaling pathway assay\",\n      \"pmids\": [\"26965371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus multiciliated cells, Cp110 at optimal levels promotes ciliogenesis by localizing to cilia-forming basal bodies and rootlets and being required for ciliary adhesion complexes that facilitate actin interactions; coiled-coil domains mediate preferential binding to centrioles over rootlets. Cp110 levels are precisely controlled by both ciliary transcription factors and miRNAs.\",\n      \"method\": \"Xenopus in vivo experiments, domain mutagenesis, immunofluorescence, knockdown/overexpression of transcription factors and miRNAs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Xenopus model, domain mutagenesis, multiple readouts, single lab\",\n      \"pmids\": [\"27623009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLK4 specifically phosphorylates CP110 at Ser98; phospho-resistant CP110 (S98A) inhibits centriole assembly while phospho-mimetic CP110 (S98D) induces centriole assembly even under PLK4-limiting conditions. Phosphorylated CP110 augments centrosomal SAS6 levels, suggesting involvement in cartwheel stabilization.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, overexpression of phospho-mutants, immunofluorescence, SAS6 quantification\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with mutagenesis, gain-of-function phenotype, single lab\",\n      \"pmids\": [\"28562169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MPP9 is recruited by KIF24 to the distal end of the mother centriole where it forms a ring-like structure that recruits the CP110-CEP97 complex by directly binding CEP97. Phosphorylation of MPP9 by TTBK2 at the onset of ciliogenesis targets MPP9 for ubiquitin-proteasome degradation, which facilitates removal of CP110 and CEP97 from the mother centriole.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, super-resolution microscopy, TTBK2 kinase assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, kinase substrate identification, siRNA epistasis, super-resolution imaging, multiple orthogonal methods\",\n      \"pmids\": [\"30375385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NudCL2 acts as a selective autophagy receptor at mother centrioles, containing an LIR motif that mediates association of CP110 with the autophagosome marker LC3. Knockout of NudCL2 induces defective CP110 removal from mother centrioles and ciliogenesis defects rescued by wild-type NudCL2 but not its LIR mutant; CP110 knockdown attenuates ciliogenesis defects in NudCL2-deficient cells.\",\n      \"method\": \"NudCL2 knockout, LIR motif mutagenesis, Co-IP, autophagy/LC3 interaction assay, RNAi epistasis, zebrafish morphant analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with domain-specific rescue, autophagy receptor mechanism, epistasis, two model systems (MEF cells and zebrafish)\",\n      \"pmids\": [\"34480124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP78 promotes ciliogenesis by negatively regulating CP110 levels via the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex involved in CP110 ubiquitination and degradation. CEP78 interacts with CEP350, which promotes centrosomal recruitment and stability of CEP78, leading to EDD1 centrosomal recruitment. Cells lacking CEP78 display significantly increased CP110 levels, and depletion of CP110 in CEP78-deficient cells restores ciliation frequency.\",\n      \"method\": \"Disease-based interactome screen, Co-IP, CEP78 knockout, RNAi epistasis, ciliogenesis assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells, multiple Co-IPs, CP110 depletion epistasis rescue, pathway ordering established\",\n      \"pmids\": [\"34259627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LUBAC (linear ubiquitin chain assembly complex) specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole during ciliogenesis. PRPF8, located at the distal end of the mother centriole, acts as a receptor for linear ubiquitin chains on CP110 to facilitate its removal at the initial stage of ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, immunofluorescence, ciliogenesis assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay demonstrating linear chain specificity, receptor identification, multiple orthogonal methods\",\n      \"pmids\": [\"34813648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Aggresome assembly at the centrosome depends on CP110, CEP97, and CEP290; the seeding of a phosphorylated HSP27 ring around centrioles (the initial aggresome structure) requires these proteins. In senescent cells, reduced CP110 levels impair aggresome formation.\",\n      \"method\": \"siRNA knockdown, quantitative immunofluorescence, aggresome formation assay, mutant huntingtin aggregation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with specific phenotypic readout, multiple proteins tested, single lab\",\n      \"pmids\": [\"35411088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CP110 and Cep97 form a complex at the distal end of centrioles in Drosophila embryos whose levels rise and fall entrained by the Cdk-Cyclin oscillator; altering CP110 and Cep97 levels changes Plk4 oscillation and cartwheel growth at the proximal end, revealing unexpected crosstalk between distal-end factors and proximal centriole assembly.