{"gene":"CEP55","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2005,"finding":"CEP55 localizes to the mother centriole during interphase. Erk2/Cdk1-dependent phosphorylation at S425 and S428 triggers centrosome dissociation at mitotic entry. S425/428 phosphorylation enables interaction with Plk1, which then phosphorylates CEP55 at S436. This phosphorylation cascade is required for CEP55 recruitment to the midbody and completion of cytokinesis; phosphorylation-deficient mutants cause cytokinesis failure.","method":"Site-directed mutagenesis, in vitro kinase assays, Co-IP, siRNA knockdown with cytokinesis readout, immunofluorescence localization","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assays and mutagenesis combined with cellular phenotype, foundational paper with 271 citations","pmids":["16198290"],"is_preprint":false},{"year":2006,"finding":"CEP55 directly binds MKLP1 in vitro and associates with the MKLP1-MgcRacGAP centralspindlin complex in vivo. CEP55 is a microtubule-bundling protein. Knockdown of centralspindlin abolishes CEP55 localization to the spindle midzone, placing CEP55 downstream of centralspindlin. CEP55 depletion causes absence of the Flemming body and mislocalization of midbody components, and controls endobrevin (v-SNARE) localization for membrane fusion during abscission.","method":"In vitro binding assay, Co-IP, siRNA knockdown, immunofluorescence, microtubule-bundling assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay plus epistasis (centralspindlin→CEP55) and functional KD phenotype; 196 citations","pmids":["16790497"],"is_preprint":false},{"year":2006,"finding":"CEP55 homodimerizes (detected by co-immunoprecipitation) and localizes to the centrosome throughout mitosis and to the midbody during cytokinesis via coiled-coil domains. Overexpression does not affect microtubule nucleation.","method":"Co-immunoprecipitation, EGFP-fusion live imaging, immunofluorescence, nocodazole/taxol treatment","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP for homodimerization, localization well documented; moderate evidence","pmids":["16406728"],"is_preprint":false},{"year":2008,"finding":"CEP55 recruits both ESCRT-I (via TSG101) and ALIX to the midbody through its EABR (ESCRT and ALIX-binding region). Crystal structure at 2.0 Å shows EABR forms an asymmetric dimeric parallel coiled coil with a single binding site for ALIX or TSG101 GPPX3Y peptides that compete with each other. Both ALIX and ESCRT-I are required for cytokinesis, implying multiple CEP55 dimers are needed.","method":"X-ray crystallography (2.0 Å), biochemical competition assays, peptide binding","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biochemical reconstitution; 219 citations, strong evidence","pmids":["18948538"],"is_preprint":false},{"year":2009,"finding":"Pin1 (peptidyl-prolyl isomerase) binds to CEP55 at the midbody ring and promotes Plk1-mediated phosphorylation of CEP55, which is critical for cytokinesis. Pin1 KO MEFs show cytokinesis delay; Pin1 knockdown does not further worsen cytokinesis in CEP55-depleted cells, indicating they act in the same pathway.","method":"Pin1 KO mouse embryonic fibroblasts, HeLa siRNA depletion, epistasis analysis, immunofluorescence, Co-IP","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (double KD) plus Co-IP and KO cell phenotype","pmids":["19638580"],"is_preprint":false},{"year":2009,"finding":"CEP55 (FLJ10540) forms a complex with the p110-alpha catalytic subunit of PI3K and activates PI3K kinase activity, driving AKT phosphorylation and oncogenic cell transformation. Knockdown of CEP55 destabilizes the PI3K p110/p85 complex.","method":"Co-immunoprecipitation, PI3K kinase activity assay, siRNA knockdown, nude mouse tumorigenicity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vitro kinase assay, single lab but multiple methods","pmids":["19337377"],"is_preprint":false},{"year":2007,"finding":"CEP55 (FLJ10540) forms a complex with PI3K and activates PI3K activity, mediating oncogenic cell transformation via the PI3K/AKT pathway in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, PI3K kinase activity assay, anchorage-independent growth, nude mouse xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vitro kinase assay; independent replication of PI3K binding finding","pmids":["17237822"],"is_preprint":false},{"year":2009,"finding":"Pin1 promotes post-translational stabilization of CEP55 during mitosis; mutation of Pin1 binding sites or Plk1 phosphorylation site in CEP55 reduces its mitotic stability. Plk1 overexpression increases CEP55 levels, linking Pin1/Plk1 to CEP55 protein stability required for cytokinesis.","method":"siRNA