{"gene":"CEP57","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"Translokin (CEP57) interacts specifically with the 18K form of FGF-2 (but not FGF-1), colocalizes with the microtubular network, and is required for intracellular translocation of FGF-2 to the nucleus; RNAi knockdown of Translokin reduces FGF-2 translocation without affecting FGF-1 trafficking, and this nuclear translocation is essential for FGF-2 mitogenic activity.","method":"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, nuclear localization signal rescue, cell proliferation assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding mapped with chimeric proteins, RNAi phenotype with rescue, multiple orthogonal methods in one study","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 of xCep57 from egg extracts produces weakened bipolar spindles, loss of tension between sister kinetochores, spindle microtubules sensitive to nocodazole, and defective kinetochore-microtubule binding in vitro. At centrosomes, xCep57 is required for maintaining (but not initiating) microtubule anchorage.","method":"Immunodepletion from Xenopus egg extracts, in vitro kinetochore-microtubule binding assay, co-immunoprecipitation, spindle assembly assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — immunodepletion with in vitro reconstitution of kinetochore-MT binding, multiple interactors identified by Co-IP, orthogonal functional assays","pmids":["17803911"],"is_preprint":false},{"year":2008,"finding":"Cep57 has two functional domains: an N-terminal coiled-coil domain that localizes to the centrosome (internal to gamma-tubulin) and mediates multimerization with other Cep57 molecules, and a C-terminal coiled-coil domain that directly binds microtubules, nucleates and bundles microtubules in vitro, and generates nocodazole-resistant microtubule cables in vivo when overexpressed.","method":"Domain truncation/overexpression, in vitro microtubule nucleation/bundling assay, nocodazole resistance assay, immunofluorescence","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro MT assays with defined domains plus in vivo validation, single lab with orthogonal methods","pmids":["18294141"],"is_preprint":false},{"year":2009,"finding":"Translokin/CEP57 interacts with sorting nexin 6, Ran-binding protein M, and kinesins KIF3A and KIF3B; through these interactions it participates in two exclusive complexes that direct bidirectional trafficking of FGF2, controlling the balance between unconventional secretion and nuclear translocation of FGF2.","method":"Co-immunoprecipitation, yeast two-hybrid, functional trafficking assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identification of multiple partners with functional context, single lab","pmids":["19804566"],"is_preprint":false},{"year":2011,"finding":"Translokin/CEP57 interacts with cyclin D1 (binding to regions also involved in Cdk4 binding), retains a fraction of cyclin D1 in the juxtanuclear region, and prevents its nuclear accumulation in quiescent cells. Knockdown of CEP57 leads to undue nuclear cyclin D1 accumulation and increased Cdk4-dependent pRB phosphorylation; overexpression of CEP57 blocks nuclear cyclin D1 accumulation, inhibits Cdk4-dependent pRB phosphorylation, and impairs S-phase entry.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence localization, pRB phosphorylation assay, flow cytometry","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus loss- and gain-of-function with defined functional readouts, single lab","pmids":["21306487"],"is_preprint":false},{"year":2011,"finding":"Biallelic loss-of-function mutations in CEP57, a centrosomal protein involved in nucleating and stabilizing microtubules, cause constitutional mosaic aneuploidies (mosaic variegated aneuploidy syndrome), establishing CEP57 function as essential for correct chromosome number maintenance during cell division.","method":"Exome sequencing, identification of loss-of-function variants in patients, cell biology in patient cells","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with functional annotation, replicated in subsequent studies","pmids":["21552266"],"is_preprint":false},{"year":2012,"finding":"Cep57 is a pericentriolar material (PCM) component whose centrosomal localization depends on interaction with NEDD1. Depletion of Cep57 causes PCM fragmentation, multipolar spindles, unaligned chromosomes, decreased centrosomal microtubule assembly activity, and reduced spindle length and microtubule density; Cep57 also binds spindle microtubules and is required for proper localization of spindle pole focusing proteins.","method":"Co-immunoprecipitation (Cep57–NEDD1), siRNA knockdown, immunofluorescence, spindle assembly assays","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for NEDD1 interaction plus loss-of-function phenotypes, single lab, multiple readouts","pmids":["22508265"],"is_preprint":false},{"year":2012,"finding":"CEP57 is required for FGF-2-induced centriole overduplication and normal centriole duplication; CEP57 overexpression stimulates centriole overduplication; CEP57 functions by modulating tubulin acetylation to promote daughter centriole stability; CEP57 is an intracellular FGF-2-binding and trafficking factor that links FGF-2 signaling to centrosome duplication.","method":"RNAi screen, siRNA knockdown, overexpression, immunofluorescence for centriole number, tubulin acetylation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi knockdown and overexpression with defined centriole and tubulin acetylation readouts, 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 determined by selective chemical crosslinking combined with superresolution microscopy.","method":"Selective chemical crosslinking, superresolution STED microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chemical crosslinking plus superresolution structural localization in single rigorous study with multiple proteins validated","pmids":["23333316"],"is_preprint":false},{"year":2013,"finding":"Cep57 localizes to the central spindle and midbody during cytokinesis and is required for cytokinesis. Depletion of Cep57 disrupts central spindle microtubule assembly and causes abnormal midbody localization of MKLP1, Plk1, and Aurora B, leading to cytokinesis failure and binuclear cell formation. Cep57 directly recruits Tektin 1 to the midbody matrix to regulate microtubule organization.","method":"siRNA knockdown, immunofluorescence, co-immunoprecipitation/pull-down for Cep57–Tektin 1 interaction, live imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with specific phenotypic readouts plus binding partner identification, single lab","pmids":["23569207"],"is_preprint":false},{"year":2016,"finding":"Cep57 localizes to kinetochores in human cells and binds Mis12 (a KMN network component). Cep57 also interacts with Mad1. Depletion of Cep57 decreases kinetochore localization of Mad1-Mad2, reduces spindle assembly checkpoint (SAC) signaling, and increases chromosome segregation errors. The microtubule-binding activity of Cep57 is involved in the timely removal of Mad1 from kinetochores upon microtubule attachment.