\",\n      \"method\": \"Live imaging in Drosophila embryos, quantitative fluorescence analysis, overexpression and knockdown of CP110/Cep97\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging in vivo with quantitative analysis, multiple perturbations, single lab\",\n      \"pmids\": [\"35707992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ENKD1 competes with CEP97 for binding to CP110; depletion of ENKD1 enhances the CP110-CEP97 interaction and retains CP110 at the mother centriole. Co-knockdown of ENKD1 and CP110 reverses ciliogenesis defects caused by ENKD1 depletion. Enkd1 knockout mice have ciliogenesis defects in multiple organs.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, siRNA knockdown, knockout mice, super-resolution microscopy, ciliogenesis assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competition binding assay, in vivo knockout, epistasis rescue, super-resolution microscopy, multiple orthogonal methods\",\n      \"pmids\": [\"35301795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EHD1 regulates CP110 ubiquitination during ciliogenesis; EHD1 controls centriolar satellite movement to the mother centriole, delivering the E3 ubiquitin ligase HERC2, which interacts with and ubiquitinates CP110. MIB1 also ubiquitinates CP110. HERC2 is required for ciliogenesis and localizes to centriolar satellites.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, immunofluorescence, centriolar satellite trafficking assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ubiquitination assay, Co-IP, loss-of-function with ciliogenesis readout, trafficking mechanism established, multiple methods\",\n      \"pmids\": [\"37074924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCP5 and CCP6 interact with CP110 (CCP5 through its N-terminus) and retain CP110 at the mother centriole to suppress cilia formation in cycling cells. Loss of CCP5 or CCP6 causes disappearance of CP110 from the mother centriole and increased ciliation; these effects are independent of their enzymatic deglutamylation activity.\",\n      \"method\": \"CoIP-MS, co-immunoprecipitation, RNAi knockdown, immunofluorescence, ciliogenesis assay, domain mapping\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS, RNAi with functional readout, enzyme-activity-independent mechanism, single lab\",\n      \"pmids\": [\"37226238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ODF2 controls CP110 levels at centrioles; ODF2 knockdown leads to decreased CP110 levels, while ODF2 most likely acts as a scaffold for NEURL4 or HYLS1 binding to mediate CP110 degradation via the ubiquitin-dependent proteasome pathway.\",\n      \"method\": \"siRNA knockdown, rapamycin-mediated dimerization recruitment assay, immunofluorescence, ciliogenesis assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (RNAi + overexpression), scaffold role proposed but not directly demonstrated by reconstitution\",\n      \"pmids\": [\"37681926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"p97/VCP (valosin-containing protein), an AAA-ATPase, is responsible for removal of CP110 from the mother centriole; p97 knockdown or inhibition impairs ciliogenesis in a mechanism dependent on CP110. p97 is proposed to unfold and extract polyubiquitinated CP110 from the mother centriole.\",\n      \"method\": \"siRNA knockdown, p97 chemical inhibition, ciliogenesis assay, immunofluorescence, epistasis with CP110\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype, epistasis, two orthogonal approaches (knockdown and inhibitor), single lab\",\n      \"pmids\": [\"39785673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EHD1 promotes CP110/CEP97 removal from the mother centriole cap through its membrane tubulation function during formation of tubular ciliogenesis intermediates; EHD1 and RAB8 orchestrate formation of tubular C-shaped and toroidal membrane intermediates upstream of the ciliary vesicle.\",\n      \"method\": \"3D electron microscopy (isotropic ultrastructure imaging), EHD1 depletion/inhibition, immunofluorescence, quantitative analysis of membrane structures\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-resolution EM with loss-of-function, novel mechanistic insight, single lab preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CP110 (CCP110) is a distal-end capping protein of centrioles that is phosphorylated by CDK2 and PLK4, recruited to centrosomes by CEP97, and positively regulates centriole duplication while restraining centriole elongation; it suppresses primary ciliogenesis by capping the mother centriole, an inhibitory function relieved by its proteasomal degradation (mediated by SCF(Cyclin F)/EDD1/LUBAC/HERC2 ubiquitin ligases and p97-dependent extraction) or autophagy (via NudCL2), with these degradation pathways counterbalanced by the deubiquitinase USP33, and further controlled by interacting proteins including Cep97, CEP290, Kif24, MPP9, ENKD1, centrin2, CCP5/6, and EHD1 that collectively gate the timing of CP110 removal and cilia assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CP110 (CCP110) is a centriolar distal-end capping protein that governs both centriole biogenesis and the licensing of ciliogenesis [#0, #4]. It localizes to the distal end of centrioles where it restrains centriolar microtubule extension, acting antagonistically to the elongation-promoting factor CPAP, such that CP110 loss yields aberrantly elongated microtubule structures [#4]. CP110 is recruited to centrosomes within a complex with CEP97 [#2], and together this complex caps the mother centriole to suppress primary cilium assembly; a separable CP110–CEP290 complex is additionally required for ciliogenesis suppression and couples to Rab8a-dependent membrane trafficking [#2, #3]. Its capping activity is reinforced by interactions with Kif24, MPP9, ENKD1, CCP5/CCP6, and centrin2, which collectively retain CP110 at the mother centriole until ciliogenesis is triggered [#6, #12, #17, #23, #25]. CP110 is required for centriole/centrosome duplication and its activity is controlled by phosphorylation: CDK2 phosphorylation supports duplication and mitotic fidelity, and PLK4 phosphorylation at Ser98 promotes centriole assembly in part by augmenting centrosomal SAS6 [#0, #16]. The timing of cilia assembly is set by regulated CP110 destruction — proteasomal degradation through SCF(Cyclin F) and additional ubiquitin ligases (EDD1/DDB1–VPRBP, LUBAC-generated linear chains read by PRPF8, HERC2 delivered via EHD1-controlled centriolar satellites), p97/VCP-dependent extraction, and selective autophagy via the LIR-containing receptor NudCL2 — counterbalanced by the deubiquitinase USP33 [#5, #8, #18, #19, #20, #24, #27]. CP110 is essential in vivo: Cp110-null mice die after birth with organogenesis defects, impaired Shh signaling, and basal-body docking failures, establishing CP110's role in subdistal appendage assembly and ciliary vesicle anchoring [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established CP110 as a CDK2 substrate at centrosomes required for centrosome duplication, defining its entry point into the centriole cycle.\",\n      \"evidence\": \"CDK substrate screen, in vitro kinase assay, and RNAi with centrosome phenotype readout\",\n      \"pmids\": [\"12361598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural target of capping\", \"Mechanism linking phosphorylation to duplication not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed CP110 assembles into large centrin/calmodulin-containing complexes and functions in late cytokinesis, broadening its role beyond duplication.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, in vitro binding, and RNAi/dominant-negative with cytokinesis readout\",\n      \"pmids\": [\"16760425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the megadalton complexes not fully resolved\", \"Link between cytokinesis role and centriolar capping unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified CEP97 as the recruiter of CP110 to centrosomes and demonstrated the CP110–CEP97 module suppresses ciliogenesis, the central regulatory axis of the gene.\",\n      \"evidence\": \"Biochemical complex purification, RNAi, dominant-negative, and cilia-formation assays\",\n      \"pmids\": [\"17719545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the cap physically blocks cilium initiation not shown\", \"Signals removing the cap unknown at this point\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved a distinct CP110–CEP290 complex required for ciliogenesis suppression and linked CP110 to Rab8a-dependent ciliary membrane trafficking.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi epistasis, and ciliogenesis assays\",\n      \"pmids\": [\"18694559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CEP290 and CEP97 complexes are coordinated unclear\", \"Direct CP110–Rab8a connection not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined CP110 mechanistically as a distal-end cap restraining centriolar microtubule elongation, antagonistic to CPAP.\",\n      \"evidence\": \"siRNA/overexpression with immunofluorescence and electron microscopy of centriole ultrastructure\",\n      \"pmids\": [\"19481458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of microtubule-end capping not structurally defined\", \"How antagonism with CPAP is balanced unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified SCF(Cyclin F) as the ubiquitin ligase that degrades CP110 in G2, establishing that timed CP110 destruction enforces mitotic fidelity.\",\n      \"evidence\": \"Interaction screen, Co-IP, in vitro ubiquitination, siRNA, and stable-mutant phenotype\",\n      \"pmids\": [\"20596027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address ciliogenesis-coupled degradation\", \"Other degradation routes not yet known\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed the kinesin-13 Kif24 acts with the CP110–CEP97 cap at mother centrioles to remodel centriolar microtubules and restrain cilia assembly.\",\n      \"evidence\": \"Co-IP, in vitro microtubule depolymerization, RNAi, and ciliogenesis assay\",\n      \"pmids\": [\"21620453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Kif24 recruitment is regulated not resolved\", \"Coupling of depolymerization to capping unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified USP33 as the deubiquitinase that stabilizes CP110, defining a ubiquitin/deubiquitin balance controlling centriole number.\",\n      \"evidence\": \"Co-IP, in vitro deubiquitination with substrate specificity, RNAi, and centrosome-number assay\",\n      \"pmids\": [\"23486064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What sets the USP33/Cyclin F balance temporally unknown\", \"Role in ciliogenesis-coupled removal not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CP110 to vertebrate motile ciliogenesis through miR-34/449-mediated repression and to a distal-cap complex with Talpid3, showing CP110 levels gate basal body maturation.\",\n      \"evidence\": \"miRNA knockout mice, Xenopus and morpholino models, Co-IP, and rescue epistasis\",\n      \"pmids\": [\"24899310\", \"24421332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcriptional/miRNA control integrates with degradation unclear\", \"Talpid3 ring assembly mechanism not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed centrin2 upstream of CP110 removal during ciliogenesis and identified CP110 as a mediator of CDK2-inhibition-driven anaphase catastrophe in cancer cells.