{"gene":"CEP192","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2007,"finding":"siRNA depletion of Cep192 in human cells causes complete loss of functional centrosomes in mitotic (but not interphase) cells, with loss of γ-tubulin, pericentrin, and other PCM proteins from centrosomes, establishing Cep192 as an essential component of centrosome maturation machinery and PCM scaffold assembly during mitosis.","method":"siRNA knockdown with immunofluorescence readout of γ-tubulin, pericentrin, and spindle assembly; overexpression studies showing ectopic γ-tubulin/pericentrin foci","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with defined cellular phenotype, replicated across multiple orthogonal readouts; foundational paper independently confirmed by multiple subsequent studies","pmids":["17980596"],"is_preprint":false},{"year":2008,"finding":"Cep192 (human homolog of C. elegans SPD-2) is a major regulator of PCM recruitment, centrosome maturation, and centriole duplication in mammalian cells; Cep192 and Pericentrin are mutually dependent for localization to mitotic centrosomes, and both are required for NEDD-1 (GCP-WD) recruitment and subsequent γ-TuRC assembly.","method":"siRNA knockdown, reciprocal co-immunoprecipitation, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus KD phenotype, replicated across multiple labs","pmids":["18207742"],"is_preprint":false},{"year":2010,"finding":"Cep192 directly interacts with Aurora A (AurA), targets AurA to mitotic centrosomes, and promotes AurA dimerization/oligomerization that triggers potent kinase activation driving microtubule assembly. This Cep192-mediated activation mechanism is distinct from TPX2-mediated AurA activation on microtubules. Depletion of Cep192 or interference with AurA–Cep192 binding abolishes centrosomal AurA activity and microtubule assembly.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA depletion, antibody-induced dimerization, dominant-negative interference","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding demonstrated, in vitro kinase activity assay, multiple interference approaches, replicated in subsequent structural studies","pmids":["21097701"],"is_preprint":false},{"year":2012,"finding":"CEP192 interacts with the K63-deubiquitinase CYLD (identified by mass spectrometry) and NEDD1; co-depletion of CYLD alleviates the bipolar spindle assembly defects caused by CEP192 depletion, placing CYLD downstream of CEP192 in regulating the spindle microtubule landscape.","method":"Mass spectrometry interactome, co-immunoprecipitation, double siRNA knockdown with spindle assembly phenotype readout","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction plus genetic epistasis (co-depletion rescue), single lab","pmids":["22895009"],"is_preprint":false},{"year":2013,"finding":"Cep192 plays a key role in centrosome recruitment of both Cep152 and Plk4; Cep192 directly binds Plk4 through an N-terminal extension specific to its largest isoform (binding region rich in negatively charged residues interacting with the positively charged polo-box domain of Plk4); double-depletion of Cep192 and Cep152 completely abolishes Plk4 binding to centrioles and centriole duplication.","method":"siRNA depletion (single and double), co-immunoprecipitation, domain mapping, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, genetic epistasis via double depletion, independently replicated by Kim et al. 2013","pmids":["23641073"],"is_preprint":false},{"year":2013,"finding":"Cep192 and Cep152 serve as two distinct, hierarchically ordered scaffolds that recruit Plk4 to centrosomes; both proteins competitively interact with the cryptic polo box of Plk4 through homologous N-terminal sequences containing acidic-α-helix and N/Q-rich motifs; loss of either Cep192- or Cep152-dependent Plk4 interaction impairs centriole duplication.","method":"Co-immunoprecipitation, domain competition assays, siRNA depletion, immunofluorescence, proximity ligation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive binding mapped to defined motifs, genetic loss-of-function, independently replicated by Sonnen et al. 2013","pmids":["24277814"],"is_preprint":false},{"year":2013,"finding":"PHD1 prolyl-4-hydroxylase hydroxylates Cep192 on proline residue 1717; this hydroxylation is required for binding of the SCF(Skp2) E3 ubiquitin ligase, which ubiquitinates Cep192 and targets it for proteasomal degradation. By modulating Cep192 protein levels, PHD1 connects oxygen/metabolic sensing to centriole duplication and centrosome maturation.","method":"Mass spectrometry to identify hydroxylation site, site-directed mutagenesis (P1717), co-immunoprecipitation with SCF(Skp2), ubiquitination assay, siRNA depletion, proteasomal inhibitor treatment","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identified PTM site by MS, mutagenesis confirms functional requirement, Co-IP validates E3 ligase interaction, single lab with multiple orthogonal methods","pmids":["23932902"],"is_preprint":false},{"year":2014,"finding":"In interphase cells, Cep192 promotes centrosomal microtubule nucleation by recruiting γ-tubulin; however, Cep192 maintains an antagonistic relationship with Pericentrin at interphase centrosomes (depletion of Cep192 increases centrosomal Pericentrin, and vice versa). Depletion of Cep192 impairs cell motility and alters cell polarization.","method":"siRNA knockdown, overexpression, immunofluorescence quantification of γ-tubulin and Pericentrin, microtubule regrowth assay, cell motility assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with multiple phenotypic readouts, single lab","pmids":["24971877"],"is_preprint":false},{"year":2015,"finding":"Plk1 interacts with Cep192 through two distinct phosphorylated motifs: p-T44 (analogous to Xenopus p-T46) via its polo-box domain, which is preferred when AurA is bound to Cep192, and a newly identified p-S995 motif preferred in the absence of AurA. Loss of both Cep192–Plk1 interactions additively impairs Plk1 and γ-tubulin recruitment to centrosomes and bipolar spindle formation.","method":"Co-immunoprecipitation with phospho-specific motif analysis, site-directed mutagenesis, siRNA depletion, immunofluorescence, in vitro binding assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — two distinct binding sites mapped by mutagenesis and Co-IP, additive loss-of-function phenotype, single lab with multiple orthogonal methods","pmids":["26012549"],"is_preprint":false},{"year":2015,"finding":"SPD-2/CEP192 and CDK activity from mitotic cells are rate-limiting for MTOC function at the centrosome; cell fusion experiments in live C. elegans embryos show that the centrosome MTOC state is dominant and reactivated by SPD-2/CEP192 and CDK from a mitotic partner cell.","method":"Cell fusion experiments in live C. elegans embryos, fluorescence live imaging, genetic analysis","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell fusion epistasis experiment in intact organism, single lab","pmids":["26119750"],"is_preprint":false},{"year":2017,"finding":"CEP192 recruits protein phosphatase 1 (PP1) via a highly conserved KHVTF docking motif; the threonine in this motif is phosphorylated during mitosis in a PLK1-dependent