{"gene":"CEP57","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"CEP57 (Translokin) interacts specifically with the 18K form of FGF-2 and mediates its intracellular trafficking and nuclear translocation; RNA interference knockdown of Translokin reduces FGF-2 translocation to the nucleus, impairing its mitogenic activity.","method":"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, nuclear localization signal rescue experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pulldown, RNAi, chimera mapping, NLS rescue) in a single study with functional readout","pmids":["12717444"],"is_preprint":false},{"year":2007,"finding":"Xenopus Cep57 (xCep57) localizes to kinetochores and interacts with kinetochore proteins Zwint, Mis12, and CLIP-170, as well as gamma-tubulin; immunodepletion yields weakened bipolar spindles, loss of sister kinetochore tension, and failure of kinetochore-microtubule binding in vitro, placing xCep57 as required for stable microtubule attachments at both kinetochores and centrosomes.","method":"Immunodepletion from Xenopus egg extracts, Co-immunoprecipitation, in vitro kinetochore-microtubule binding assay, live imaging","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution/depletion in egg extracts, in vitro binding assay, multiple interactors identified by Co-IP","pmids":["17803911"],"is_preprint":false},{"year":2008,"finding":"Cep57 contains two functional domains: an N-terminal coiled-coil domain that localizes to the centrosome (internal to gamma-tubulin) and multimerizes with other Cep57 molecules, and a C-terminal coiled-coil domain that directly binds, nucleates, and bundles microtubules in vitro and generates nocodazole-resistant MT cables in vivo.","method":"Domain truncation/overexpression, in vitro microtubule nucleation and bundling assay, immunofluorescence, nocodazole resistance assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro microtubule binding/nucleation assay with domain mutagenesis, validated in vivo","pmids":["18294141"],"is_preprint":false},{"year":2009,"finding":"CEP57 (Translokin) interacts with sorting nexin 6, Ran-binding protein M, and kinesins KIF3A and KIF3B, forming two exclusive complexes that mediate bidirectional FGF2 trafficking; CEP57 is pivotal for the decision between FGF2 nuclear translocation and unconventional secretion.","method":"Co-immunoprecipitation, interaction partner identification, functional trafficking assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP-based partner identification with functional context from prior work","pmids":["19804566"],"is_preprint":false},{"year":2011,"finding":"CEP57 (Translokin) binds cyclin D1 at regions overlapping the Cdk4 binding site and sequesters cyclin D1 in the cytoplasm in quiescent cells; Tlk knockdown causes nuclear accumulation of cyclin D1 and increased Cdk4-dependent pRB phosphorylation, while overexpression prevents cyclin D1 nuclear import and inhibits S phase entry.","method":"Co-immunoprecipitation, RNAi knockdown, overexpression, pRB phosphorylation assay, cell cycle analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP, functional knockdown/OE with defined molecular readouts in single study","pmids":["21306487"],"is_preprint":false},{"year":2011,"finding":"Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome; CEP57 is a centrosomal protein involved in nucleating and stabilizing microtubules, and loss of these functions leads to constitutional aneuploidies.","method":"Exome sequencing, loss-of-function variant identification in patients","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human genetics with defined molecular function cited, but mechanism established mainly by prior functional studies","pmids":["21552266"],"is_preprint":false},{"year":2012,"finding":"Cep57 is a pericentriolar material (PCM) component; its interaction with NEDD1 is required for centrosome localization of Cep57; depletion leads to PCM fragmentation, multipolar spindles, unaligned chromosomes, weakened centrosome microtubule assembly, and Cep57 directly binds spindle microtubules to stabilize spindle pole focusing proteins.","method":"Co-immunoprecipitation (Cep57-NEDD1), RNAi depletion with spindle/chromosome phenotype readouts, microtubule binding assay, immunofluorescence","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotype, multiple orthogonal methods","pmids":["22508265"],"is_preprint":false},{"year":2012,"finding":"CEP57 functions as an intracellular FGF-2 binding and trafficking factor that promotes centriole overduplication; CEP57 is required for both FGF-2-induced and normal centriole duplication and modulates tubulin acetylation to promote daughter centriole stability.","method":"RNAi screen, overexpression, RNAi knockdown, tubulin acetylation assay, centrosome counting","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional RNAi and OE with specific mechanistic readout (tubulin acetylation), single lab","pmids":["23243019"],"is_preprint":false},{"year":2013,"finding":"Cep57, Cep63, and Cep152 form a ring-like complex localizing around the proximal end of centrioles, as revealed by selective chemical crosslinking and superresolution microscopy.","method":"Selective chemical crosslinking, superresolution microscopy (STED), protein interaction analysis of 31 centrosomal proteins","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — chemical crosslinking with superresolution structural validation, strong methodology","pmids":["23333316"],"is_preprint":false},{"year":2013,"finding":"Cep57 localizes to the central spindle and midbody during cytokinesis and is required for central spindle microtubule organization; depletion disrupts midbody localization of MKLP1, Plk1, and Aurora B, causing cytokinesis failure; Cep57 directly recruits Tektin 1 to the midbody matrix to regulate microtubule organization.","method":"Immunofluorescence localization, RNAi depletion, cytokinesis failure assay, direct protein interaction (Cep57-Tektin 1)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KD with specific phenotype, novel interactor identified, multiple functional readouts","pmids":["23569207"],"is_preprint":false},{"year":2016,"finding":"Cep57 localizes to kinetochores in human cells and binds to Mis12 (a KMN network component); Cep57 also interacts with Mad1; depletion of Cep57 reduces kinetochore localization of Mad1-Mad2, weakens spindle assembly checkpoint (SAC) signaling, and increases chromosome segregation errors; Cep57's microtubule-binding activity is involved in timely Mad1 removal from kinetochores.","method":"Immunofluorescence localization, Co-immunoprecipitation (Cep57-Mis12, Cep57-Mad1), RNAi depletion with SAC and chromosome segregation readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple Co-IPs, clean KD with specific pathway phenotype (SAC), multiple orthogonal readouts","pmids":["26743940"],"is_preprint":false},{"year":2018,"finding":"Cep57 truncation mutation causes failure of centrosome maturation in G2 phase, leading to premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high-rate chromosome missegregation; Cep57 also functions in Fgf2-mediated bone formation in vivo.","method":"Mouse knock-in model (Cep57T/T), MEF