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for kinetochore Mad1-Mad2 localization, SAC signaling assay, chromosome segregation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for Mis12 and Mad1 interactions, loss-of-function with multiple orthogonal readouts (SAC, chromosome segregation, kinetochore localization), single lab","pmids":["26743940"],"is_preprint":false},{"year":2019,"finding":"Cep57 is required for PCM organization to regulate centriole engagement; depletion of Cep57 causes PCM disorganization and precocious centriole disengagement during mitosis, leading to ectopic MTOC activity of disengaged daughter centrioles and chromosome mis-segregation. Cep57 directly binds the PACT domain of pericentrin, providing a critical interface between the centriole core and PCM. Microcephaly osteodysplastic primordial dwarfism (MOPDII)-associated pericentrin mutations impair the Cep57–pericentrin interaction and cause PCM disorganization.","method":"siRNA depletion, pull-down assay (Cep57–pericentrin PACT domain), patient-derived cells (MVA and MOPDII), immunofluorescence, live imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped to PACT domain with loss-of-function in multiple cell types (patient cells + siRNA), multiple orthogonal methods","pmids":["30804344"],"is_preprint":false},{"year":2018,"finding":"Cep57 mutant (truncating frameshift) mouse embryonic fibroblasts and patient-derived fibroblasts fail to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high chromosome missegregation rates. In vivo, Cep57 is required for Fgf2-mediated bone formation, and Cep57 haploinsufficiency predisposes to cancer (tumor suppressor role).","method":"Mouse knockout/knock-in model, patient-derived fibroblasts, immunofluorescence for centrosome maturation, chromosome analysis, tumor incidence measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model plus patient-derived cells, multiple readouts (centrosome maturation, centriole disjunction, chromosome segregation, cancer), replicated in two cell systems","pmids":["30035751"],"is_preprint":false},{"year":2021,"finding":"Cep57 and its paralog Cep57L1 cooperatively maintain centriole engagement during interphase. Co-depletion induces precocious centriole disengagement in interphase; the disengaged daughter centrioles convert into centrosomes in a Plk1-dependent manner, leading to centriole reduplication, increased centriole number, and chromosome segregation errors.","method":"siRNA co-depletion, immunofluorescence, live imaging, Plk1 inhibitor rescue experiment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-depletion epistasis with Plk1-dependent rescue, multiple orthogonal readouts, single lab with rigorous controls","pmids":["33492359"],"is_preprint":false},{"year":2024,"finding":"Cep57 undergoes liquid-liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN motif). In vitro Cep57 condensates catalyze microtubule nucleation via LMN motif-mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity. Overexpression of competitive multivalent-interaction constructs (including an MVA mutation) leads to excessive centrosome duplication. Self-assembly mutants of Cep57 fail to rescue centriole disengagement and PCM disorganization in Cep57-depleted cells.","method":"In vitro LLPS assay, in vitro microtubule nucleation assay, domain mutagenesis, overexpression, rescue experiments in Cep57-depleted cells, SAXS (small-angle X-ray scattering)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution of LLPS and MT nucleation, mutagenesis, domain mapping, and in-cell rescue, multiple orthogonal methods in one study","pmids":["38857398"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of the human Cep57 C-terminal microtubule-binding domain reveals a leucine zipper with an adjacent possible microtubule-binding region, forming a stabilizing scaffold proposed to accommodate microtubule nucleation and tension. Conserved structural features are maintained across evolution.","method":"X-ray crystallography","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure determined but functional validation of structural elements not reported in abstract beyond prediction/proposal","pmids":["38699879"],"is_preprint":false},{"year":2026,"finding":"NuSAP localizes to centrioles, and its depletion disrupts centriole tubulin architecture and premature centriole disengagement, as well as disrupting the spatial organization of the CEP57-CEP63-CEP152 torus assembly. CEP57 is identified as a direct interactor of NuSAP by TurboID-based proteomics and biochemical assays. NuSAP is essential for the initial recruitment of the CEP57-CEP63-CEP152 complex to the proximal end of procentrioles, placing NuSAP upstream of CEP57 in torus complex assembly.","method":"TurboID-based proximity proteomics, co-immunoprecipitation/biochemical assays, super-resolution microscopy, siRNA depletion","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — TurboID proteomics plus biochemical validation of NuSAP–CEP57 interaction with epistasis for torus recruitment, single lab","pmids":["41616107"],"is_preprint":false},{"year":2025,"finding":"In early zebrafish embryos, Cep57 localizes to both the nucleus and centrosomes. Cep57 interacts with Rad21 (cohesin), and its loss causes Rad21 depletion, supernumerary nuclei, and PCM disorganization. Cep57 also interacts with Geminin and induces Rb1-dependent G1 arrest; loss of Cep57 leads to G1/S cell cycle defects, genome instability, and increased apoptosis. Quantitative proteomics in Cep57-deficient embryos reveals induction of DNA damage response and checkpoint pathways.","method":"Zebrafish morpholino/loss-of-function, co-immunoprecipitation (Cep57–Rad21, Cep57–Geminin), immunofluorescence localization, quantitative proteomics, cell cycle analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, zebrafish model, Co-IP interactions reported but functional validation is limited in abstract; not