manner.","method":"Peptide pull-down, co-immunoprecipitation, phospho-site identification, kinase inhibitor studies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and pull-down with motif identification, single lab, single method","pmids":["28188792"],"is_preprint":false},{"year":2017,"finding":"CIP2A is reciprocally associated with CEP192 and acts as a scaffold promoting CEP192-mediated MTOC assembly by recruiting Aurora A and Plk1 at spindle poles during mouse oocyte meiotic maturation; CIP2A is phosphorylated by Plk1 at S904, which targets CIP2A to MTOCs.","method":"Co-immunoprecipitation, microinjection-based depletion (morpholino/antibody), immunofluorescence, site-directed mutagenesis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, phospho-site mutagenesis, and KD phenotype, single lab","pmids":["28935709"],"is_preprint":false},{"year":2018,"finding":"FBXL13 (SCF-family F-box protein) interacts with CEP192 at centrosomes and specifically targets CEP192 for proteasomal degradation; FBXL13-induced CEP192 degradation downregulates centrosomal γ-tubulin and disrupts centrosomal microtubule arrays, while FBXL13 depletion causes CEP192 and γ-tubulin accumulation with cell motility defects.","method":"Co-immunoprecipitation, ubiquitination assay, inducible overexpression, siRNA depletion, immunofluorescence","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and reciprocal KD/OE phenotypes, single lab","pmids":["29348145"],"is_preprint":false},{"year":2018,"finding":"In mouse oocytes lacking centrioles, Cep192 is required for MTOC integrity; Cep192 depletion ablates MTOCs, delays spindle formation, and causes abnormal chromosomal alignment. CDK1 activity regulates Cep152 exclusion from MTOCs (but not Cep192 removal), establishing distinct regulatory mechanisms for the two proteins.","method":"Microinjection-based depletion (morpholino), immunofluorescence, CDK1 inhibitor treatment, live imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — depletion with defined spindle phenotype and pharmacological pathway placement, single lab","pmids":["28970258"],"is_preprint":false},{"year":2020,"finding":"Cep215 (CDK5RAP2) contains a mitosis-specific centrosome-targeting domain (215N) that directly interacts with Cep192 and phosphorylated Aurora A; Cep192 is essential for targeting 215N to centrosomes, and centrosomal localization of 215N and phospho-AurA is mutually dependent.","method":"Co-immunoprecipitation, domain deletion/truncation analysis, siRNA depletion, immunofluorescence, rescue experiments","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level Co-IP and mutual dependence of localization established, single lab","pmids":["33376154"],"is_preprint":false},{"year":2021,"finding":"CEP192 recruitment to spindle poles during mitosis requires cooperative input from the centriole wall and PCM scaffold proteins pericentrin and CDK5RAP2; CEP192 remaining at centriole walls is sufficient for bipolar spindle formation when PCM scaffolds are absent, but pericentrin and CDK5RAP2 can recruit CEP192 at acentriolar spindle poles, with PLK1 activity required for this PCM-based pathway.","method":"Systematic siRNA double and triple depletions, centriole removal by Plk4 inhibition, immunofluorescence, multiple cell line validation (HeLa, RPE1, A549)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic epistasis across multiple cell lines and centriole-removal conditions, multiple orthogonal depletions","pmids":["33443571"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of a conserved helix (Helix-1) of CEP192 bound to Aurora A (AURKA) revealed a distinct binding site different from the TPX2 binding site; disrupting the Helix-1–AURKA interaction in cells prevented centrosomal accumulation of AURKA, reduced activation-loop phosphorylation of AURKA, and caused mitotic defects.","method":"Crystal structure (X-ray crystallography), quantitative binding studies, cell-based interference (Helix-1 domain deletion), immunofluorescence for AURKA localization","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by domain deletion in cells, single lab but Tier 1 method","pmids":["37083534"],"is_preprint":false},{"year":2024,"finding":"CEP192 wraps around Aurora A and occupies binding sites used by spindle-associated partners, competing with them. CEP192 interaction with Aurora A modifies kinase activity through the same site used for TPX2-mediated activation. Deleting the Aurora A-binding interface in CEP192 prevents centrosomal Aurora A accumulation, reduces activation-loop phosphorylation, and decreases spindle-bound TPX2:Aurora A complexes, resulting in error-prone mitosis. CEP192 thereby supplies the pool of phosphorylated Aurora A required for TPX2 binding on spindles.","method":"Crystal structure/cryo-EM structural comparison, mutagenesis of CEP192 Aurora A-binding interface, immunofluorescence, cell-based spindle phenotype analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination plus mutagenesis with functional readout in cells, single lab but multiple orthogonal methods","pmids":["39327527"],"is_preprint":false},{"year":2025,"finding":"Crystal structures of the human and honeybee Spd-2 domain (SP2D) of CEP192 revealed an unusual 'extended cradle' structure formed by two closely spaced ASH domains with a conserved interaction interface. The SP2D does not target CEP192 to centrosomes but promotes PCM scaffold assembly; PLK1-dependent phosphorylation of Drosophila SP2D drives higher-order oligomerization, and mutations at the oligomerization interface perturb PCM scaffold assembly in vivo.","method":"X-ray crystallography (human and honeybee SP2D), in vitro phosphorylation by PLK1, SEC-MALS oligomerization assay, Drosophila in vivo functional rescue with interface mutants, AlphaFold predictions","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and in vivo functional validation across species, single lab but multiple orthogonal methods","pmids":["40106572"],"is_preprint":false},{"year":2025,"finding":"CEP192 loss by auxin-inducible degron in live mice decreased γ-tubulin recruitment to centrosomes, impaired mitotic spindle assembly, and caused cell division failure and cell death in proliferative tissues, but did not affect centriole duplication.","method":"AID2 auxin-inducible degron system in vivo, immunofluorescence for γ-tubulin and spindle markers, histological analysis of proliferative tissues","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — acute conditional depletion in live organism with specific molecular (γ-tubulin) and cellular readouts, single lab","pmids":["40020058"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, SPD-2 (CEP192 ortholog) is a substrate of APC/C(FZR-1); SPD-2 physically associates with FZR-1 in vivo, and canonical D-box motifs (D-box1, D-box2, D-box3) each contribute to SPD-2 degradation with distinct functional consequences for centrosomal localization and centriole duplication.","method":"In vivo co-immunoprecipitation (SPD-2 with FZR-1), D-box mutagenesis, genetic epistasis with zyg-1 mutants, fluorescence quantification of centrosomal SPD-2 levels","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multi-site mutagenesis with in vivo