cell analysis, patient-derived fibroblast analysis, centrosome maturation assay, chromosome missegregation quantification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model + patient cells, multiple orthogonal phenotypic readouts, strong evidence","pmids":["30035751"],"is_preprint":false},{"year":2019,"finding":"Cep57 is required for PCM organization that regulates centriole engagement; Cep57 binds the PACT domain of pericentrin; depletion causes PCM disorganization and precocious centriole disengagement in mitosis; MOPD pericentrin mutations that impair the Cep57-pericentrin interaction lead to the same PCM disorganization phenotype.","method":"RNAi depletion, Co-immunoprecipitation (Cep57-pericentrin PACT domain), live imaging of centriole disengagement, patient cell analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — direct binding mapped to PACT domain, clean KD phenotype, patient cell validation, multiple orthogonal methods","pmids":["30804344"],"is_preprint":false},{"year":2021,"finding":"Cep57 and Cep57L1 cooperatively maintain centriole engagement during interphase; co-depletion induces precocious centriole disengagement in interphase in a Plk1-dependent manner, leading to centriole reduplication and chromosome segregation errors.","method":"Double RNAi depletion, live imaging of centriole disengagement, Plk1 inhibitor epistasis, centriole number quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — double KD with defined interphase phenotype, Plk1 epistasis, and functional consequence on chromosome segregation","pmids":["33492359"],"is_preprint":false},{"year":2024,"finding":"Cep57 undergoes liquid-liquid phase separation (LLPS) driven by NTD, CTD, and a polybasic LMN motif; in vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif-mediated tubulin concentration; Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity; the LMN motif is required in cells for centrosomal microtubule aster formation.","method":"In vitro phase separation assay, in vitro microtubule nucleation assay, domain mutagenesis, overexpression of competitive constructs, rescue assay in Cep57-depleted cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of LLPS and microtubule nucleation, domain mutagenesis, in-cell rescue, multiple orthogonal methods","pmids":["38857398"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of the human Cep57 C-terminal microtubule-binding domain reveals a leucine zipper and an adjacent potential microtubule-binding region that likely forms a stabilizing scaffold for microtubule nucleation.","method":"X-ray crystallography of Cep57 C-terminal domain","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 structure, but functional validation of individual structural elements not reported in this study alone","pmids":["38699879"],"is_preprint":false},{"year":2026,"finding":"NuSAP localizes to centrioles and directly interacts with CEP57; NuSAP depletion disrupts centriole tubulin architecture and prevents recruitment of the CEP57-CEP63-CEP152 torus complex to the proximal end of procentrioles, establishing that NuSAP-mediated tubulin stabilization is required as an initial step for CEP57 loading.","method":"Super-resolution microscopy, TurboID-based proximity proteomics, biochemical Co-IP (CEP57-NuSAP), RNAi depletion with complex localization readout","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — TurboID proteomics plus direct Co-IP plus super-resolution imaging, single study","pmids":["41616107"],"is_preprint":false}],"current_model":"CEP57 is a multidomain coiled-coil centrosomal scaffold protein that undergoes liquid-liquid phase separation through its NTD, CTD, and LMN motifs to nucleate and stabilize microtubules, anchors the proximal centriole via its N-terminus while the C-terminal leucine zipper/microtubule-binding domain bundles microtubules, forms a ring-like complex with CEP63 and CEP152 at the centriole proximal end (with CEP63 restricting Cep57 assembly), binds pericentrin's PACT domain to organize PCM and maintain centriole engagement through interphase and mitosis in cooperation with CEP57L1, localizes to kinetochores where it connects the KMN network (via Mis12) to spindle assembly checkpoint signaling (via Mad1-Mad2), mediates intracellular FGF-2 trafficking toward the nucleus via kinesin KIF3A/KIF3B-containing complexes, and sequesters cyclin D1 in the cytoplasm to prevent premature S-phase entry; loss-of-function causes premature centriole disengagement, centrosome amplification, multipolar spindles, and mosaic variegated aneuploidy syndrome."},"narrative":{"teleology":[{"year":2003,"claim":"The initial molecular function of CEP57 (Translokin) was established as an intracellular trafficking factor for FGF-2, revealing that a centrosome-associated protein could also direct cytoplasmic cargo toward the nucleus.","evidence":"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, and NLS-rescue experiments in cultured cells","pmids":["12717444"],"confidence":"High","gaps":["Structural basis of FGF-2 recognition unknown","Whether trafficking function is independent of centrosome localization untested","In vivo relevance of FGF-2 trafficking not demonstrated"]},{"year":2007,"claim":"Xenopus CEP57 was shown to localize to kinetochores and interact with Mis12, Zwint, CLIP-170, and γ-tubulin, establishing a dual centrosome–kinetochore localization and a role in stable kinetochore–microtubule attachment.","evidence":"Immunodepletion from Xenopus egg extracts, Co-IP, in vitro kinetochore–microtubule binding assay, live imaging","pmids":["17803911"],"confidence":"High","gaps":["Whether kinetochore function is conserved in mammalian cells was unknown","Direct versus bridged binding to kinetochore components not distinguished","Relationship to spindle checkpoint signaling unexplored"]},{"year":2008,"claim":"Domain dissection revealed that CEP57's N-terminal coiled-coil mediates centrosome targeting and self-multimerization, while the C-terminal coiled-coil directly nucleates and bundles microtubules in vitro, defining the protein's two core biochemical activities.","evidence":"Domain truncation/overexpression, in vitro microtubule nucleation and bundling assays, nocodazole resistance assay","pmids":["18294141"],"confidence":"High","gaps":["Molecular basis of multimerization unresolved","How the two domains coordinate in full-length protein unknown","In vivo contribution of each domain to centrosome integrity untested"]},{"year":2009,"claim":"CEP57 was placed in two exclusive kinesin-containing complexes (with KIF3A/KIF3B) that govern bidirectional FGF-2 trafficking, explaining how FGF-2 is partitioned between nuclear translocation and unconventional secretion.","evidence":"Co-immunoprecipitation and interaction partner identification with functional trafficking assays","pmids":["19804566"],"confidence":"Medium","gaps":["Whether these trafficking complexes operate at the centrosome or elsewhere unresolved","Stoichiometry and regulatory switches between the two complexes unknown"]},{"year":2011,"claim":"CEP57 was shown to sequester cyclin D1 in the cytoplasm of quiescent cells, preventing Cdk4-dependent Rb phosphorylation and premature S-phase entry, expanding