knockdown, phosphorylation-site mutagenesis, immunoblotting for protein stability, Pin1 KO MEFs","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus Pin1 KO validation, single lab","pmids":["19855176"],"is_preprint":false},{"year":2010,"finding":"Plk1 phosphorylates CEP55 in trans during mitotic exit, preventing premature recruitment of CEP55 to the anaphase spindle. Only after Plk1 degradation can CEP55 target the midbody to promote abscission. A Plk1-site mutant of CEP55 is prematurely recruited to the anaphase spindle and fails to support abscission. Blocking Plk1 degradation prevents CEP55 midbody recruitment.","method":"Phosphomutant expression, Plk1 inhibitor treatment (BI2536, GW842862), live-cell imaging, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and genetic manipulation with defined cellular phenotype; 126 citations","pmids":["21079244"],"is_preprint":false},{"year":2010,"finding":"TEX14 uses a conserved GPPX3Y motif to bind strongly to CEP55 and block the same GPPX3Y motifs of ALIX and TSG101 from binding CEP55, thereby preventing abscission and establishing stable intercellular bridges in male germ cells. CEP55 is a stable component of the intercellular bridge in testes.","method":"Biochemical enrichment of intercellular bridges, Co-IP, competitive binding assay, TEX14 KO mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — competitive binding biochemistry plus genetic model; 68 citations","pmids":["20176808"],"is_preprint":false},{"year":2011,"finding":"p53 negatively regulates CEP55 protein stability and promoter activity through suppression of Plk1; Plk1 is a positive regulator of CEP55 post-translational stability. Overexpression of Plk1 or knockdown of p53 enhances CEP55 stability; the Plk1 inhibitor BI2356 prevents CEP55 accumulation in p53-depleted cells, defining a p53–Plk1–CEP55 regulatory axis.","method":"p53 overexpression/siRNA knockdown, Plk1 inhibitor, luciferase promoter assay, immunoblotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic and pharmacological interventions, single lab","pmids":["22184120"],"is_preprint":false},{"year":2012,"finding":"BRCA2 localizes to the midbody through interaction with Filamin A, where it facilitates formation of CEP55-ALIX and CEP55-TSG101 complexes and proper recruitment of ESCRT-associated proteins during abscission. Cancer-associated BRCA2 mutations disrupt these interactions and increase cytokinetic defects without affecting homologous recombination.","method":"Co-IP, siRNA knockdown, immunofluorescence, cancer mutation analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional KD phenotype, 71 citations","pmids":["22771033"],"is_preprint":false},{"year":2015,"finding":"In zebrafish, cep55 loss-of-function causes destabilization of Akt protein; constitutively active PIK3CA or AKT1 partially rescues cep55 mutant phenotype. Proteasome inhibitor MG132 also partially rescues, indicating CEP55 promotes Akt stability by protecting it from proteasomal degradation.","method":"Zebrafish cep55 nonsense mutant, morpholino knockdown, mRNA rescue, pharmacological rescue (MG132), constitutively active PI3K/AKT expression","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — genetic model plus multiple orthogonal rescue experiments","pmids":["25667221"],"is_preprint":false},{"year":2017,"finding":"A truncating mutation in CEP55 causes MARCH syndrome. The truncated protein fails to localize to the midbody, leading to abscission failure and multinucleated daughter cells. Full-length but not truncated CEP55 rescues zebrafish cep55l knockdown phenotypes.","method":"Exome sequencing, patient-derived cell immunofluorescence, zebrafish morpholino knockdown, mRNA rescue with full-length vs. truncated CEP55","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — human mutation + cellular localization defect + zebrafish rescue, multiple orthogonal methods","pmids":["28264986"],"is_preprint":false},{"year":2018,"finding":"iASPP acts as a PP1-targeting subunit that facilitates PP1-CEP55 interaction to remove Plk1-mediated Ser436 phosphorylation from CEP55 during late mitosis, enabling timely CEP55 recruitment to the midbody. iASPP depletion results in abnormal midbody structure and failed cytokinesis.","method":"Protein affinity purification, Co-IP, phospho-specific immunoblotting, siRNA knockdown with cytokinesis readout","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical Co-IP plus phosphorylation analysis and KD phenotype, single lab","pmids":["29743530"],"is_preprint":false},{"year":2018,"finding":"CEP55 overexpression dictates cell fate during perturbed mitosis; it is a downstream effector of the MEK1/2-MYC axis. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and caspase-dependent mitotic death. Blocking MEK1/2-PLK1 signaling reduces breast tumor outgrowth in vivo.","method":"CEP55 KD/overexpression in breast cancer cells and syngeneic mouse models, CDK1 activity assays, epistasis (MEK inhibitors, PLK1 inhibition)","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo tumor models plus mechanistic signaling pathway epistasis, single lab","pmids":["30108112"],"is_preprint":false},{"year":2018,"finding":"SPAG5 interacts with CEP55 (detected by Co-IP) to trigger phosphorylation of AKT at Ser473 and activate PI3K/AKT signaling in hepatocellular carcinoma. Inhibition of PI3K/AKT markedly attenuates SPAG5-mediated cell growth.","method":"Co-immunoprecipitation, AKT phosphorylation assay, in vitro/in vivo tumor models, PI3K/AKT inhibitor treatment","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP with functional follow-up, PI3K/AKT inhibitor rescue","pmids":["30089483"],"is_preprint":false},{"year":2018,"finding":"CEP55 overexpression in mice causes hyperactivation of PI3K/Akt signaling in testis, increased phosphorylation of FoxO1 suppressing its nuclear retention, enrichment of PLZF-positive undifferentiated spermatogonia, and progressive germ cell loss causing male sterility.","method":"Ubiquitous Cep55 transgenic mice, phospho-Akt/FoxO1 immunoblotting, immunofluorescence, gene expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo transgenic model with defined signaling mechanism, single lab","pmids":["29683733"],"is_preprint":false},{"year":2018,"finding":"CEP55 physically interacts with JAK2 and promotes its phosphorylation, activating downstream STAT3 signaling and target genes MMP2/9, thereby promoting HCC cell migration and invasion. Blocking JAK2 or STAT3 blunts the migration/invasion stimulated by CEP55 overexpression.","method":"Co-immunoprecipitation, phospho-JAK2/STAT3 immunoblotting, JAK2/STAT3 inhibitor rescue, transwell migration assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus pharmacological epistasis, single lab","pmids":["30096813"],"is_preprint":false},{"year":2019,"finding":"CEP55 contains two NEMO-like ubiquitin-binding domains (NOA, a dimeric coiled coil; ZF, a UBZ scaffold). Structure-guided mutations in either domain cause severe abscission defects in reconstituted CEP55-KD cells. The ZF domain's ubiquitin-receptor function can be replaced by other UBZ-family domains, indicating CEP55 participates in non-degradative ubiquitin signaling during cytokinetic abscission.","method":"In vitro domain characterization, structure-guided mutagenesis, CEP55 KD reconstitution assays, abscission phenotype readout","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1-2 — structural characterization plus functional mutagenesis and cellular reconstitution, single lab","pmids":["31605944"],"is_preprint":false},{"year":2019,"finding":"CEP55 depletion during meiotic anaphase I in mouse oocytes causes persistent Cdk1 activity due to inadequate inhibitory Cdk1 phosphorylation consequent on failure to suppress Cdc25 phosphatase, identifying a proteolysis-independent step required for anaphase I exit.","method":"siRNA injection in mouse oocytes, Cdk1 kinase activity assay, Cdc25 analysis, live imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with biochemical readout in primary oocytes, single lab","pmids":["31427428"],"is_preprint":false},{"year":2020,"finding":"Cep55 knockout mice show that Cep55 is dispensable for most somatic cell divisions but required specifically for neural progenitor cell (NPC) abscission and survival. Cep55 facilitates ESCRT recruitment and timely microtubule disassembly during abscission in NPCs. Binucleate NPCs (but not fibroblasts) elevate p53 and undergo apoptosis; double KO of p53 and Cep55 blocks apoptosis but only partially rescues brain size.","method":"Cep55 and p53/Cep55 double-KO mice, quantitative abscission assays in fixed and live NSCs, ESCRT localization, p53/apoptosis analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO model with quantitative cellular assays and genetic epistasis (double KO), multiple orthogonal methods","pmids":["32269212"],"is_preprint":false},{"year":2020,"finding":"Cep55 overexpression in MEFs compromises the Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, and a prolonged aberrant mitosis. PI3K/Akt inhibition or expression of Akt-insensitive Chk1 (S280A) rescues this phenotype, placing Cep55→Pi3k/Akt→Chk1 in a pathway regulating genomic stability. Cep55 overexpression also causes microtubule stabilization.","method":"Cep55 transgenic MEFs, Chk1 phosphorylation assay, DNA fiber assay, pharmacological PI3K/Akt