epistasis, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.14.682142"],"is_preprint":true},{"year":2025,"finding":"CEP192 (through its centrosomal localization) is a key activator of Plk1 specifically for the centriole disengagement step of the centrosome cycle; Bora drives Plk1 activation for mitotic entry and centrosome maturation whereas CEP192 and Cenexin control a distinct Plk1 pool governing centriole disengagement. Additionally, Plk1 and CEP192 promote replication origin firing during S-phase.","method":"Selective depletion of Plk1 coactivators (Bora, Cep192, Cenexin) with cell-cycle stage-specific phenotype readouts, DNA replication assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis through individual coactivator depletion, multiple cell-cycle stage readouts, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.30.679461"],"is_preprint":true},{"year":2026,"finding":"Nur77 phosphorylated at Thr143 by Cdk1 accumulates at the centrosome during mitosis and directly binds CEP192; this interaction maintains centrosome integrity in tumor cells and facilitates PLK1 recruitment to centrosomes. Disruption of the Nur77–CEP192 interaction (by siRNA or the small molecule NMA39) causes mitotic arrest.","method":"Co-immunoprecipitation, site-directed mutagenesis (T143), immunofluorescence, small-molecule inhibitor (NMA39), siRNA depletion","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phospho-mutagenesis and pharmacological validation, single lab","pmids":["42236697"],"is_preprint":false}],"current_model":"CEP192 is a large centrosomal scaffold protein (SPD-2 ortholog) that nucleates PCM assembly through its conserved SP2D domain, directly activates Aurora A at centrosomes via a unique binding interface to supply phospho-AurA for subsequent TPX2-dependent spindle function, recruits Plk4/Plk1 to centrosomes via distinct phosphorylated motifs to drive centriole duplication and maturation, and is regulated by multiple post-translational modifications including PHD1-mediated prolyl hydroxylation (triggering SCF(Skp2) ubiquitination and degradation), FBXL13-dependent ubiquitination, and PLK1-phosphorylation of its PP1-docking motif."},"narrative":{"mechanistic_narrative":"CEP192 (the mammalian ortholog of C. elegans SPD-2) is an essential centrosomal scaffold that drives pericentriolar material (PCM) assembly and centrosome maturation during mitosis, with its acute loss causing collapse of functional mitotic centrosomes and loss of γ-tubulin, pericentrin, and downstream PCM proteins [PMID:17980596, PMID:18207742]. Its conserved Spd-2 (SP2D) domain, built from two closely spaced ASH domains forming an 'extended cradle', does not itself target CEP192 to centrosomes but promotes higher-order oligomerization of the PCM scaffold in a PLK1-phosphorylation-dependent manner [PMID:40106572]. CEP192 functions as a master organizer of two centrosomal kinases: it directly binds and activates Aurora A by wrapping around the kinase through a conserved Helix-1 interface that overlaps the TPX2 site, supplying the pool of phosphorylated Aurora A required for centrosomal accumulation and for subsequent TPX2-dependent spindle function [PMID:21097701, PMID:37083534, PMID:39327527], and it recruits Plk4 and Plk1 to centrioles—cooperating hierarchically and competitively with CEP152 to load Plk4 onto the centriole for duplication [PMID:23641073, PMID:24277814], and engaging Plk1 through two phosphorylated motifs (p-T44 and p-S995) to recruit Plk1 and γ-tubulin for bipolar spindle formation [PMID:26012549]. CEP192 itself is recruited to spindle poles by combined input from the centriole wall and the PCM scaffolds pericentrin and CDK5RAP2 in a PLK1-dependent manner [PMID:33443571], and its abundance is tuned by multiple degradation pathways including PHD1 prolyl-hydroxylation of Pro1717 licensing SCF(Skp2) ubiquitination [PMID:23932902] and FBXL13-mediated ubiquitination and degradation [PMID:29348145]. In vivo, acute CEP192 degradation in mice impairs γ-tubulin recruitment and spindle assembly and causes division failure in proliferative tissues without blocking centriole duplication, establishing PCM/spindle assembly as its core organismal requirement [PMID:40020058].","teleology":[{"year":2007,"claim":"Established that CEP192 is required to build a functional mitotic centrosome, defining it as a core PCM scaffolding factor rather than a passive structural component.","evidence":"siRNA depletion in human cells with immunofluorescence readout of γ-tubulin and pericentrin","pmids":["17980596"],"confidence":"High","gaps":["Did not define the molecular interactions through which CEP192 recruits PCM","Interphase role not addressed"]},{"year":2008,"claim":"Placed CEP192 in a recruitment hierarchy by showing mutual dependence with pericentrin and a shared requirement for NEDD1/γ-TuRC assembly, framing CEP192 as part of an interdependent maturation network.","evidence":"siRNA knockdown and reciprocal co-immunoprecipitation in mammalian cells","pmids":["18207742"],"confidence":"High","gaps":["Direct vs. indirect nature of the pericentrin dependency not resolved","No structural basis for the interactions"]},{"year":2010,"claim":"Identified the first kinase-activation function of CEP192 by showing it directly binds Aurora A, promotes its dimerization/activation, and targets it to centrosomes independently of TPX2.","evidence":"Co-IP, in vitro kinase assays, antibody-induced dimerization, and dominant-negative interference","pmids":["21097701"],"confidence":"High","gaps":["Structural interface of the CEP192–Aurora A interaction unknown","Relationship to TPX2 pool of Aurora A not defined"]},{"year":2013,"claim":"Defined CEP192 as a Plk4-recruiting scaffold acting in parallel with CEP152, mapping a negatively charged N-terminal region that engages the Plk4 polo-box domain and showing both scaffolds are required for centriole duplication.","evidence":"Single/double siRNA depletion, domain mapping, and competitive Co-IP across two independent studies","pmids":["23641073","24277814"],"confidence":"High","gaps":["Stoichiometry and temporal order of CEP192 vs CEP152 handoff not fully resolved","Regulation of the competition in cells unclear"]},{"year":2013,"claim":"Connected centrosome biogenesis to metabolic/oxygen sensing by showing PHD1 hydroxylates CEP192 at Pro1717 to license SCF(Skp2)-mediated degradation.","evidence":"MS site identification, P1717 mutagenesis, Co-IP with SCF(Skp2), ubiquitination and proteasome-inhibitor assays","pmids":["23932902"],"confidence":"High","gaps":["Physiological conditions controlling PHD1 activity on CEP192 not defined","Whether this regulates a specific cell-cycle window unclear"]},{"year":2015,"claim":"Resolved how CEP192 recruits Plk1 by identifying two distinct phospho-motifs (p-T44 and p-S995) with Aurora-A-dependent preference, linking the two kinase-recruitment functions of CEP192.","evidence":"Phospho-specific Co-IP, mutagenesis, and additive loss-of-function phenotype analysis","pmids":["26012549"],"confidence":"High","gaps":["Kinase generating p-T44/p-S995 not fully established","Quantitative contribution of each motif in vivo unclear"]},{"year":2017,"claim":"Extended CEP192 regulation to phosphatase recruitment, identifying