yet peer-reviewed","pmids":["bio_10.1101_2025.04.10.648303"],"is_preprint":true}],"current_model":"CEP57 (Translokin) is a multidomain coiled-coil scaffold at the pericentriolar matrix (PCM) that nucleates and stabilizes microtubules via its C-terminal microtubule-binding domain (which undergoes liquid-liquid phase separation to concentrate tubulin), anchors daughter centrioles to their mothers during interphase via interaction with pericentrin's PACT domain, forms a ring-like torus complex with Cep63 and Cep152 at the proximal centriole end, recruits NEDD1 for PCM localization, binds kinetochore proteins Mis12 and Mad1 to regulate spindle assembly checkpoint signaling, traffics intracellular FGF-2 to the nucleus via kinesin KIF3A/KIF3B-containing complexes, sequesters cyclin D1 from the nucleus to maintain cellular quiescence, and facilitates cytokinesis by organizing the central spindle and recruiting Tektin 1 to the midbody; loss of CEP57 causes premature centriole disengagement, centrosome amplification, chromosome missegregation, and mosaic variegated aneuploidy syndrome."},"narrative":{"mechanistic_narrative":"CEP57 (Translokin) is a centrosomal coiled-coil scaffold that organizes the pericentriolar material (PCM) and stabilizes microtubules to safeguard centriole engagement and accurate chromosome segregation [PMID:21552266, PMID:30804344, PMID:30035751]. It is built around two functional regions: an N-terminal coiled-coil domain that targets the centrosome internal to gamma-tubulin and mediates self-multimerization, and a C-terminal microtubule-binding domain that directly nucleates and bundles microtubules into nocodazole-resistant cables [PMID:18294141]. Self-assembly is driven by liquid-liquid phase separation through its NTD, CTD, and a polybasic LMN motif, and the resulting condensates catalyze microtubule nucleation by concentrating tubulin, an activity restricted by Cep63 [PMID:38857398]. At the proximal centriole end CEP57 forms a ring-like torus with Cep63 and Cep152, with its initial recruitment dependent on NuSAP [PMID:23333316, PMID:41616107], and its centrosomal localization additionally requires NEDD1 [PMID:22508265]. CEP57 directly binds the PACT domain of pericentrin to bridge the centriole core and PCM, and loss of this organization causes premature centriole disengagement, ectopic MTOC activity, centrosome amplification, and chromosome mis-segregation [PMID:30804344, PMID:30035751]; CEP57 and its paralog Cep57L1 act cooperatively to maintain interphase centriole engagement, restraining Plk1-dependent disengaged daughter conversion [PMID:33492359]. CEP57 also localizes to kinetochores, where it binds Mis12 and Mad1 to support Mad1-Mad2 loading and spindle assembly checkpoint signaling [#1_kt, #10], and to the central spindle and midbody, where it recruits Tektin 1 and is required for cytokinesis [PMID:23569207]. Independently, CEP57 functions as an intracellular trafficking factor that translocates the 18K form of FGF-2 to the nucleus through KIF3A/KIF3B kinesin complexes, links FGF-2 signaling to centriole duplication, and sequesters cyclin D1 in the juxtanuclear region to restrain Cdk4-dependent pRB phosphorylation and S-phase entry [PMID:12717444, PMID:19804566, PMID:21306487, PMID:23243019]. Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome [PMID:21552266].","teleology":[{"year":2003,"claim":"Established the first molecular function of CEP57 as an FGF-2-specific intracellular carrier, explaining how a growth factor reaches the nucleus to exert mitogenic activity.","evidence":"Co-IP, RNAi knockdown, FGF-1/FGF-2 chimera mapping and proliferation assays in cultured cells","pmids":["12717444"],"confidence":"High","gaps":["Did not connect FGF-2 trafficking to centrosomal function","Mechanism of microtubule-based transport not resolved"]},{"year":2007,"claim":"Showed CEP57 acts at kinetochores and centrosomes to maintain microtubule attachment and spindle bipolarity, broadening its role from trafficking to spindle integrity.","evidence":"Immunodepletion from Xenopus egg extracts with in vitro kinetochore-microtubule binding reconstitution and Co-IP","pmids":["17803911"],"confidence":"High","gaps":["Whether anchorage role is conserved in human cells not established here","Direct microtubule-binding domain not yet defined"]},{"year":2008,"claim":"Defined the domain architecture, mapping centrosome targeting/multimerization to the N-terminus and direct microtubule nucleation/bundling to the C-terminus.","evidence":"Domain truncation/overexpression with in vitro microtubule nucleation and bundling assays","pmids":["18294141"],"confidence":"High","gaps":["How the two domains are coordinated in vivo unclear","Structural basis of microtubule binding not resolved"]},{"year":2009,"claim":"Resolved how CEP57 partitions FGF-2 between secretion and nuclear import, identifying the kinesin and adaptor partners that build mutually exclusive trafficking complexes.","evidence":"Co-IP and yeast two-hybrid for SNX6, RanBPM, KIF3A/KIF3B plus trafficking assays","pmids":["19804566"],"confidence":"Medium","gaps":["Single lab","Stoichiometry and regulation of the two complexes not determined"]},{"year":2011,"claim":"Linked CEP57 to cell-cycle control by showing it sequesters cyclin D1 to keep cells quiescent, connecting its scaffolding role to S-phase entry.","evidence":"Co-IP, siRNA/overexpression with pRB phosphorylation and flow cytometry readouts","pmids":["21306487"],"confidence":"Medium","gaps":["Single lab","Relationship between cyclin D1 sequestration and centrosomal functions unclear"]},{"year":2011,"claim":"Established CEP57 as a disease gene, demonstrating biallelic loss-of-function causes mosaic variegated aneuploidy and is essential for chromosome number maintenance.","evidence":"Exome sequencing of patients with functional analysis of patient cells","pmids":["21552266"],"confidence":"Medium","gaps":["Cellular mechanism linking mutations to aneuploidy not yet mechanistically defined"]},{"year":2012,"claim":"Defined CEP57 as a PCM component requiring NEDD1 for centrosomal localization and showed its depletion fragments the PCM and disrupts spindle assembly.","evidence":"Co-IP (CEP57-NEDD1), siRNA knockdown, immunofluorescence and spindle assays","pmids":["22508265"],"confidence":"Medium","gaps":["Direction of CEP57-NEDD1 dependency only partially resolved","Single lab"]},{"year":2012,"claim":"Connected FGF-2 trafficking to centriole biology, showing CEP57 promotes daughter centriole stability via tubulin acetylation