inhibition, Chk1 S280A mutant rescue","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic model with multiple mechanistic readouts and rescue experiments, single lab","pmids":["33087841"],"is_preprint":false},{"year":2021,"finding":"CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase through facilitation of the chaperonin CCT complex to Aurora A. Cep55-/- mice exhibit abnormally elongated cilia and Meckel-Gruber syndrome features. CEP55 mutations in MKS cause failure of cilia disassembly.","method":"Cep55 KO mice, Co-IP of CEP55 with Aurora A and CCT complex, cilia length measurement, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO plus Co-IP and mechanistic dissection with CCT chaperonin, multiple methods","pmids":["33475699"],"is_preprint":false},{"year":2021,"finding":"Loss of Cep55 in mouse cortical NSCs causes abscission defects (increased failure rate and slowed abscission), and binucleate NSCs activate p53-dependent apoptosis. Most NSCs complete abscission without Cep55, but failures trigger a cell-type-specific p53 response not seen in fibroblasts.","method":"Cep55 KO and p53/Cep55 double-KO mice, quantitative live and fixed abscission assays, p53/apoptosis immunostaining","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO model with quantitative cellular analysis and genetic epistasis","pmids":["33622776"],"is_preprint":false},{"year":2016,"finding":"Integrin-mediated FAK-Src signaling decelerates PLK1 degradation at the midbody, thereby controlling the timing of CEP55 accumulation and subsequent ALIX/TSG101/CHMP4B (ESCRT-III) recruitment. In non-adherent cells, PLK1 disappears more rapidly and CEP55 cannot efficiently recruit ESCRT components, causing abscission failure.","method":"FAK/Src inhibitor treatment, PLK1 inhibition, immunofluorescence of midbody proteins, adherent vs. non-adherent cell comparison","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis plus localization analysis, single lab","pmids":["27127172"],"is_preprint":false},{"year":2022,"finding":"NEDD4L ubiquitinates CEP55 and promotes its degradation; M2-macrophage-derived exosomal miR-342-3p suppresses NEDD4L, thereby elevating CEP55 protein via reduced ubiquitination and activating the PI3K/AKT/mTOR pathway in renal cell carcinoma.","method":"Ubiquitination assay, miR-342-3p/NEDD4L luciferase reporter, Co-IP, in vivo xenograft","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 — ubiquitination assay with regulatory pathway delineation, single lab","pmids":["37305161"],"is_preprint":false},{"year":2021,"finding":"CEP55 loading into exosomes does not occur via canonical early-to-late endosome trafficking but instead through Alix-mediated recruitment to secretory CD63-positive late endosomes. Mutation of the CEP55-Alix interaction site strongly reduces CEP55 dot formation and CEP55 presence in extracellular vesicles.","method":"High-resolution microscopy, EGFP-CEP55 trafficking analysis, Rab5/Rab7/CD63 marker co-localization, CEP55-Alix interaction-site mutagenesis","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging plus mutagenesis of interaction site, single lab","pmids":["39976236"],"is_preprint":false},{"year":2021,"finding":"UXT is a novel TSG101-interacting protein; CEP55 is recruited to TSG101-containing cytoplasmic vesicles and degraded via the lysosome pathway. UXT depletion promotes TSG101 vesicle-lysosome association and enhances CEP55 degradation upon TSG101 overexpression.","method":"Co-IP, lysosome inhibitor treatment, immunofluorescence, siRNA depletion","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/localization study, single lab","pmids":["33486193"],"is_preprint":false},{"year":2023,"finding":"α-catenin physically interacts with CEP55 in the cytoplasm of HCC cells (identified by BioID mass spectrometry and confirmed by Co-IP and proximity ligation), stabilizing CEP55 protein. CEP55 is also transcriptionally induced by a FoxM1/TEAD/YAP complex. CEP55 supports HCC cell migration in conjunction with α-catenin but does not affect proliferation.","method":"BioID proximity labeling + mass spectrometry, Co-IP, proximity ligation assay, chromatin immunoprecipitation, siRNA knockdown","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — BioID discovery plus Co-IP/PLA validation and ChIP for transcriptional regulation, single lab","pmids":["37381005"],"is_preprint":false},{"year":2025,"finding":"USP8 deubiquitinates CEP55 to maintain its protein stability; CEP55 binds to CHMP6 (confirmed by Co-IP) and promotes its expression, thereby facilitating ferroptosis resistance and macrophage M2 polarization in TNBC. USP8 knockdown effects on tumor growth are reversed by CEP55 