a conserved KHVTF PP1-docking motif whose threonine is PLK1-phosphorylated in mitosis.","evidence":"Peptide pull-down, Co-IP, phospho-site identification, kinase-inhibitor studies","pmids":["28188792"],"confidence":"Medium","gaps":["Single method/lab; functional consequence of CEP192–PP1 docking not demonstrated","No reciprocal validation"]},{"year":2017,"claim":"Showed in oocyte meiosis that CIP2A scaffolds CEP192-mediated MTOC assembly by helping recruit Aurora A and Plk1, broadening CEP192's role to acentriolar spindle-pole organization.","evidence":"Reciprocal Co-IP, microinjection depletion, and S904 phospho-mutagenesis in mouse oocytes","pmids":["28935709"],"confidence":"Medium","gaps":["Directness of CIP2A–CEP192 association not structurally defined","Single lab"]},{"year":2018,"claim":"Identified FBXL13 as a second E3-pathway controlling CEP192 abundance, linking its degradation to centrosomal γ-tubulin levels and cell motility.","evidence":"Co-IP, ubiquitination assay, and reciprocal overexpression/depletion phenotypes","pmids":["29348145"],"confidence":"Medium","gaps":["Relationship between FBXL13 and PHD1/Skp2 degradation pathways unclear","Single lab"]},{"year":2018,"claim":"Demonstrated in centriole-free oocytes that CEP192 is required for MTOC integrity and that CDK1 differentially regulates CEP152 (but not CEP192) exclusion, distinguishing the regulation of the two scaffolds.","evidence":"Morpholino depletion, CDK1-inhibitor treatment, and live imaging in mouse oocytes","pmids":["28970258"],"confidence":"Medium","gaps":["Mechanism of CEP192 retention at acentriolar MTOCs unresolved","Single lab"]},{"year":2021,"claim":"Defined how CEP192 itself is recruited to spindle poles, showing cooperative input from the centriole wall and the PCM scaffolds pericentrin and CDK5RAP2 in a PLK1-dependent manner.","evidence":"Systematic double/triple siRNA depletions and centriole removal across HeLa, RPE1, and A549 cells","pmids":["33443571"],"confidence":"High","gaps":["Direct binding partners at the centriole wall not identified","PLK1 substrate(s) enabling PCM-based recruitment unknown"]},{"year":2023,"claim":"Provided structural basis for CEP192's Aurora A activation, showing a Helix-1 interface distinct from the TPX2 site that is required for centrosomal AURKA accumulation and activation-loop phosphorylation.","evidence":"X-ray crystallography of the CEP192 Helix-1–AURKA complex with cell-based interface deletion","pmids":["37083534"],"confidence":"High","gaps":["Did not resolve how CEP192-activated AURKA is handed to spindle effectors","Full-length CEP192–AURKA architecture not determined"]},{"year":2024,"claim":"Unified the Aurora A and TPX2 axes by showing CEP192 wraps around Aurora A, competes with spindle partners, and supplies the phospho-Aurora A pool needed for TPX2 binding on spindles.","evidence":"Structural comparison plus interface mutagenesis with cell-based spindle phenotype analysis","pmids":["39327527"],"confidence":"High","gaps":["Spatial choreography of Aurora A transfer from CEP192 to TPX2 in cells not directly visualized"]},{"year":2025,"claim":"Solved the CEP192 Spd-2 (SP2D) domain structure, revealing a two-ASH 'extended cradle' that drives PLK1-dependent oligomerization to assemble the PCM scaffold rather than to target CEP192 to centrosomes.","evidence":"X-ray crystallography (human and honeybee SP2D), in vitro PLK1 phosphorylation, SEC-MALS, and Drosophila in vivo rescue with interface mutants","pmids":["40106572"],"confidence":"High","gaps":["How oligomerized SP2D scaffolds specific PCM clients not defined","Human in vivo requirement of the oligomerization interface not tested"]},{"year":2025,"claim":"Established the organismal requirement for CEP192 in mammals, showing acute degradation impairs γ-tubulin recruitment and spindle assembly causing lethal division failure in proliferative tissues but sparing centriole duplication.","evidence":"AID2 auxin-inducible degron in live mice with γ-tubulin/spindle immunofluorescence and tissue histology","pmids":["40020058"],"confidence":"High","gaps":["Tissue-specific differences in CEP192 dependence not detailed","Decoupling of PCM vs centriole roles mechanistically unexplained"]},{"year":null,"claim":"It remains unresolved how the multiple CEP192 degradation pathways (PHD1/Skp2, FBXL13, APC/C(FZR-1)) and kinase/phosphatase docking events are integrated to time PCM assembly, kinase activation, and centriole disengagement within a single cell cycle.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking the distinct E3 pathways to specific cell-cycle stages","Functional output of CEP192–PP1 docking undefined","Disease relevance of CEP192 dysregulation in human tissue not directly established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5,8,17]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,16,17]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,4,15]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,4,8,19]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,18]}],"complexes":["centrosome/pericentriolar material (PCM)"],"partners":["AURKA","PLK4","PLK1","CEP152","PCNT","CDK5RAP2","FBXL13","NEDD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TEP8","full_name":"Centrosomal protein of 192 kDa","aliases":[],"length_aa":2537,"mass_kda":279.1,"function":"Required for mitotic centrosome maturation and bipolar spindle assembly (PubMed:17980596, PubMed:18207742, PubMed:25042804). Appears to be a major regulator of pericentriolar material (PCM) recruitment, centrosome maturation, and centriole duplication (PubMed:17980596, PubMed:18207742, PubMed:25042804). Centrosome-specific activating scaffold for AURKA and PLK1 (PubMed:25042804)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q8TEP8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP192","classification":"Common Essential","n_dependent_lines":1056,"n_total_lines":1208,"dependency_fraction":0.8741721854304636},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101639","cell_line_id":"CID000204","localizations":[{"compartment":"centrosome","grade":3}],"interactors":[{"gene":"S100A10","stoichiometry":0.2},{"gene":"FLOT2","stoichiometry":0.2},{"gene":"LAMTOR1","stoichiometry":0.2},{"gene":"ANXA6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000204","total_profiled":1310},"omim":[{"mim_id":"620791","title":"CENTROSOMAL PROTEIN, 76-KD; CEP76","url":"https://www.omim.org/entry/620791"},{"mim_id":"620217","title":"CENTROSOMAL PROTEIN, 44-KD; CEP44","url":"https://www.omim.org/entry/620217"},{"mim_id":"617728","title":"CENTROSOMAL PROTEIN, 295-KD; CEP295","url":"https://www.omim.org/entry/617728"},{"mim_id":"616426","title":"CENTROSOMAL PROTEIN, 192-KD; CEP192","url":"https://www.omim.org/entry/616426"},{"mim_id":"613529","title":"CENTROSOMAL PROTEIN, 152-KD; CEP152","url":"https://www.omim.org/entry/613529"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP192"},"hgnc":{"alias_symbol":["KIAA1569","FLJ10352","PPP1R62"],"prev_symbol":[]},"alphafold":{"accession":"Q8TEP8","domains":[{"cath_id":"2.60.40.10","chopping":"1378-1492","consensus_level":"high","plddt":85.1043,"start":1378,"end":1492},{"cath_id":"-","chopping":"1496-1644_1887-1996_2012-2039","consensus_level":"high","plddt":77.4485,"start":1496,"end":2039},{"cath_id":"2.60.40.10","chopping":"1647-1733","consensus_level":"medium","plddt":84.1199,"start":1647,"end":1733},{"cath_id":"2.60.40.10","chopping":"1780-1880","consensus_level":"medium","plddt":81.2188,"start":1780,"end":1880},{"cath_id":"2.60.40.10","chopping":"2131-2232","consensus_level":"high","plddt":80.2269,"start":2131,"end":2232},{"cath_id":"2.60.40.10","chopping":"2269-2391","consensus_level":"medium","plddt":83.4204,"start":2269,"end":2391},{"cath_id":"2.60.40.10","chopping":"2437-2537","consensus_level":"medium","plddt":85.2984,"start":2437,"end":2537}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEP8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEP8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEP8-F1-predicted_aligned_error_v6.png","plddt_mean":50.