its functional repertoire beyond microtubule and trafficking biology to cell-cycle control.","evidence":"Co-IP, RNAi knockdown, overexpression, pRB phosphorylation and cell-cycle analysis","pmids":["21306487"],"confidence":"Medium","gaps":["Whether cyclin D1 binding occurs at the centrosome or in the cytosol is unclear","Physiological relevance in vivo not tested","Relationship to the aneuploidy phenotype not explored"]},{"year":2011,"claim":"Human genetic evidence linked biallelic CEP57 loss-of-function mutations to mosaic variegated aneuploidy syndrome, providing the first disease causality and placing centrosomal microtubule nucleation failure as the disease mechanism.","evidence":"Exome sequencing of MVA patients with identification of loss-of-function variants","pmids":["21552266"],"confidence":"Medium","gaps":["Genotype–phenotype correlation across different mutations unknown","Relative contribution of centrosome versus kinetochore dysfunction to patient aneuploidy untested"]},{"year":2012,"claim":"CEP57 was integrated into pericentriolar material organization through its interaction with NEDD1; depletion revealed PCM fragmentation, multipolar spindles, and weakened centrosomal microtubule assembly, demonstrating that CEP57 is essential for spindle pole integrity.","evidence":"Reciprocal Co-IP (CEP57–NEDD1), RNAi depletion, spindle and chromosome phenotyping, microtubule binding assay","pmids":["22508265"],"confidence":"High","gaps":["Whether NEDD1 interaction is direct or mediated by γ-tubulin not resolved","Role of CEP57 in PCM expansion versus maintenance not distinguished"]},{"year":2013,"claim":"Superresolution microscopy and chemical crosslinking revealed that CEP57, CEP63, and CEP152 form a ring-like complex at the proximal end of centrioles, providing the first structural context for how these proteins scaffold centriole duplication licensing.","evidence":"Selective chemical crosslinking, STED superresolution microscopy, systematic interaction analysis of 31 centrosomal proteins","pmids":["23333316"],"confidence":"High","gaps":["Stoichiometry and assembly order of the ring unclear","Functional hierarchy among the three ring components not defined"]},{"year":2013,"claim":"CEP57 was found at the central spindle and midbody during cytokinesis, where it recruits Tektin 1 and organizes midbody microtubules, establishing a post-mitotic function beyond centrosome biology.","evidence":"Immunofluorescence, RNAi depletion, cytokinesis failure assay, CEP57–Tektin 1 direct interaction","pmids":["23569207"],"confidence":"High","gaps":["How CEP57 transitions from centrosome to central spindle is unknown","Relationship between midbody function and aneuploidy phenotype untested"]},{"year":2016,"claim":"Human CEP57 was confirmed at kinetochores where it bridges Mis12 (KMN network) to Mad1, establishing it as a direct molecular link between kinetochore attachment and spindle assembly checkpoint activation; its microtubule-binding activity participates in timely Mad1 removal upon attachment.","evidence":"Co-IP (CEP57–Mis12, CEP57–Mad1), RNAi depletion with SAC signaling and chromosome segregation readouts in human cells","pmids":["26743940"],"confidence":"High","gaps":["Whether CEP57's kinetochore role is independent of its centrosome function unclear","Structural basis of the Mis12–CEP57–Mad1 ternary interaction unresolved"]},{"year":2018,"claim":"A mouse knock-in truncation model recapitulated MVA features—premature centriole disjunction, centrosome amplification, and high-rate chromosome missegregation—and revealed that CEP57 also functions in FGF2-mediated bone formation in vivo.","evidence":"Cep57T/T mouse model, MEF and patient fibroblast analysis, centrosome maturation assay, chromosome missegregation quantification","pmids":["30035751"],"confidence":"High","gaps":["Which CEP57 domain is critical for bone phenotype not determined","Contribution of kinetochore versus centrosome defects to in vivo aneuploidy still ambiguous"]},{"year":2019,"claim":"The mechanism of centriole engagement was resolved: CEP57 binds the PACT domain of pericentrin, and this interaction organizes PCM to prevent precocious centriole disengagement; MOPD pericentrin mutations that disrupt this interface phenocopy CEP57 loss.","evidence":"Co-IP mapping CEP57 to pericentrin PACT domain, RNAi, live imaging of centriole disengagement, MOPD patient cell analysis","pmids":["30804344"],"confidence":"High","gaps":["Whether other PCM proteins also contribute to engagement maintenance untested","Structural details of CEP57–PACT interface unknown"]},{"year":2021,"claim":"CEP57 and its paralog CEP57L1 were shown to cooperatively maintain centriole engagement throughout interphase, with co-depletion triggering Plk1-dependent precocious disengagement and centriole reduplication.","evidence":"Double RNAi depletion, live imaging, Plk1 inhibitor epistasis, centriole number quantification","pmids":["33492359"],"confidence":"High","gaps":["How Plk1 triggers disengagement in the absence of CEP57/CEP57L1 unknown","Whether CEP57 and CEP57L1 occupy identical or distinct centriolar positions unclear"]},{"year":2024,"claim":"CEP57 was shown to undergo liquid-liquid phase separation via its NTD, CTD, and a polybasic LMN motif; condensates concentrate tubulin to catalyze microtubule nucleation in vitro, with CEP63 restricting this activity, redefining the centrosomal scaffold as a phase-separated nucleation catalyst.","evidence":"In vitro LLPS reconstitution, in vitro microtubule nucleation assay, domain mutagenesis, competitive overexpression, rescue in CEP57-depleted cells","pmids":["38857398"],"confidence":"High","gaps":["How LLPS is regulated in vivo during the cell cycle unknown","Whether LLPS contributes to kinetochore or midbody functions untested","How the LMN motif integrates with γ-tubulin ring complex-mediated nucleation unclear"]},{"year":2024,"claim":"The crystal structure of the CEP57 C-terminal microtubule-binding domain revealed a leucine zipper with an adjacent microtubule-binding region, providing the first atomic-resolution view of the microtubule-scaffolding module.","evidence":"X-ray crystallography of the CEP57 C-terminal domain","pmids":["38699879"],"confidence":"Medium","gaps":["Functional validation of individual structural elements not reported","No structure of full-length CEP57 or CEP57 in complex with microtubules available"]},{"year":2026,"claim":"NuSAP was identified as a direct CEP57 interactor at centrioles; NuSAP-mediated tubulin stabilization is required for the initial loading of the CEP57–CEP63–CEP152 torus complex onto procentrioles, establishing an upstream assembly step.","evidence":"Super-resolution microscopy, TurboID proximity proteomics, Co-IP (CEP57–NuSAP), RNAi depletion with complex localization readout","pmids":["41616107"],"confidence":"Medium","gaps":["Whether NuSAP–CEP57 interaction is direct or mediated by tubulin not fully resolved","Temporal regulation of NuSAP loading relative to centriole duplication licensing unknown"]},{"year":null,"claim":"Key unresolved questions include: how CEP57's phase separation is cell-cycle regulated, the structural basis of the CEP57–pericentrin PACT and CEP57–Mis12–Mad1 interfaces, the relative contributions of centrosome versus kinetochore dysfunction to MVA pathogenesis, and whether the trafficking and cyclin D1 sequestration functions operate through the same or distinct CEP57 pools.