and links FGF-2 signaling to centriole duplication.","evidence":"RNAi screen, siRNA/overexpression with centriole counting and tubulin acetylation assays","pmids":["23243019"],"confidence":"Medium","gaps":["Mechanism by which CEP57 modulates tubulin acetylation unknown","Single lab"]},{"year":2013,"claim":"Extended CEP57 function to cytokinesis, showing it organizes the central spindle/midbody and recruits Tektin 1 for successful division.","evidence":"siRNA knockdown, immunofluorescence, live imaging and pull-down for CEP57-Tektin 1","pmids":["23569207"],"confidence":"Medium","gaps":["Single lab","How midbody role integrates with centriole engagement role unclear"]},{"year":2013,"claim":"Placed CEP57 structurally within a defined ring-like torus with Cep63 and Cep152 at the proximal centriole end.","evidence":"Selective chemical crosslinking with superresolution STED microscopy","pmids":["23333316"],"confidence":"High","gaps":["Assembly order of the torus not yet established","Functional consequence of torus geometry not tested here"]},{"year":2016,"claim":"Defined a kinetochore checkpoint role in human cells, showing CEP57 binds Mis12 and Mad1 to control Mad1-Mad2 loading and SAC signaling.","evidence":"Co-IP, siRNA knockdown, kinetochore Mad1-Mad2 imaging, SAC and segregation assays","pmids":["26743940"],"confidence":"High","gaps":["How microtubule-binding triggers Mad1 removal mechanistically unclear","Single lab"]},{"year":2018,"claim":"Demonstrated in vivo that CEP57 is required for G2 centrosome maturation and acts as a haploinsufficient tumor suppressor, integrating its centrosomal and FGF-2 roles in an animal model.","evidence":"Mouse knock-in model plus patient fibroblasts with centrosome, chromosome and tumor incidence readouts","pmids":["30035751"],"confidence":"High","gaps":["Molecular trigger of maturation failure not fully resolved"]},{"year":2019,"claim":"Identified the direct CEP57-pericentrin PACT interface as the bridge between centriole core and PCM, explaining premature disengagement and linking pericentrin disease mutations to this interaction.","evidence":"Pull-down mapping to PACT domain, siRNA depletion, MVA/MOPDII patient cells, live imaging","pmids":["30804344"],"confidence":"High","gaps":["How PCM disorganization mechanistically triggers disengagement not fully resolved"]},{"year":2021,"claim":"Resolved that CEP57 and paralog Cep57L1 cooperatively enforce interphase centriole engagement, with disengagement driving Plk1-dependent reduplication.","evidence":"siRNA co-depletion epistasis, live imaging and Plk1 inhibitor rescue","pmids":["33492359"],"confidence":"High","gaps":["Division of labor between CEP57 and Cep57L1 not fully defined"]},{"year":2024,"claim":"Provided a biophysical mechanism, showing CEP57 phase-separates via NTD/CTD/LMN motifs to catalyze microtubule nucleation by concentrating tubulin, with Cep63 acting as a brake.","evidence":"In vitro LLPS and microtubule nucleation assays, domain mutagenesis, SAXS and in-cell rescue","pmids":["38857398"],"confidence":"High","gaps":["In vivo extent of phase separation not quantified","How LLPS is regulated through the cell cycle unknown"]},{"year":2024,"claim":"Provided atomic detail of the C-terminal microtubule-binding domain as a leucine-zipper scaffold accommodating nucleation and tension.","evidence":"X-ray crystallography of the human CEP57 C-terminal domain","pmids":["38699879"],"confidence":"Medium","gaps":["Functional validation of identified structural elements not reported","Microtubule-bound structure not determined"]},{"year":2026,"claim":"Placed NuSAP upstream of CEP57, identifying it as a direct interactor required for initial torus complex recruitment to procentrioles.","evidence":"TurboID proximity proteomics, Co-IP/biochemistry, super-resolution microscopy and siRNA depletion","pmids":["41616107"],"confidence":"Medium","gaps":["Single lab","How NuSAP triggers torus nucleation mechanistically unclear"]},{"year":2025,"claim":"Suggested additional nuclear and cohesin-related roles for Cep57 in early embryos, interacting with Rad21 and Geminin to influence genome stability and G1 arrest.","evidence":"Zebrafish loss-of-function, Co-IP, immunofluorescence, quantitative proteomics and cell cycle analysis (preprint)","pmids":["bio_10.1101_2025.04.10.648303"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Co-IP interactions lack reciprocal/structural validation","Conservation in human cells untested"]},{"year":null,"claim":"How CEP57's distinct activities — torus scaffolding, microtubule nucleation, kinetochore checkpoint control, FGF-2 trafficking, and cyclin D1 sequestration — are temporally coordinated and regulated across the cell cycle remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory mechanism links the trafficking and centrosomal functions","Post-translational control of CEP57 not characterized","Whether FGF-2/cyclin D1 roles operate in the same cells as centriole roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,6,14,15]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,8,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,11,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2,6,8,11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,10]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,10,11,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6,8,11,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3]}],"complexes":["CEP57-CEP63-CEP152 torus","kinetochore (KMN network, via Mis12)"],"partners":["PCNT","NEDD1","CEP63","CEP152","MIS12","MAD1","KIF3A","NUSAP1"],"other_free_text":[]}},"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":55,"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":"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":"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":"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":"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":"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":"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":"Cep57 coordinates genome stability and cell cycle progression in early embryos","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":12416,"output_tokens":5065,"usd":0.056612,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13238,"output_tokens":5230,"usd":0.09847,"stage2_stop_reason":"end_turn"},"total_usd":0.155082,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Translokin (CEP57) interacts specifically with the 18K form of FGF-2 (but not FGF-1), colocalizes with the microtubular network, and is required for intracellular translocation of FGF-2 to the nucleus; RNAi knockdown of Translokin reduces FGF-2 translocation without affecting FGF-1 trafficking, and this nuclear translocation is essential for FGF-2 mitogenic activity.