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP192","jax_strain_url":"https://www.jax.org/strain/search?query=CEP192"},"sequence":{"accession":"Q8TEP8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TEP8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TEP8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEP8"}},"corpus_meta":[{"pmid":"23641073","id":"PMC_23641073","title":"Human 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mitosis.\",\n      \"method\": \"siRNA knockdown with immunofluorescence readout of γ-tubulin, pericentrin, and spindle assembly; overexpression studies showing ectopic γ-tubulin/pericentrin foci\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD with defined cellular phenotype, replicated across multiple orthogonal readouts; foundational paper independently confirmed by multiple subsequent studies\",\n      \"pmids\": [\"17980596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cep192 (human homolog of C. elegans SPD-2) is a major regulator of PCM recruitment, centrosome maturation, and centriole duplication in mammalian cells; Cep192 and Pericentrin are mutually dependent for localization to mitotic centrosomes, and both are required for NEDD-1 (GCP-WD) recruitment and subsequent γ-TuRC assembly.\",\n      \"method\": \"siRNA knockdown, reciprocal co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus KD phenotype, replicated across multiple labs\",\n      \"pmids\": [\"18207742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cep192 directly interacts with Aurora A (AurA), targets AurA to mitotic centrosomes, and promotes AurA dimerization/oligomerization that triggers potent kinase activation driving microtubule assembly. This Cep192-mediated activation mechanism is distinct from TPX2-mediated AurA activation on microtubules. Depletion of Cep192 or interference with AurA–Cep192 binding abolishes centrosomal AurA activity and microtubule assembly.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA depletion, antibody-induced dimerization, dominant-negative interference\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding demonstrated, in vitro kinase activity assay, multiple interference approaches, replicated in subsequent structural studies\",\n      \"pmids\": [\"21097701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEP192 interacts with the K63-deubiquitinase CYLD (identified by mass spectrometry) and NEDD1; co-depletion of CYLD alleviates the bipolar spindle assembly defects caused by CEP192 depletion, placing CYLD downstream of CEP192 in regulating the spindle microtubule landscape.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, double siRNA knockdown with spindle assembly phenotype readout\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction plus genetic epistasis (co-depletion rescue), single lab\",\n      \"pmids\": [\"22895009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cep192 plays a key role in centrosome recruitment of both Cep152 and Plk4; Cep192 directly binds Plk4 through an N-terminal extension specific to its largest isoform (binding region rich in negatively charged residues interacting with the positively charged polo-box domain of Plk4); double-depletion of Cep192 and Cep152 completely abolishes Plk4 binding to centrioles and centriole duplication.\",\n      \"method\": \"siRNA depletion (single and double), co-immunoprecipitation, domain mapping, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, genetic epistasis via double depletion, independently replicated by Kim et al. 2013\",\n      \"pmids\": [\"23641073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cep192 and Cep152 serve as two distinct, hierarchically ordered scaffolds that recruit Plk4 to centrosomes; both proteins competitively interact with the cryptic polo box of Plk4 through homologous N-terminal sequences containing acidic-α-helix and N/Q-rich motifs; loss of either Cep192- or Cep152-dependent Plk4 interaction impairs centriole duplication.\",\n      \"method\": \"Co-immunoprecipitation, domain competition assays, siRNA depletion, immunofluorescence, proximity ligation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive binding mapped to defined motifs, genetic loss-of-function, independently replicated by Sonnen et al. 2013\",\n      \"pmids\": [\"24277814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PHD1 prolyl-4-hydroxylase hydroxylates Cep192 on proline residue 1717; this hydroxylation is required for binding of the SCF(Skp2) E3 ubiquitin ligase, which ubiquitinates Cep192 and targets it for proteasomal degradation. By modulating Cep192 protein levels, PHD1 connects oxygen/metabolic sensing to centriole duplication and centrosome maturation.\",\n      \"method\": \"Mass spectrometry to identify hydroxylation site, site-directed mutagenesis (P1717), co-immunoprecipitation with SCF(Skp2), ubiquitination assay, siRNA depletion, proteasomal inhibitor treatment\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identified PTM site by MS, mutagenesis confirms functional requirement, Co-IP validates E3 ligase interaction, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23932902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In interphase cells, Cep192 promotes centrosomal microtubule nucleation by recruiting γ-tubulin; however, Cep192 maintains an antagonistic relationship with Pericentrin at interphase centrosomes (depletion of Cep192 increases centrosomal Pericentrin, and vice versa). Depletion of Cep192 impairs cell motility and alters cell polarization.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence quantification of γ-tubulin and Pericentrin, microtubule regrowth assay, cell motility assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"24971877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Plk1 interacts with Cep192 through two distinct phosphorylated motifs: p-T44 (analogous to Xenopus p-T46) via its polo-box domain, which is preferred when AurA is bound to Cep192, and a newly identified p-S995 motif preferred in the absence of AurA. Loss of both Cep192–Plk1 interactions additively impairs Plk1 and γ-tubulin recruitment to centrosomes and bipolar spindle formation.