\",\n      \"evidence\": \"CETN2 gene disruption with epistasis rescue; siRNA/overexpression, site-directed mutagenesis (Ser170/Thr194), and live imaging\",\n      \"pmids\": [\"25753040\", \"25808870\", \"26304236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How centrin2 triggers cap removal mechanistically unknown\", \"Anaphase catastrophe link is correlative at the centrosome-clustering level\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated CP110 is required in vivo for basal body membrane docking, subdistal appendage assembly, and Shh signaling, and that optimal CP110 levels can promote ciliogenesis context-dependently.\",\n      \"evidence\": \"Cp110 knockout mouse with multi-tissue ciliogenesis and signaling readouts; Xenopus domain mutagenesis\",\n      \"pmids\": [\"26965371\", \"27623009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dual inhibitory/promoting roles not mechanistically reconciled\", \"Direct CP110 role in SDA assembly versus indirect effect unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PLK4 phosphorylation of CP110 at Ser98 as a positive regulator of centriole assembly linked to SAS6 levels.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mutant overexpression, and SAS6 quantification\",\n      \"pmids\": [\"28562169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; in vivo relevance of Ser98 not tested in animals\", \"Direct effect on cartwheel stabilization inferred, not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a KIF24–MPP9 ring that recruits the CP110–CEP97 cap and showed TTBK2-driven MPP9 degradation licenses cap removal at ciliogenesis onset.\",\n      \"evidence\": \"Co-IP, direct binding, super-resolution microscopy, siRNA, and TTBK2 kinase assay\",\n      \"pmids\": [\"30375385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TTBK2 activation is timed not resolved\", \"Quantitative stoichiometry of the cap assembly unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded CP110 removal mechanisms to selective autophagy (NudCL2/LC3), the CEP78–EDD1 ubiquitin pathway, and LUBAC linear ubiquitination read by PRPF8, showing redundant degradation routes converge on cap clearance.\",\n      \"evidence\": \"Knockouts with domain/LIR mutagenesis, Co-IP, in vitro ubiquitination, epistasis rescue, and zebrafish models\",\n      \"pmids\": [\"34480124\", \"34259627\", \"34813648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How proteasomal, autophagic, and linear-ubiquitin routes are prioritized unknown\", \"Spatial coordination of multiple ligases at the mother centriole unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed additional regulators of CP110 retention/removal (ENKD1 competing with CEP97) and a non-ciliary role in centrosomal aggresome seeding, plus Cdk–Cyclin-entrained crosstalk with proximal centriole assembly.\",\n      \"evidence\": \"Competitive binding, knockout mice, super-resolution microscopy, aggresome assays, and Drosophila live imaging\",\n      \"pmids\": [\"35301795\", \"35411088\", \"35707992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Aggresome role mechanistically separable from capping unclear\", \"Distal-to-proximal crosstalk mechanism not molecularly defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified satellite-delivered HERC2 (via EHD1) and MIB1 as CP110 ligases, CCP5/CCP6 as enzymatic-activity-independent retention factors, and ODF2 as a scaffold influencing CP110 levels.\",\n      \"evidence\": \"Co-IP/CoIP-MS, ubiquitination assays, RNAi, satellite trafficking assays, and dimerization recruitment\",\n      \"pmids\": [\"37074924\", \"37226238\", \"37681926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ODF2 scaffold role not directly reconstituted (Low confidence)\", \"How many parallel ligases are physiologically rate-limiting unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established p97/VCP as the AAA-ATPase that extracts polyubiquitinated CP110 from the mother centriole and linked CP110/CEP97 removal to EHD1-driven tubular ciliary membrane intermediates.\",\n      \"evidence\": \"siRNA/chemical inhibition with CP110 epistasis; 3D electron microscopy of membrane intermediates (preprint)\",\n      \"pmids\": [\"39785673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of p97 unfolding CP110 not shown\", \"Coupling of membrane tubulation to ubiquitin-dependent extraction not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the cell integrates multiple parallel CP110-removal pathways (proteasome, autophagy, p97 extraction) with membrane remodeling and the diverse retention factors into a single deterministic ciliogenesis switch remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of pathway hierarchy or redundancy\", \"Structural basis of CP110 microtubule-end capping unknown\", \"Quantitative dynamics of cap assembly/disassembly at the mother centriole undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8, 20, 24]}\n    ],\n    \"complexes\": [\n      \"CP110-CEP97 complex\",\n      \"CP110-CEP290 complex\"\n    ],\n    \"partners\": [\n      \"CEP97\",\n      \"CEP290\",\n      \"KIF24\",\n      \"MPP9\",\n      \"ENKD1\",\n      \"USP33\",\n      \"Cyclin F\",\n      \"CETN2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}