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cell-cycle-resolved LLPS regulation data","No high-resolution structure of CEP57 in complex with pericentrin or kinetochore partners","Centrosome versus kinetochore contribution to disease aneuploidy not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,6,10,14,15]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2,6,8,12,14]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,10,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[8,12,13,14,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,11]}],"complexes":["CEP57-CEP63-CEP152 torus complex"],"partners":["CEP63","CEP152","PCNT","NEDD1","MIS12","MAD1L1","CEP57L1","NUSAP1"],"other_free_text":[]},"mechanistic_narrative":"CEP57 is a multidomain coiled-coil centrosomal scaffold protein that nucleates and stabilizes microtubules, maintains centriole engagement, and connects kinetochores to spindle assembly checkpoint signaling. Its N-terminal domain anchors the protein to the proximal centriole where it forms a ring-like complex with CEP63 and CEP152, while the C-terminal leucine zipper domain directly binds, nucleates, and bundles microtubules; liquid-liquid phase separation driven by its NTD, CTD, and a polybasic LMN motif concentrates tubulin to catalyze microtubule nucleation, with CEP63 acting as a negative regulator of this condensation [PMID:38857398, PMID:18294141, PMID:23333316]. CEP57 binds the PACT domain of pericentrin to organize pericentriolar material and, together with CEP57L1, maintains centriole engagement through interphase and mitosis in a Plk1-regulated manner; at kinetochores it bridges the KMN network component Mis12 to Mad1–Mad2, thereby promoting spindle assembly checkpoint signaling and accurate chromosome segregation [PMID:30804344, PMID:33492359, PMID:26743940]. Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome, characterized by premature centriole disengagement, centrosome amplification, and constitutional aneuploidies [PMID:21552266, PMID:30035751]."},"prefetch_data":{"uniprot":{"accession":"Q86XR8","full_name":"Centrosomal protein of 57 kDa","aliases":["FGF2-interacting protein","Testis-specific protein 57","Translokin"],"length_aa":500,"mass_kda":57.1,"function":"Centrosomal protein which may be required for microtubule attachment to centrosomes. May act by forming ring-like structures around microtubules. Mediates nuclear translocation and mitogenic activity of the internalized growth factor FGF2, but that of FGF1","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q86XR8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP57","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEP57","total_profiled":1310},"omim":[{"mim_id":"621412","title":"CENTROSOMAL PROTEIN 57-LIKE 1; CEP57L1","url":"https://www.omim.org/entry/621412"},{"mim_id":"614114","title":"MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 2; MVA2","url":"https://www.omim.org/entry/614114"},{"mim_id":"610342","title":"PROLYL 3-HYDROXYLASE 3; P3H3","url":"https://www.omim.org/entry/610342"},{"mim_id":"607951","title":"CENTROSOMAL PROTEIN, 57-KD; CEP57","url":"https://www.omim.org/entry/607951"},{"mim_id":"257300","title":"MOSAIC VARIEGATED ANEUPLOIDY SYNDROME 1; MVA1","url":"https://www.omim.org/entry/257300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP57"},"hgnc":{"alias_symbol":["Translokin","TSP57","KIAA0092"],"prev_symbol":[]},"alphafold":{"accession":"Q86XR8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XR8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XR8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XR8-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP57","jax_strain_url":"https://www.jax.org/strain/search?query=CEP57"},"sequence":{"accession":"Q86XR8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86XR8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86XR8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XR8"}},"corpus_meta":[{"pmid":"21552266","id":"PMC_21552266","title":"Mutations in CEP57 cause mosaic variegated aneuploidy syndrome.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21552266","citation_count":101,"is_preprint":false},{"pmid":"23333316","id":"PMC_23333316","title":"Selective chemical crosslinking reveals a Cep57-Cep63-Cep152 centrosomal complex.","date":"2013","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/23333316","citation_count":100,"is_preprint":false},{"pmid":"12717444","id":"PMC_12717444","title":"Translokin is an intracellular mediator of FGF-2 trafficking.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12717444","citation_count":60,"is_preprint":false},{"pmid":"30804344","id":"PMC_30804344","title":"The Cep57-pericentrin module organizes PCM expansion and centriole engagement.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30804344","citation_count":54,"is_preprint":false},{"pmid":"17803911","id":"PMC_17803911","title":"Xenopus Cep57 is a novel kinetochore component involved in microtubule attachment.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17803911","citation_count":44,"is_preprint":false},{"pmid":"18294141","id":"PMC_18294141","title":"Cep57, a multidomain protein with unique microtubule and centrosomal localization domains.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18294141","citation_count":36,"is_preprint":false},{"pmid":"22508265","id":"PMC_22508265","title":"Cep57, a NEDD1-binding pericentriolar material component, is essential for spindle pole integrity.","date":"2012","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/22508265","citation_count":30,"is_preprint":false},{"pmid":"26743940","id":"PMC_26743940","title":"Cep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1-Mad2.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26743940","citation_count":27,"is_preprint":false},{"pmid":"23243019","id":"PMC_23243019","title":"FGF-2 disrupts mitotic stability in prostate cancer through the intracellular trafficking protein CEP57.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23243019","citation_count":21,"is_preprint":false},{"pmid":"24259107","id":"PMC_24259107","title":"CEP57 mutation in a girl with mosaic variegated aneuploidy syndrome.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24259107","citation_count":21,"is_preprint":false},{"pmid":"19804566","id":"PMC_19804566","title":"Pivotal role of translokin/CEP57 in the unconventional secretion versus nuclear translocation of FGF2.","date":"2009","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/19804566","citation_count":20,"is_preprint":false},{"pmid":"30035751","id":"PMC_30035751","title":"Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30035751","citation_count":19,"is_preprint":false},{"pmid":"33492359","id":"PMC_33492359","title":"Cep57 and Cep57L1 maintain centriole engagement in interphase to ensure centriole duplication cycle.