\",\n      \"method\": \"Co-immunoprecipitation with phospho-specific motif analysis, site-directed mutagenesis, siRNA depletion, immunofluorescence, in vitro binding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — two distinct binding sites mapped by mutagenesis and Co-IP, additive loss-of-function phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26012549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPD-2/CEP192 and CDK activity from mitotic cells are rate-limiting for MTOC function at the centrosome; cell fusion experiments in live C. elegans embryos show that the centrosome MTOC state is dominant and reactivated by SPD-2/CEP192 and CDK from a mitotic partner cell.\",\n      \"method\": \"Cell fusion experiments in live C. elegans embryos, fluorescence live imaging, genetic analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell fusion epistasis experiment in intact organism, single lab\",\n      \"pmids\": [\"26119750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CEP192 recruits protein phosphatase 1 (PP1) via a highly conserved KHVTF docking motif; the threonine in this motif is phosphorylated during mitosis in a PLK1-dependent manner.\",\n      \"method\": \"Peptide pull-down, co-immunoprecipitation, phospho-site identification, kinase inhibitor studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and pull-down with motif identification, single lab, single method\",\n      \"pmids\": [\"28188792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CIP2A is reciprocally associated with CEP192 and acts as a scaffold promoting CEP192-mediated MTOC assembly by recruiting Aurora A and Plk1 at spindle poles during mouse oocyte meiotic maturation; CIP2A is phosphorylated by Plk1 at S904, which targets CIP2A to MTOCs.\",\n      \"method\": \"Co-immunoprecipitation, microinjection-based depletion (morpholino/antibody), immunofluorescence, site-directed mutagenesis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, phospho-site mutagenesis, and KD phenotype, single lab\",\n      \"pmids\": [\"28935709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXL13 (SCF-family F-box protein) interacts with CEP192 at centrosomes and specifically targets CEP192 for proteasomal degradation; FBXL13-induced CEP192 degradation downregulates centrosomal γ-tubulin and disrupts centrosomal microtubule arrays, while FBXL13 depletion causes CEP192 and γ-tubulin accumulation with cell motility defects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, inducible overexpression, siRNA depletion, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and reciprocal KD/OE phenotypes, single lab\",\n      \"pmids\": [\"29348145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocytes lacking centrioles, Cep192 is required for MTOC integrity; Cep192 depletion ablates MTOCs, delays spindle formation, and causes abnormal chromosomal alignment. CDK1 activity regulates Cep152 exclusion from MTOCs (but not Cep192 removal), establishing distinct regulatory mechanisms for the two proteins.\",\n      \"method\": \"Microinjection-based depletion (morpholino), immunofluorescence, CDK1 inhibitor treatment, live imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — depletion with defined spindle phenotype and pharmacological pathway placement, single lab\",\n      \"pmids\": [\"28970258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cep215 (CDK5RAP2) contains a mitosis-specific centrosome-targeting domain (215N) that directly interacts with Cep192 and phosphorylated Aurora A; Cep192 is essential for targeting 215N to centrosomes, and centrosomal localization of 215N and phospho-AurA is mutually dependent.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/truncation analysis, siRNA depletion, immunofluorescence, rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level Co-IP and mutual dependence of localization established, single lab\",\n      \"pmids\": [\"33376154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP192 recruitment to spindle poles during mitosis requires cooperative input from the centriole wall and PCM scaffold proteins pericentrin and CDK5RAP2; CEP192 remaining at centriole walls is sufficient for bipolar spindle formation when PCM scaffolds are absent, but pericentrin and CDK5RAP2 can recruit CEP192 at acentriolar spindle poles, with PLK1 activity required for this PCM-based pathway.\",\n      \"method\": \"Systematic siRNA double and triple depletions, centriole removal by Plk4 inhibition, immunofluorescence, multiple cell line validation (HeLa, RPE1, A549)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic epistasis across multiple cell lines and centriole-removal conditions, multiple orthogonal depletions\",\n      \"pmids\": [\"33443571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of a conserved helix (Helix-1) of CEP192 bound to Aurora A (AURKA) revealed a distinct binding site different from the TPX2 binding site; disrupting the Helix-1–AURKA interaction in cells prevented centrosomal accumulation of AURKA, reduced activation-loop phosphorylation of AURKA, and caused mitotic defects.\",\n      \"method\": \"Crystal structure (X-ray crystallography), quantitative binding studies, cell-based interference (Helix-1 domain deletion), immunofluorescence for AURKA localization\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by domain deletion in cells, single lab but Tier 1 method\",\n      \"pmids\": [\"37083534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEP192 wraps around Aurora A and occupies binding sites used by spindle-associated partners, competing with them. CEP192 interaction with Aurora A modifies kinase activity through the same site used for TPX2-mediated activation. Deleting the Aurora A-binding interface in CEP192 prevents centrosomal Aurora A accumulation, reduces activation-loop phosphorylation, and decreases spindle-bound TPX2:Aurora A complexes, resulting in error-prone mitosis. CEP192 thereby supplies the pool of phosphorylated Aurora A required for TPX2 binding on spindles.\",\n      \"method\": \"Crystal structure/cryo-EM structural comparison, mutagenesis of CEP192 Aurora A-binding interface, immunofluorescence, cell-based spindle phenotype analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination plus mutagenesis with functional readout in cells, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39327527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structures of the human and honeybee Spd-2 domain (SP2D) of CEP192 revealed an unusual 'extended cradle' structure formed by two closely spaced ASH domains with a conserved interaction interface. The SP2D does not target CEP192 to centrosomes but promotes PCM scaffold assembly; PLK1-dependent phosphorylation of Drosophila SP2D drives higher-order oligomerization, and mutations at the oligomerization interface perturb PCM scaffold assembly in vivo.\",\n      \"method\": \"X-ray crystallography (human and honeybee SP2D), in vitro phosphorylation by PLK1, SEC-MALS oligomerization assay, Drosophila in vivo functional rescue with interface mutants, AlphaFold predictions\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and in vivo functional validation across species, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40106572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP192 loss by auxin-inducible degron in live mice decreased γ-tubulin recruitment to centrosomes, impaired mitotic spindle assembly, and caused cell division failure and cell death in proliferative tissues, but did not affect centriole duplication.