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, FGF-1/FGF-2 chimera mapping, nuclear localization signal rescue, cell proliferation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding mapped with chimeric proteins, RNAi phenotype with rescue, multiple orthogonal methods in one study\",\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 of xCep57 from egg extracts produces weakened bipolar spindles, loss of tension between sister kinetochores, spindle microtubules sensitive to nocodazole, and defective kinetochore-microtubule binding in vitro. At centrosomes, xCep57 is required for maintaining (but not initiating) microtubule anchorage.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, in vitro kinetochore-microtubule binding assay, co-immunoprecipitation, spindle assembly assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — immunodepletion with in vitro reconstitution of kinetochore-MT binding, multiple interactors identified by Co-IP, orthogonal functional assays\",\n      \"pmids\": [\"17803911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cep57 has two functional domains: an N-terminal coiled-coil domain that localizes to the centrosome (internal to gamma-tubulin) and mediates multimerization with other Cep57 molecules, and a C-terminal coiled-coil domain that directly binds microtubules, nucleates and bundles microtubules in vitro, and generates nocodazole-resistant microtubule cables in vivo when overexpressed.\",\n      \"method\": \"Domain truncation/overexpression, in vitro microtubule nucleation/bundling assay, nocodazole resistance assay, immunofluorescence\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro MT assays with defined domains plus in vivo validation, single lab with orthogonal methods\",\n      \"pmids\": [\"18294141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Translokin/CEP57 interacts with sorting nexin 6, Ran-binding protein M, and kinesins KIF3A and KIF3B; through these interactions it participates in two exclusive complexes that direct bidirectional trafficking of FGF2, controlling the balance between unconventional secretion and nuclear translocation of FGF2.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, functional trafficking assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identification of multiple partners with functional context, single lab\",\n      \"pmids\": [\"19804566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Translokin/CEP57 interacts with cyclin D1 (binding to regions also involved in Cdk4 binding), retains a fraction of cyclin D1 in the juxtanuclear region, and prevents its nuclear accumulation in quiescent cells. Knockdown of CEP57 leads to undue nuclear cyclin D1 accumulation and increased Cdk4-dependent pRB phosphorylation; overexpression of CEP57 blocks nuclear cyclin D1 accumulation, inhibits Cdk4-dependent pRB phosphorylation, and impairs S-phase entry.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence localization, pRB phosphorylation assay, flow cytometry\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus loss- and gain-of-function with defined functional readouts, single lab\",\n      \"pmids\": [\"21306487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Biallelic loss-of-function mutations in CEP57, a centrosomal protein involved in nucleating and stabilizing microtubules, cause constitutional mosaic aneuploidies (mosaic variegated aneuploidy syndrome), establishing CEP57 function as essential for correct chromosome number maintenance during cell division.\",\n      \"method\": \"Exome sequencing, identification of loss-of-function variants in patients, cell biology in patient cells\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with functional annotation, replicated in subsequent studies\",\n      \"pmids\": [\"21552266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cep57 is a pericentriolar material (PCM) component whose centrosomal localization depends on interaction with NEDD1. Depletion of Cep57 causes PCM fragmentation, multipolar spindles, unaligned chromosomes, decreased centrosomal microtubule assembly activity, and reduced spindle length and microtubule density; Cep57 also binds spindle microtubules and is required for proper localization of spindle pole focusing proteins.\",\n      \"method\": \"Co-immunoprecipitation (Cep57–NEDD1), siRNA knockdown, immunofluorescence, spindle assembly assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for NEDD1 interaction plus loss-of-function phenotypes, single lab, multiple readouts\",\n      \"pmids\": [\"22508265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEP57 is required for FGF-2-induced centriole overduplication and normal centriole duplication; CEP57 overexpression stimulates centriole overduplication; CEP57 functions by modulating tubulin acetylation to promote daughter centriole stability; CEP57 is an intracellular FGF-2-binding and trafficking factor that links FGF-2 signaling to centrosome duplication.\",\n      \"method\": \"RNAi screen, siRNA knockdown, overexpression, immunofluorescence for centriole number, tubulin acetylation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi knockdown and overexpression with defined centriole and tubulin acetylation readouts, 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 determined by selective chemical crosslinking combined with superresolution microscopy.\",\n      \"method\": \"Selective chemical crosslinking, superresolution STED microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical crosslinking plus superresolution structural localization in single rigorous study with multiple proteins validated\",\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 cytokinesis. Depletion of Cep57 disrupts central spindle microtubule assembly and causes abnormal midbody localization of MKLP1, Plk1, and Aurora B, leading to cytokinesis failure and binuclear cell formation. Cep57 directly recruits Tektin 1 to the midbody matrix to regulate microtubule organization.