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33492359","citation_count":16,"is_preprint":false},{"pmid":"30147898","id":"PMC_30147898","title":"Mosaic variegated aneuploidy syndrome caused by a CEP57 mutation diagnosed by whole exome sequencing.","date":"2018","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/30147898","citation_count":13,"is_preprint":false},{"pmid":"23569207","id":"PMC_23569207","title":"Cep57 protein is required for cytokinesis by facilitating central spindle microtubule organization.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23569207","citation_count":12,"is_preprint":false},{"pmid":"21306487","id":"PMC_21306487","title":"Translokin (Cep57) interacts with cyclin D1 and prevents its nuclear accumulation in quiescent fibroblasts.","date":"2011","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/21306487","citation_count":10,"is_preprint":false},{"pmid":"31943948","id":"PMC_31943948","title":"Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype?","date":"2020","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31943948","citation_count":10,"is_preprint":false},{"pmid":"34500087","id":"PMC_34500087","title":"Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34500087","citation_count":9,"is_preprint":false},{"pmid":"30010053","id":"PMC_30010053","title":"A homozygous CEP57 c.915_925dupCAATGTTCAGC mutation in a patient with mosaic variegated aneuploidy syndrome with rhizomelic shortening in the upper and lower limbs and a narrow thorax.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30010053","citation_count":9,"is_preprint":false},{"pmid":"38857398","id":"PMC_38857398","title":"Cep57 regulates human centrosomes through multivalent interactions.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38857398","citation_count":7,"is_preprint":false},{"pmid":"36635612","id":"PMC_36635612","title":"Mosaic variegated aneuploidy syndrome 2 with biallelic novel CEP57 splice site variation in Indian siblings: Expanding the clinical and molecular spectrum.","date":"2023","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36635612","citation_count":6,"is_preprint":false},{"pmid":"12954732","id":"PMC_12954732","title":"Tsp57: a novel gene induced during a specific stage of spermatogenesis.","date":"2003","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12954732","citation_count":5,"is_preprint":false},{"pmid":"38699879","id":"PMC_38699879","title":"Crystal structure of human Cep57 C-terminal domain reveals the presence of leucine zipper and the potential microtubule binding region.","date":"2024","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/38699879","citation_count":0,"is_preprint":false},{"pmid":"41700350","id":"PMC_41700350","title":"A novel CEP57 gene mutation in mosaic variegated aneuploidy syndrome 2: case report.","date":"2026","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/41700350","citation_count":0,"is_preprint":false},{"pmid":"41616107","id":"PMC_41616107","title":"NuSAP Safeguards Centriole Integrity to Mediate CEP57-CEP152 Torus Recruitment for Proper Engagement.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41616107","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.10.648303","title":"Loss of <i>cep57</i> function induces G1 arrest and microcephaly","date":"2025-04-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.10.648303","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11489,"output_tokens":4178,"usd":0.048569},"stage2":{"model":"claude-opus-4-6","input_tokens":7616,"output_tokens":4086,"usd":0.210345},"total_usd":0.258914,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"CEP57 (Translokin) interacts specifically with the 18K form of FGF-2 and mediates its intracellular trafficking and nuclear translocation; RNA interference knockdown of Translokin reduces FGF-2 translocation to the nucleus, impairing its mitogenic activity.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, nuclear localization signal rescue experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pulldown, RNAi, chimera mapping, NLS rescue) in a single study with functional readout\",\n      \"pmids\": [\"12717444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Xenopus Cep57 (xCep57) localizes to kinetochores and interacts with kinetochore proteins Zwint, Mis12, and CLIP-170, as well as gamma-tubulin; immunodepletion yields weakened bipolar spindles, loss of sister kinetochore tension, and failure of kinetochore-microtubule binding in vitro, placing xCep57 as required for stable microtubule attachments at both kinetochores and centrosomes.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, Co-immunoprecipitation, in vitro kinetochore-microtubule binding assay, live imaging\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution/depletion in egg extracts, in vitro binding assay, multiple interactors identified by Co-IP\",\n      \"pmids\": [\"17803911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cep57 contains two functional domains: an N-terminal coiled-coil domain that localizes to the centrosome (internal to gamma-tubulin) and multimerizes with other Cep57 molecules, and a C-terminal coiled-coil domain that directly binds, nucleates, and bundles microtubules in vitro and generates nocodazole-resistant MT cables in vivo.\",\n      \"method\": \"Domain truncation/overexpression, in vitro microtubule nucleation and bundling assay, immunofluorescence, nocodazole resistance assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro microtubule binding/nucleation assay with domain mutagenesis, validated in vivo\",\n      \"pmids\": [\"18294141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CEP57 (Translokin) interacts with sorting nexin 6, Ran-binding protein M, and kinesins KIF3A and KIF3B, forming two exclusive complexes that mediate bidirectional FGF2 trafficking; CEP57 is pivotal for the decision between FGF2 nuclear translocation and unconventional secretion.\",\n      \"method\": \"Co-immunoprecipitation, interaction partner identification, functional trafficking assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP-based partner identification with functional context from prior work\",\n      \"pmids\": [\"19804566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CEP57 (Translokin) binds cyclin D1 at regions overlapping the Cdk4 binding site and sequesters cyclin D1 in the cytoplasm in quiescent cells; Tlk knockdown causes nuclear accumulation of cyclin D1 and increased Cdk4-dependent pRB phosphorylation, while overexpression prevents cyclin D1 nuclear import and inhibits S phase entry.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, overexpression, pRB phosphorylation assay, cell cycle analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP, functional knockdown/OE with defined molecular readouts in single study\",\n      \"pmids\": [\"21306487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome; CEP57 is a centrosomal protein involved in nucleating and stabilizing microtubules, and loss of these functions leads to constitutional aneuploidies.