\",\n      \"method\": \"AID2 auxin-inducible degron system in vivo, immunofluorescence for γ-tubulin and spindle markers, histological analysis of proliferative tissues\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acute conditional depletion in live organism with specific molecular (γ-tubulin) and cellular readouts, single lab\",\n      \"pmids\": [\"40020058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, SPD-2 (CEP192 ortholog) is a substrate of APC/C(FZR-1); SPD-2 physically associates with FZR-1 in vivo, and canonical D-box motifs (D-box1, D-box2, D-box3) each contribute to SPD-2 degradation with distinct functional consequences for centrosomal localization and centriole duplication.\",\n      \"method\": \"In vivo co-immunoprecipitation (SPD-2 with FZR-1), D-box mutagenesis, genetic epistasis with zyg-1 mutants, fluorescence quantification of centrosomal SPD-2 levels\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multi-site mutagenesis with in vivo epistasis, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682142\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP192 (through its centrosomal localization) is a key activator of Plk1 specifically for the centriole disengagement step of the centrosome cycle; Bora drives Plk1 activation for mitotic entry and centrosome maturation whereas CEP192 and Cenexin control a distinct Plk1 pool governing centriole disengagement. Additionally, Plk1 and CEP192 promote replication origin firing during S-phase.\",\n      \"method\": \"Selective depletion of Plk1 coactivators (Bora, Cep192, Cenexin) with cell-cycle stage-specific phenotype readouts, DNA replication assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis through individual coactivator depletion, multiple cell-cycle stage readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.30.679461\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Nur77 phosphorylated at Thr143 by Cdk1 accumulates at the centrosome during mitosis and directly binds CEP192; this interaction maintains centrosome integrity in tumor cells and facilitates PLK1 recruitment to centrosomes. Disruption of the Nur77–CEP192 interaction (by siRNA or the small molecule NMA39) causes mitotic arrest.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (T143), immunofluorescence, small-molecule inhibitor (NMA39), siRNA depletion\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phospho-mutagenesis and pharmacological validation, single lab\",\n      \"pmids\": [\"42236697\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP192 is a large centrosomal scaffold protein (SPD-2 ortholog) that nucleates PCM assembly through its conserved SP2D domain, directly activates Aurora A at centrosomes via a unique binding interface to supply phospho-AurA for subsequent TPX2-dependent spindle function, recruits Plk4/Plk1 to centrosomes via distinct phosphorylated motifs to drive centriole duplication and maturation, and is regulated by multiple post-translational modifications including PHD1-mediated prolyl hydroxylation (triggering SCF(Skp2) ubiquitination and degradation), FBXL13-dependent ubiquitination, and PLK1-phosphorylation of its PP1-docking motif.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP192 (the mammalian ortholog of C. elegans SPD-2) is an essential centrosomal scaffold that drives pericentriolar material (PCM) assembly and centrosome maturation during mitosis, with its acute loss causing collapse of functional mitotic centrosomes and loss of \\u03b3-tubulin, pericentrin, and downstream PCM proteins [#0, #1]. Its conserved Spd-2 (SP2D) domain, built from two closely spaced ASH domains forming an 'extended cradle', does not itself target CEP192 to centrosomes but promotes higher-order oligomerization of the PCM scaffold in a PLK1-phosphorylation-dependent manner [#18]. CEP192 functions as a master organizer of two centrosomal kinases: it directly binds and activates Aurora A by wrapping around the kinase through a conserved Helix-1 interface that overlaps the TPX2 site, supplying the pool of phosphorylated Aurora A required for centrosomal accumulation and for subsequent TPX2-dependent spindle function [#2, #16, #17], and it recruits Plk4 and Plk1 to centrioles\\u2014cooperating hierarchically and competitively with CEP152 to load Plk4 onto the centriole for duplication [#4, #5], and engaging Plk1 through two phosphorylated motifs (p-T44 and p-S995) to recruit Plk1 and \\u03b3-tubulin for bipolar spindle formation [#8]. CEP192 itself is recruited to spindle poles by combined input from the centriole wall and the PCM scaffolds pericentrin and CDK5RAP2 in a PLK1-dependent manner [#15], and its abundance is tuned by multiple degradation pathways including PHD1 prolyl-hydroxylation of Pro1717 licensing SCF(Skp2) ubiquitination [#6] and FBXL13-mediated ubiquitination and degradation [#12]. In vivo, acute CEP192 degradation in mice impairs \\u03b3-tubulin recruitment and spindle assembly and causes division failure in proliferative tissues without blocking centriole duplication, establishing PCM/spindle assembly as its core organismal requirement [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that CEP192 is required to build a functional mitotic centrosome, defining it as a core PCM scaffolding factor rather than a passive structural component.\",\n      \"evidence\": \"siRNA depletion in human cells with immunofluorescence readout of \\u03b3-tubulin and pericentrin\",\n      \"pmids\": [\"17980596\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular interactions through which CEP192 recruits PCM\", \"Interphase role not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed CEP192 in a recruitment hierarchy by showing mutual dependence with pericentrin and a shared requirement for NEDD1/\\u03b3-TuRC assembly, framing CEP192 as part of an interdependent maturation network.\",\n      \"evidence\": \"siRNA knockdown and reciprocal co-immunoprecipitation in mammalian cells\",\n      \"pmids\": [\"18207742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect nature of the pericentrin dependency not resolved\", \"No structural basis for the interactions\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the first kinase-activation function of CEP192 by showing it directly binds Aurora A, promotes its dimerization/activation, and targets it to centrosomes independently of TPX2.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, antibody-induced dimerization, and dominant-negative interference\",\n      \"pmids\": [\"21097701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface of the CEP192\\u2013Aurora A interaction unknown\", \"Relationship to TPX2 pool of Aurora A not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CEP192 as a Plk4-recruiting scaffold acting in parallel with CEP152, mapping a negatively charged N-terminal region that engages the Plk4 polo-box domain and showing both scaffolds are required for centriole duplication.