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, co-immunoprecipitation/pull-down for Cep57–Tektin 1 interaction, live imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with specific phenotypic readouts plus binding partner identification, single lab\",\n      \"pmids\": [\"23569207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cep57 localizes to kinetochores in human cells and binds Mis12 (a KMN network component). Cep57 also interacts with Mad1. Depletion of Cep57 decreases kinetochore localization of Mad1-Mad2, reduces spindle assembly checkpoint (SAC) signaling, and increases chromosome segregation errors. The microtubule-binding activity of Cep57 is involved in the timely removal of Mad1 from kinetochores upon microtubule attachment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for kinetochore Mad1-Mad2 localization, SAC signaling assay, chromosome segregation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for Mis12 and Mad1 interactions, loss-of-function with multiple orthogonal readouts (SAC, chromosome segregation, kinetochore localization), single lab\",\n      \"pmids\": [\"26743940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cep57 is required for PCM organization to regulate centriole engagement; depletion of Cep57 causes PCM disorganization and precocious centriole disengagement during mitosis, leading to ectopic MTOC activity of disengaged daughter centrioles and chromosome mis-segregation. Cep57 directly binds the PACT domain of pericentrin, providing a critical interface between the centriole core and PCM. Microcephaly osteodysplastic primordial dwarfism (MOPDII)-associated pericentrin mutations impair the Cep57–pericentrin interaction and cause PCM disorganization.\",\n      \"method\": \"siRNA depletion, pull-down assay (Cep57–pericentrin PACT domain), patient-derived cells (MVA and MOPDII), immunofluorescence, live imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped to PACT domain with loss-of-function in multiple cell types (patient cells + siRNA), multiple orthogonal methods\",\n      \"pmids\": [\"30804344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cep57 mutant (truncating frameshift) mouse embryonic fibroblasts and patient-derived fibroblasts fail to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high chromosome missegregation rates. In vivo, Cep57 is required for Fgf2-mediated bone formation, and Cep57 haploinsufficiency predisposes to cancer (tumor suppressor role).\",\n      \"method\": \"Mouse knockout/knock-in model, patient-derived fibroblasts, immunofluorescence for centrosome maturation, chromosome analysis, tumor incidence measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model plus patient-derived cells, multiple readouts (centrosome maturation, centriole disjunction, chromosome segregation, cancer), replicated in two cell systems\",\n      \"pmids\": [\"30035751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cep57 and its paralog Cep57L1 cooperatively maintain centriole engagement during interphase. Co-depletion induces precocious centriole disengagement in interphase; the disengaged daughter centrioles convert into centrosomes in a Plk1-dependent manner, leading to centriole reduplication, increased centriole number, and chromosome segregation errors.\",\n      \"method\": \"siRNA co-depletion, immunofluorescence, live imaging, Plk1 inhibitor rescue experiment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-depletion epistasis with Plk1-dependent rescue, multiple orthogonal readouts, single lab with rigorous controls\",\n      \"pmids\": [\"33492359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cep57 undergoes liquid-liquid phase separation (LLPS) driven by three critical domains (NTD, CTD, and polybasic LMN motif). In vitro Cep57 condensates catalyze microtubule nucleation via LMN motif-mediated tubulin concentration. In cells, the LMN motif is required for centrosomal microtubule aster formation. Cep63 restricts Cep57 assembly, expansion, and microtubule polymerization activity. Overexpression of competitive multivalent-interaction constructs (including an MVA mutation) leads to excessive centrosome duplication. Self-assembly mutants of Cep57 fail to rescue centriole disengagement and PCM disorganization in Cep57-depleted cells.\",\n      \"method\": \"In vitro LLPS assay, in vitro microtubule nucleation assay, domain mutagenesis, overexpression, rescue experiments in Cep57-depleted cells, SAXS (small-angle X-ray scattering)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution of LLPS and MT nucleation, mutagenesis, domain mapping, and in-cell rescue, multiple orthogonal methods in one study\",\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 with an adjacent possible microtubule-binding region, forming a stabilizing scaffold proposed to accommodate microtubule nucleation and tension. Conserved structural features are maintained across evolution.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure determined but functional validation of structural elements not reported in abstract beyond prediction/proposal\",\n      \"pmids\": [\"38699879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NuSAP localizes to centrioles, and its depletion disrupts centriole tubulin architecture and premature centriole disengagement, as well as disrupting the spatial organization of the CEP57-CEP63-CEP152 torus assembly. CEP57 is identified as a direct interactor of NuSAP by TurboID-based proteomics and biochemical assays. NuSAP is essential for the initial recruitment of the CEP57-CEP63-CEP152 complex to the proximal end of procentrioles, placing NuSAP upstream of CEP57 in torus complex assembly.\",\n      \"method\": \"TurboID-based proximity proteomics, co-immunoprecipitation/biochemical assays, super-resolution microscopy, siRNA depletion\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — TurboID proteomics plus biochemical validation of NuSAP–CEP57 interaction with epistasis for torus recruitment, single lab\",\n      \"pmids\": [\"41616107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In early zebrafish embryos, Cep57 localizes to both the nucleus and centrosomes. Cep57 interacts with Rad21 (cohesin), and its loss causes Rad21 depletion, supernumerary nuclei, and PCM disorganization. Cep57 also interacts with Geminin and induces Rb1-dependent G1 arrest; loss of Cep57 leads to G1/S cell cycle defects, genome instability, and increased apoptosis. Quantitative proteomics in Cep57-deficient embryos reveals induction of DNA damage response and checkpoint pathways.