\",\n      \"method\": \"Exome sequencing, loss-of-function variant identification in patients\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with defined molecular function cited, but mechanism established mainly by prior functional studies\",\n      \"pmids\": [\"21552266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cep57 is a pericentriolar material (PCM) component; its interaction with NEDD1 is required for centrosome localization of Cep57; depletion leads to PCM fragmentation, multipolar spindles, unaligned chromosomes, weakened centrosome microtubule assembly, and Cep57 directly binds spindle microtubules to stabilize spindle pole focusing proteins.\",\n      \"method\": \"Co-immunoprecipitation (Cep57-NEDD1), RNAi depletion with spindle/chromosome phenotype readouts, microtubule binding assay, immunofluorescence\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KD with defined cellular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"22508265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEP57 functions as an intracellular FGF-2 binding and trafficking factor that promotes centriole overduplication; CEP57 is required for both FGF-2-induced and normal centriole duplication and modulates tubulin acetylation to promote daughter centriole stability.\",\n      \"method\": \"RNAi screen, overexpression, RNAi knockdown, tubulin acetylation assay, centrosome counting\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional RNAi and OE with specific mechanistic readout (tubulin acetylation), single lab\",\n      \"pmids\": [\"23243019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cep57, Cep63, and Cep152 form a ring-like complex localizing around the proximal end of centrioles, as revealed by selective chemical crosslinking and superresolution microscopy.\",\n      \"method\": \"Selective chemical crosslinking, superresolution microscopy (STED), protein interaction analysis of 31 centrosomal proteins\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — chemical crosslinking with superresolution structural validation, strong methodology\",\n      \"pmids\": [\"23333316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cep57 localizes to the central spindle and midbody during cytokinesis and is required for central spindle microtubule organization; depletion disrupts midbody localization of MKLP1, Plk1, and Aurora B, causing cytokinesis failure; Cep57 directly recruits Tektin 1 to the midbody matrix to regulate microtubule organization.\",\n      \"method\": \"Immunofluorescence localization, RNAi depletion, cytokinesis failure assay, direct protein interaction (Cep57-Tektin 1)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific phenotype, novel interactor identified, multiple functional readouts\",\n      \"pmids\": [\"23569207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cep57 localizes to kinetochores in human cells and binds to Mis12 (a KMN network component); Cep57 also interacts with Mad1; depletion of Cep57 reduces kinetochore localization of Mad1-Mad2, weakens spindle assembly checkpoint (SAC) signaling, and increases chromosome segregation errors; Cep57's microtubule-binding activity is involved in timely Mad1 removal from kinetochores.\",\n      \"method\": \"Immunofluorescence localization, Co-immunoprecipitation (Cep57-Mis12, Cep57-Mad1), RNAi depletion with SAC and chromosome segregation readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Co-IPs, clean KD with specific pathway phenotype (SAC), multiple orthogonal readouts\",\n      \"pmids\": [\"26743940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cep57 truncation mutation causes failure of centrosome maturation in G2 phase, leading to premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high-rate chromosome missegregation; Cep57 also functions in Fgf2-mediated bone formation in vivo.\",\n      \"method\": \"Mouse knock-in model (Cep57T/T), MEF cell analysis, patient-derived fibroblast analysis, centrosome maturation assay, chromosome missegregation quantification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model + patient cells, multiple orthogonal phenotypic readouts, strong evidence\",\n      \"pmids\": [\"30035751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cep57 is required for PCM organization that regulates centriole engagement; Cep57 binds the PACT domain of pericentrin; depletion causes PCM disorganization and precocious centriole disengagement in mitosis; MOPD pericentrin mutations that impair the Cep57-pericentrin interaction lead to the same PCM disorganization phenotype.\",\n      \"method\": \"RNAi depletion, Co-immunoprecipitation (Cep57-pericentrin PACT domain), live imaging of centriole disengagement, patient cell analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped to PACT domain, clean KD phenotype, patient cell validation, multiple orthogonal methods\",\n      \"pmids\": [\"30804344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cep57 and Cep57L1 cooperatively maintain centriole engagement during interphase; co-depletion induces precocious centriole disengagement in interphase in a Plk1-dependent manner, leading to centriole reduplication and chromosome segregation errors.\",\n      \"method\": \"Double RNAi depletion, live imaging of centriole disengagement, Plk1 inhibitor epistasis, centriole number quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double KD with defined interphase phenotype, Plk1 epistasis, and functional consequence on chromosome segregation\",\n      \"pmids\": [\"33492359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cep57 undergoes liquid-liquid phase separation (LLPS) driven by NTD, CTD, and a polybasic LMN motif; in vitro Cep57 condensates catalyze microtubule nucleation via the LMN motif-mediated tubulin concentration; Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity; the LMN motif is required in cells for centrosomal microtubule aster formation.\",\n      \"method\": \"In vitro phase separation assay, in vitro microtubule nucleation assay, domain mutagenesis, overexpression of competitive constructs, rescue assay in Cep57-depleted cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of LLPS and microtubule nucleation, domain mutagenesis, in-cell rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38857398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure of the human Cep57 C-terminal microtubule-binding domain reveals a leucine zipper and an adjacent potential microtubule-binding region that likely forms a stabilizing scaffold for microtubule nucleation.\",\n      \"method\": \"X-ray crystallography of Cep57 C-terminal domain\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structure, but functional validation of individual structural elements not reported in this study alone\",\n      \"pmids\": [\"38699879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NuSAP localizes to centrioles and directly interacts with CEP57; NuSAP depletion disrupts centriole tubulin architecture and prevents recruitment of the CEP57-CEP63-CEP152 torus complex to the proximal end of procentrioles, establishing that NuSAP-mediated tubulin stabilization is required as an initial step for CEP57 loading.