\",\n      \"evidence\": \"Single/double siRNA depletion, domain mapping, and competitive Co-IP across two independent studies\",\n      \"pmids\": [\"23641073\", \"24277814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and temporal order of CEP192 vs CEP152 handoff not fully resolved\", \"Regulation of the competition in cells unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected centrosome biogenesis to metabolic/oxygen sensing by showing PHD1 hydroxylates CEP192 at Pro1717 to license SCF(Skp2)-mediated degradation.\",\n      \"evidence\": \"MS site identification, P1717 mutagenesis, Co-IP with SCF(Skp2), ubiquitination and proteasome-inhibitor assays\",\n      \"pmids\": [\"23932902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions controlling PHD1 activity on CEP192 not defined\", \"Whether this regulates a specific cell-cycle window unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how CEP192 recruits Plk1 by identifying two distinct phospho-motifs (p-T44 and p-S995) with Aurora-A-dependent preference, linking the two kinase-recruitment functions of CEP192.\",\n      \"evidence\": \"Phospho-specific Co-IP, mutagenesis, and additive loss-of-function phenotype analysis\",\n      \"pmids\": [\"26012549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase generating p-T44/p-S995 not fully established\", \"Quantitative contribution of each motif in vivo unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended CEP192 regulation to phosphatase recruitment, identifying a conserved KHVTF PP1-docking motif whose threonine is PLK1-phosphorylated in mitosis.\",\n      \"evidence\": \"Peptide pull-down, Co-IP, phospho-site identification, kinase-inhibitor studies\",\n      \"pmids\": [\"28188792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method/lab; functional consequence of CEP192\\u2013PP1 docking not demonstrated\", \"No reciprocal validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed in oocyte meiosis that CIP2A scaffolds CEP192-mediated MTOC assembly by helping recruit Aurora A and Plk1, broadening CEP192's role to acentriolar spindle-pole organization.\",\n      \"evidence\": \"Reciprocal Co-IP, microinjection depletion, and S904 phospho-mutagenesis in mouse oocytes\",\n      \"pmids\": [\"28935709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of CIP2A\\u2013CEP192 association not structurally defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FBXL13 as a second E3-pathway controlling CEP192 abundance, linking its degradation to centrosomal \\u03b3-tubulin levels and cell motility.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and reciprocal overexpression/depletion phenotypes\",\n      \"pmids\": [\"29348145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between FBXL13 and PHD1/Skp2 degradation pathways unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated in centriole-free oocytes that CEP192 is required for MTOC integrity and that CDK1 differentially regulates CEP152 (but not CEP192) exclusion, distinguishing the regulation of the two scaffolds.\",\n      \"evidence\": \"Morpholino depletion, CDK1-inhibitor treatment, and live imaging in mouse oocytes\",\n      \"pmids\": [\"28970258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CEP192 retention at acentriolar MTOCs unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined how CEP192 itself is recruited to spindle poles, showing cooperative input from the centriole wall and the PCM scaffolds pericentrin and CDK5RAP2 in a PLK1-dependent manner.\",\n      \"evidence\": \"Systematic double/triple siRNA depletions and centriole removal across HeLa, RPE1, and A549 cells\",\n      \"pmids\": [\"33443571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners at the centriole wall not identified\", \"PLK1 substrate(s) enabling PCM-based recruitment unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided structural basis for CEP192's Aurora A activation, showing a Helix-1 interface distinct from the TPX2 site that is required for centrosomal AURKA accumulation and activation-loop phosphorylation.\",\n      \"evidence\": \"X-ray crystallography of the CEP192 Helix-1\\u2013AURKA complex with cell-based interface deletion\",\n      \"pmids\": [\"37083534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how CEP192-activated AURKA is handed to spindle effectors\", \"Full-length CEP192\\u2013AURKA architecture not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Unified the Aurora A and TPX2 axes by showing CEP192 wraps around Aurora A, competes with spindle partners, and supplies the phospho-Aurora A pool needed for TPX2 binding on spindles.\",\n      \"evidence\": \"Structural comparison plus interface mutagenesis with cell-based spindle phenotype analysis\",\n      \"pmids\": [\"39327527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial choreography of Aurora A transfer from CEP192 to TPX2 in cells not directly visualized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Solved the CEP192 Spd-2 (SP2D) domain structure, revealing a two-ASH 'extended cradle' that drives PLK1-dependent oligomerization to assemble the PCM scaffold rather than to target CEP192 to centrosomes.\",\n      \"evidence\": \"X-ray crystallography (human and honeybee SP2D), in vitro PLK1 phosphorylation, SEC-MALS, and Drosophila in vivo rescue with interface mutants\",\n      \"pmids\": [\"40106572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How oligomerized SP2D scaffolds specific PCM clients not defined\", \"Human in vivo requirement of the oligomerization interface not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the organismal requirement for CEP192 in mammals, showing acute degradation impairs \\u03b3-tubulin recruitment and spindle assembly causing lethal division failure in proliferative tissues but sparing centriole duplication.\",\n      \"evidence\": \"AID2 auxin-inducible degron in live mice with \\u03b3-tubulin/spindle immunofluorescence and tissue histology\",\n      \"pmids\": [\"40020058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific differences in CEP192 dependence not detailed\", \"Decoupling of PCM vs centriole roles mechanistically unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the multiple CEP192 degradation pathways (PHD1/Skp2, FBXL13, APC/C(FZR-1)) and kinase/phosphatase docking events are integrated to time PCM assembly, kinase activation, and centriole disengagement within a single cell cycle.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking the distinct E3 pathways to specific cell-cycle stages\", \"Functional output of CEP192\\u2013PP1 docking undefined\", \"Disease relevance of CEP192 dysregulation in human tissue not directly established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5, 8, 17]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 4, 15]},\n      {\"term_id\": \"GO:0005813\", \"supporting_discovery_ids\": [0, 1, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 4, 8, 19]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 18]}\n    ],\n    \"complexes\": [\n      \"centrosome/pericentriolar material (PCM)\"\n    ],\n    \"partners\": [\n      \"AURKA\",\n      \"PLK4\",\n      \"PLK1\",\n      \"CEP152\",\n      \"PCNT\",\n      \"CDK5RAP2\",\n      \"FBXL13\",\n      \"NEDD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}