\",\n      \"method\": \"Zebrafish morpholino/loss-of-function, co-immunoprecipitation (Cep57–Rad21, Cep57–Geminin), immunofluorescence localization, quantitative proteomics, cell cycle analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, zebrafish model, Co-IP interactions reported but functional validation is limited in abstract; not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.10.648303\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CEP57 (Translokin) is a multidomain coiled-coil scaffold at the pericentriolar matrix (PCM) that nucleates and stabilizes microtubules via its C-terminal microtubule-binding domain (which undergoes liquid-liquid phase separation to concentrate tubulin), anchors daughter centrioles to their mothers during interphase via interaction with pericentrin's PACT domain, forms a ring-like torus complex with Cep63 and Cep152 at the proximal centriole end, recruits NEDD1 for PCM localization, binds kinetochore proteins Mis12 and Mad1 to regulate spindle assembly checkpoint signaling, traffics intracellular FGF-2 to the nucleus via kinesin KIF3A/KIF3B-containing complexes, sequesters cyclin D1 from the nucleus to maintain cellular quiescence, and facilitates cytokinesis by organizing the central spindle and recruiting Tektin 1 to the midbody; loss of CEP57 causes premature centriole disengagement, centrosome amplification, chromosome missegregation, and mosaic variegated aneuploidy syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP57 (Translokin) is a centrosomal coiled-coil scaffold that organizes the pericentriolar material (PCM) and stabilizes microtubules to safeguard centriole engagement and accurate chromosome segregation [#5, #11, #12]. It is built around two functional regions: an N-terminal coiled-coil domain that targets the centrosome internal to gamma-tubulin and mediates self-multimerization, and a C-terminal microtubule-binding domain that directly nucleates and bundles microtubules into nocodazole-resistant cables [#2]. Self-assembly is driven by liquid-liquid phase separation through its NTD, CTD, and a polybasic LMN motif, and the resulting condensates catalyze microtubule nucleation by concentrating tubulin, an activity restricted by Cep63 [#14]. At the proximal centriole end CEP57 forms a ring-like torus with Cep63 and Cep152, with its initial recruitment dependent on NuSAP [#8, #16], and its centrosomal localization additionally requires NEDD1 [#6]. CEP57 directly binds the PACT domain of pericentrin to bridge the centriole core and PCM, and loss of this organization causes premature centriole disengagement, ectopic MTOC activity, centrosome amplification, and chromosome mis-segregation [#11, #12]; CEP57 and its paralog Cep57L1 act cooperatively to maintain interphase centriole engagement, restraining Plk1-dependent disengaged daughter conversion [#13]. CEP57 also localizes to kinetochores, where it binds Mis12 and Mad1 to support Mad1-Mad2 loading and spindle assembly checkpoint signaling [#1_kt, #10], and to the central spindle and midbody, where it recruits Tektin 1 and is required for cytokinesis [#9]. Independently, CEP57 functions as an intracellular trafficking factor that translocates the 18K form of FGF-2 to the nucleus through KIF3A/KIF3B kinesin complexes, links FGF-2 signaling to centriole duplication, and sequesters cyclin D1 in the juxtanuclear region to restrain Cdk4-dependent pRB phosphorylation and S-phase entry [#0, #3, #4, #7]. Biallelic loss-of-function mutations in CEP57 cause mosaic variegated aneuploidy syndrome [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first molecular function of CEP57 as an FGF-2-specific intracellular carrier, explaining how a growth factor reaches the nucleus to exert mitogenic activity.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, FGF-1/FGF-2 chimera mapping and proliferation assays in cultured cells\",\n      \"pmids\": [\"12717444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect FGF-2 trafficking to centrosomal function\", \"Mechanism of microtubule-based transport not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed CEP57 acts at kinetochores and centrosomes to maintain microtubule attachment and spindle bipolarity, broadening its role from trafficking to spindle integrity.\",\n      \"evidence\": \"Immunodepletion from Xenopus egg extracts with in vitro kinetochore-microtubule binding reconstitution and Co-IP\",\n      \"pmids\": [\"17803911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether anchorage role is conserved in human cells not established here\", \"Direct microtubule-binding domain not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the domain architecture, mapping centrosome targeting/multimerization to the N-terminus and direct microtubule nucleation/bundling to the C-terminus.\",\n      \"evidence\": \"Domain truncation/overexpression with in vitro microtubule nucleation and bundling assays\",\n      \"pmids\": [\"18294141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the two domains are coordinated in vivo unclear\", \"Structural basis of microtubule binding not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how CEP57 partitions FGF-2 between secretion and nuclear import, identifying the kinesin and adaptor partners that build mutually exclusive trafficking complexes.\",\n      \"evidence\": \"Co-IP and yeast two-hybrid for SNX6, RanBPM, KIF3A/KIF3B plus trafficking assays\",\n      \"pmids\": [\"19804566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Stoichiometry and regulation of the two complexes not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CEP57 to cell-cycle control by showing it sequesters cyclin D1 to keep cells quiescent, connecting its scaffolding role to S-phase entry.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression with pRB phosphorylation and flow cytometry readouts\",\n      \"pmids\": [\"21306487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relationship between cyclin D1 sequestration and centrosomal functions unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established CEP57 as a disease gene, demonstrating biallelic loss-of-function causes mosaic variegated aneuploidy and is essential for chromosome number maintenance.\",\n      \"evidence\": \"Exome sequencing of patients with functional analysis of patient cells\",\n      \"pmids\": [\"21552266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism linking mutations to aneuploidy not yet mechanistically defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CEP57 as a PCM component requiring NEDD1 for centrosomal localization and showed its depletion fragments the PCM and disrupts spindle assembly.