\",\n      \"method\": \"Super-resolution microscopy, TurboID-based proximity proteomics, biochemical Co-IP (CEP57-NuSAP), RNAi depletion with complex localization readout\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — TurboID proteomics plus direct Co-IP plus super-resolution imaging, single study\",\n      \"pmids\": [\"41616107\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP57 is a multidomain coiled-coil centrosomal scaffold protein that undergoes liquid-liquid phase separation through its NTD, CTD, and LMN motifs to nucleate and stabilize microtubules, anchors the proximal centriole via its N-terminus while the C-terminal leucine zipper/microtubule-binding domain bundles microtubules, forms a ring-like complex with CEP63 and CEP152 at the centriole proximal end (with CEP63 restricting Cep57 assembly), binds pericentrin's PACT domain to organize PCM and maintain centriole engagement through interphase and mitosis in cooperation with CEP57L1, localizes to kinetochores where it connects the KMN network (via Mis12) to spindle assembly checkpoint signaling (via Mad1-Mad2), mediates intracellular FGF-2 trafficking toward the nucleus via kinesin KIF3A/KIF3B-containing complexes, and sequesters cyclin D1 in the cytoplasm to prevent premature S-phase entry; loss-of-function causes premature centriole disengagement, centrosome amplification, multipolar spindles, and mosaic variegated aneuploidy syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CEP57 is a multidomain coiled-coil centrosomal scaffold protein that nucleates and stabilizes microtubules, maintains centriole engagement, and connects kinetochores to spindle assembly checkpoint signaling. Its N-terminal domain anchors the protein to the proximal centriole where it forms a ring-like complex with CEP63 and CEP152, while the C-terminal leucine zipper domain directly binds, nucleates, and bundles microtubules; liquid-liquid phase separation driven by its NTD, CTD, and a polybasic LMN motif concentrates tubulin to catalyze microtubule nucleation, with CEP63 acting as a negative regulator of this condensation [PMID:38857398, PMID:18294141, PMID:23333316]. CEP57 binds the PACT domain of pericentrin to organize pericentriolar material and, together with CEP57L1, maintains centriole engagement through interphase and mitosis in a Plk1-regulated manner; at kinetochores it bridges the KMN network component Mis12 to Mad1–Mad2, thereby promoting spindle assembly checkpoint signaling and accurate chromosome segregation [PMID:30804344, PMID:33492359, PMID:26743940]. Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome, characterized by premature centriole disengagement, centrosome amplification, and constitutional aneuploidies [PMID:21552266, PMID:30035751].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The initial molecular function of CEP57 (Translokin) was established as an intracellular trafficking factor for FGF-2, revealing that a centrosome-associated protein could also direct cytoplasmic cargo toward the nucleus.\",\n      \"evidence\": \"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, and NLS-rescue experiments in cultured cells\",\n      \"pmids\": [\"12717444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FGF-2 recognition unknown\", \"Whether trafficking function is independent of centrosome localization untested\", \"In vivo relevance of FGF-2 trafficking not demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Xenopus CEP57 was shown to localize to kinetochores and interact with Mis12, Zwint, CLIP-170, and γ-tubulin, establishing a dual centrosome–kinetochore localization and a role in stable kinetochore–microtubule attachment.\",\n      \"evidence\": \"Immunodepletion from Xenopus egg extracts, Co-IP, in vitro kinetochore–microtubule binding assay, live imaging\",\n      \"pmids\": [\"17803911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether kinetochore function is conserved in mammalian cells was unknown\", \"Direct versus bridged binding to kinetochore components not distinguished\", \"Relationship to spindle checkpoint signaling unexplored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Domain dissection revealed that CEP57's N-terminal coiled-coil mediates centrosome targeting and self-multimerization, while the C-terminal coiled-coil directly nucleates and bundles microtubules in vitro, defining the protein's two core biochemical activities.\",\n      \"evidence\": \"Domain truncation/overexpression, in vitro microtubule nucleation and bundling assays, nocodazole resistance assay\",\n      \"pmids\": [\"18294141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of multimerization unresolved\", \"How the two domains coordinate in full-length protein unknown\", \"In vivo contribution of each domain to centrosome integrity untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"CEP57 was placed in two exclusive kinesin-containing complexes (with KIF3A/KIF3B) that govern bidirectional FGF-2 trafficking, explaining how FGF-2 is partitioned between nuclear translocation and unconventional secretion.\",\n      \"evidence\": \"Co-immunoprecipitation and interaction partner identification with functional trafficking assays\",\n      \"pmids\": [\"19804566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these trafficking complexes operate at the centrosome or elsewhere unresolved\", \"Stoichiometry and regulatory switches between the two complexes unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"CEP57 was shown to sequester cyclin D1 in the cytoplasm of quiescent cells, preventing Cdk4-dependent Rb phosphorylation and premature S-phase entry, expanding its functional repertoire beyond microtubule and trafficking biology to cell-cycle control.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, overexpression, pRB phosphorylation and cell-cycle analysis\",\n      \"pmids\": [\"21306487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cyclin D1 binding occurs at the centrosome or in the cytosol is unclear\", \"Physiological relevance in vivo not tested\", \"Relationship to the aneuploidy phenotype not explored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human genetic evidence linked biallelic CEP57 loss-of-function mutations to mosaic variegated aneuploidy syndrome, providing the first disease causality and placing centrosomal microtubule nucleation failure as the disease mechanism.\",\n      \"evidence\": \"Exome sequencing of MVA patients with identification of loss-of-function variants\",\n      \"pmids\": [\"21552266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype–phenotype correlation across different mutations unknown\", \"Relative contribution of centrosome versus kinetochore dysfunction to patient aneuploidy untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CEP57 was integrated into pericentriolar material organization through its interaction with NEDD1; depletion revealed PCM fragmentation, multipolar spindles, and weakened centrosomal microtubule assembly, demonstrating that CEP57 is essential for spindle pole integrity.\",\n      \"evidence\": \"Reciprocal Co-IP (CEP57–NEDD1), RNAi depletion, spindle and chromosome phenotyping, microtubule binding assay\",\n      \"pmids\": [\"22508265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEDD1 interaction is direct or mediated by γ-tubulin not resolved\", \"Role of CEP57 in PCM expansion versus maintenance not distinguished\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Superresolution microscopy and chemical crosslinking revealed that CEP57, CEP63, and CEP152 form a ring-like complex at the proximal end of centrioles, providing the first structural context for how these proteins scaffold centriole duplication licensing.