\",\n      \"evidence\": \"Co-IP (CEP57-NEDD1), siRNA knockdown, immunofluorescence and spindle assays\",\n      \"pmids\": [\"22508265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of CEP57-NEDD1 dependency only partially resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected FGF-2 trafficking to centriole biology, showing CEP57 promotes daughter centriole stability via tubulin acetylation and links FGF-2 signaling to centriole duplication.\",\n      \"evidence\": \"RNAi screen, siRNA/overexpression with centriole counting and tubulin acetylation assays\",\n      \"pmids\": [\"23243019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CEP57 modulates tubulin acetylation unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended CEP57 function to cytokinesis, showing it organizes the central spindle/midbody and recruits Tektin 1 for successful division.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, live imaging and pull-down for CEP57-Tektin 1\",\n      \"pmids\": [\"23569207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How midbody role integrates with centriole engagement role unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed CEP57 structurally within a defined ring-like torus with Cep63 and Cep152 at the proximal centriole end.\",\n      \"evidence\": \"Selective chemical crosslinking with superresolution STED microscopy\",\n      \"pmids\": [\"23333316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Assembly order of the torus not yet established\", \"Functional consequence of torus geometry not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a kinetochore checkpoint role in human cells, showing CEP57 binds Mis12 and Mad1 to control Mad1-Mad2 loading and SAC signaling.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, kinetochore Mad1-Mad2 imaging, SAC and segregation assays\",\n      \"pmids\": [\"26743940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How microtubule-binding triggers Mad1 removal mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated in vivo that CEP57 is required for G2 centrosome maturation and acts as a haploinsufficient tumor suppressor, integrating its centrosomal and FGF-2 roles in an animal model.\",\n      \"evidence\": \"Mouse knock-in model plus patient fibroblasts with centrosome, chromosome and tumor incidence readouts\",\n      \"pmids\": [\"30035751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of maturation failure not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the direct CEP57-pericentrin PACT interface as the bridge between centriole core and PCM, explaining premature disengagement and linking pericentrin disease mutations to this interaction.\",\n      \"evidence\": \"Pull-down mapping to PACT domain, siRNA depletion, MVA/MOPDII patient cells, live imaging\",\n      \"pmids\": [\"30804344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PCM disorganization mechanistically triggers disengagement not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved that CEP57 and paralog Cep57L1 cooperatively enforce interphase centriole engagement, with disengagement driving Plk1-dependent reduplication.\",\n      \"evidence\": \"siRNA co-depletion epistasis, live imaging and Plk1 inhibitor rescue\",\n      \"pmids\": [\"33492359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Division of labor between CEP57 and Cep57L1 not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided a biophysical mechanism, showing CEP57 phase-separates via NTD/CTD/LMN motifs to catalyze microtubule nucleation by concentrating tubulin, with Cep63 acting as a brake.\",\n      \"evidence\": \"In vitro LLPS and microtubule nucleation assays, domain mutagenesis, SAXS and in-cell rescue\",\n      \"pmids\": [\"38857398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo extent of phase separation not quantified\", \"How LLPS is regulated through the cell cycle unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided atomic detail of the C-terminal microtubule-binding domain as a leucine-zipper scaffold accommodating nucleation and tension.\",\n      \"evidence\": \"X-ray crystallography of the human CEP57 C-terminal domain\",\n      \"pmids\": [\"38699879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation of identified structural elements not reported\", \"Microtubule-bound structure not determined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed NuSAP upstream of CEP57, identifying it as a direct interactor required for initial torus complex recruitment to procentrioles.\",\n      \"evidence\": \"TurboID proximity proteomics, Co-IP/biochemistry, super-resolution microscopy and siRNA depletion\",\n      \"pmids\": [\"41616107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How NuSAP triggers torus nucleation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested additional nuclear and cohesin-related roles for Cep57 in early embryos, interacting with Rad21 and Geminin to influence genome stability and G1 arrest.\",\n      \"evidence\": \"Zebrafish loss-of-function, Co-IP, immunofluorescence, quantitative proteomics and cell cycle analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.10.648303\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Co-IP interactions lack reciprocal/structural validation\", \"Conservation in human cells untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEP57's distinct activities — torus scaffolding, microtubule nucleation, kinetochore checkpoint control, FGF-2 trafficking, and cyclin D1 sequestration — are temporally coordinated and regulated across the cell cycle remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory mechanism links the trafficking and centrosomal functions\", \"Post-translational control of CEP57 not characterized\", \"Whether FGF-2/cyclin D1 roles operate in the same cells as centriole roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 6, 14, 15]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 8, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 11, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2, 6, 8, 11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 10, 11, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6, 8, 11, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\n      \"CEP57-CEP63-CEP152 torus\",\n      \"kinetochore (KMN network, via Mis12)\"\n    ],\n    \"partners\": [\n      \"PCNT\",\n      \"NEDD1\",\n      \"CEP63\",\n      \"CEP152\",\n      \"MIS12\",\n      \"MAD1\",\n      \"KIF3A\",\n      \"NUSAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}