\",\n      \"evidence\": \"Selective chemical crosslinking, STED superresolution microscopy, systematic interaction analysis of 31 centrosomal proteins\",\n      \"pmids\": [\"23333316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the ring unclear\", \"Functional hierarchy among the three ring components not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CEP57 was found at the central spindle and midbody during cytokinesis, where it recruits Tektin 1 and organizes midbody microtubules, establishing a post-mitotic function beyond centrosome biology.\",\n      \"evidence\": \"Immunofluorescence, RNAi depletion, cytokinesis failure assay, CEP57–Tektin 1 direct interaction\",\n      \"pmids\": [\"23569207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CEP57 transitions from centrosome to central spindle is unknown\", \"Relationship between midbody function and aneuploidy phenotype untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Human CEP57 was confirmed at kinetochores where it bridges Mis12 (KMN network) to Mad1, establishing it as a direct molecular link between kinetochore attachment and spindle assembly checkpoint activation; its microtubule-binding activity participates in timely Mad1 removal upon attachment.\",\n      \"evidence\": \"Co-IP (CEP57–Mis12, CEP57–Mad1), RNAi depletion with SAC signaling and chromosome segregation readouts in human cells\",\n      \"pmids\": [\"26743940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CEP57's kinetochore role is independent of its centrosome function unclear\", \"Structural basis of the Mis12–CEP57–Mad1 ternary interaction unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A mouse knock-in truncation model recapitulated MVA features—premature centriole disjunction, centrosome amplification, and high-rate chromosome missegregation—and revealed that CEP57 also functions in FGF2-mediated bone formation in vivo.\",\n      \"evidence\": \"Cep57T/T mouse model, MEF and patient fibroblast analysis, centrosome maturation assay, chromosome missegregation quantification\",\n      \"pmids\": [\"30035751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which CEP57 domain is critical for bone phenotype not determined\", \"Contribution of kinetochore versus centrosome defects to in vivo aneuploidy still ambiguous\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The mechanism of centriole engagement was resolved: CEP57 binds the PACT domain of pericentrin, and this interaction organizes PCM to prevent precocious centriole disengagement; MOPD pericentrin mutations that disrupt this interface phenocopy CEP57 loss.\",\n      \"evidence\": \"Co-IP mapping CEP57 to pericentrin PACT domain, RNAi, live imaging of centriole disengagement, MOPD patient cell analysis\",\n      \"pmids\": [\"30804344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other PCM proteins also contribute to engagement maintenance untested\", \"Structural details of CEP57–PACT interface unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CEP57 and its paralog CEP57L1 were shown to cooperatively maintain centriole engagement throughout interphase, with co-depletion triggering Plk1-dependent precocious disengagement and centriole reduplication.\",\n      \"evidence\": \"Double RNAi depletion, live imaging, Plk1 inhibitor epistasis, centriole number quantification\",\n      \"pmids\": [\"33492359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Plk1 triggers disengagement in the absence of CEP57/CEP57L1 unknown\", \"Whether CEP57 and CEP57L1 occupy identical or distinct centriolar positions unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CEP57 was shown to undergo liquid-liquid phase separation via its NTD, CTD, and a polybasic LMN motif; condensates concentrate tubulin to catalyze microtubule nucleation in vitro, with CEP63 restricting this activity, redefining the centrosomal scaffold as a phase-separated nucleation catalyst.\",\n      \"evidence\": \"In vitro LLPS reconstitution, in vitro microtubule nucleation assay, domain mutagenesis, competitive overexpression, rescue in CEP57-depleted cells\",\n      \"pmids\": [\"38857398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LLPS is regulated in vivo during the cell cycle unknown\", \"Whether LLPS contributes to kinetochore or midbody functions untested\", \"How the LMN motif integrates with γ-tubulin ring complex-mediated nucleation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The crystal structure of the CEP57 C-terminal microtubule-binding domain revealed a leucine zipper with an adjacent microtubule-binding region, providing the first atomic-resolution view of the microtubule-scaffolding module.\",\n      \"evidence\": \"X-ray crystallography of the CEP57 C-terminal domain\",\n      \"pmids\": [\"38699879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation of individual structural elements not reported\", \"No structure of full-length CEP57 or CEP57 in complex with microtubules available\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"NuSAP was identified as a direct CEP57 interactor at centrioles; NuSAP-mediated tubulin stabilization is required for the initial loading of the CEP57–CEP63–CEP152 torus complex onto procentrioles, establishing an upstream assembly step.\",\n      \"evidence\": \"Super-resolution microscopy, TurboID proximity proteomics, Co-IP (CEP57–NuSAP), RNAi depletion with complex localization readout\",\n      \"pmids\": [\"41616107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NuSAP–CEP57 interaction is direct or mediated by tubulin not fully resolved\", \"Temporal regulation of NuSAP loading relative to centriole duplication licensing unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how CEP57's phase separation is cell-cycle regulated, the structural basis of the CEP57–pericentrin PACT and CEP57–Mis12–Mad1 interfaces, the relative contributions of centrosome versus kinetochore dysfunction to MVA pathogenesis, and whether the trafficking and cyclin D1 sequestration functions operate through the same or distinct CEP57 pools.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cell-cycle-resolved LLPS regulation data\", \"No high-resolution structure of CEP57 in complex with pericentrin or kinetochore partners\", \"Centrosome versus kinetochore contribution to disease aneuploidy not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 6, 10, 14, 15]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2, 6, 8, 12, 14]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 10, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8, 12, 13, 14, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"complexes\": [\n      \"CEP57-CEP63-CEP152 torus complex\"\n    ],\n    \"partners\": [\n      \"CEP63\",\n      \"CEP152\",\n      \"PCNT\",\n      \"NEDD1\",\n      \"MIS12\",\n      \"MAD1L1\",\n      \"CEP57L1\",\n      \"NUSAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}