overexpression.","method":"Ubiquitination/deubiquitination assay, Co-IP, siRNA knockdown, flow cytometry (ferroptosis markers, macrophage polarization), xenograft model","journal":"Clinical breast cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination assay plus Co-IP and in vivo rescue, single lab","pmids":["40925844"],"is_preprint":false},{"year":2025,"finding":"ILF3 stabilizes CEP55 mRNA (confirmed by RIP and mRNA stability assay), maintaining CEP55 protein levels in breast cancer cells. ILF3 depletion reduces CEP55 expression, impairs cell growth and invasion, and promotes ferroptosis; CEP55 restoration rescues these effects.","method":"RNA immunoprecipitation (RIP), CEP55 mRNA stability assay, siRNA knockdown, xenograft model","journal":"Hereditas","confidence":"Medium","confidence_rationale":"Tier 2 — RIP plus mRNA stability assay and functional rescue, single lab","pmids":["39871389"],"is_preprint":false},{"year":2025,"finding":"CEP55 promotes resistance to cisplatin in prostate cancer by regulating CDK1 phosphorylation at Tyr15, driving neuroendocrine differentiation. CEP55 overexpression enhances NEPC biomarker expression; knockdown reduces proliferation and invasiveness.","method":"scRNA-seq analysis, in vitro/in vivo CEP55 KD/overexpression, CDK1 Tyr15 phosphorylation immunoblot, clinical sample validation","journal":"Cancer pathogenesis and therapy","confidence":"Low","confidence_rationale":"Tier 3 — CDK1 phosphorylation readout without direct kinase-CEP55 mechanistic assay, single lab","pmids":["41403895"],"is_preprint":false}],"current_model":"CEP55 is a coiled-coil centrosomal protein that, upon mitotic entry, is phosphorylated by Erk2/Cdk1 (at S425/428) enabling Plk1 interaction and subsequent S436 phosphorylation, which is then dephosphorylated by iASPP-PP1; this phosphorylation cycle—kept in check by Pin1 and negatively regulated by p53 via Plk1—controls the precise timing of CEP55 recruitment to the midbody, where its dimeric EABR domain sequentially recruits ALIX and ESCRT-I (TSG101) in a competitive manner to drive ESCRT-III-mediated membrane abscission; in male germ cells, TEX14 competes with ALIX/TSG101 for the same CEP55 binding site to arrest abscission and form stable intercellular bridges; beyond cytokinesis, CEP55 activates PI3K/AKT signaling by forming a complex with PI3K and stabilizing AKT against proteasomal degradation, and promotes cilia disassembly by stabilizing Aurora A kinase through the CCT chaperonin complex."},"narrative":{"teleology":[{"year":2005,"claim":"The first mechanistic study established that CEP55 is a centrosomal protein whose sequential phosphorylation by Erk2/Cdk1 and Plk1 drives its mitotic redistribution to the midbody and is essential for cytokinesis, answering how CEP55 dynamics are controlled across the cell cycle.","evidence":"Site-directed mutagenesis of S425/S428/S436, in vitro kinase assays, siRNA knockdown with cytokinesis readout in HeLa cells","pmids":["16198290"],"confidence":"High","gaps":["Upstream signal triggering Erk2/Cdk1 phosphorylation of CEP55 at mitotic entry was not defined","No structural basis for how phosphorylation alters CEP55 centrosome association"]},{"year":2006,"claim":"Identification of centralspindlin (MKLP1–MgcRacGAP) as the midbody-targeting platform for CEP55 established the epistatic hierarchy: centralspindlin recruits CEP55, which in turn organizes the Flemming body and v-SNARE trafficking for abscission.","evidence":"Direct in vitro binding of CEP55 to MKLP1, siRNA epistasis (centralspindlin KD abolishes CEP55 midbody localization), microtubule-bundling assay","pmids":["16790497"],"confidence":"High","gaps":["Whether CEP55 microtubule-bundling activity is required for abscission was not tested","Structural basis of CEP55–MKLP1 interaction unresolved"]},{"year":2007,"claim":"Discovery that CEP55 forms a complex with PI3K p110α and activates PI3K/AKT signaling revealed a cytokinesis-independent oncogenic function, later validated in multiple cancer types.","evidence":"Co-IP of CEP55 with PI3K, in vitro PI3K kinase assay, nude mouse xenograft in HCC cells","pmids":["17237822","19337377"],"confidence":"Medium","gaps":["Direct binding domain on CEP55 for PI3K not mapped","Whether PI3K activation requires CEP55 midbody localization or occurs independently was not determined"]},{"year":2008,"claim":"The crystal structure of the CEP55 EABR domain revealed the structural basis for ESCRT recruitment: an asymmetric dimeric coiled coil presents a single GPPX3Y-binding groove that competitively accommodates ALIX or TSG101, explaining why multiple CEP55 dimers are needed for abscission.","evidence":"X-ray crystallography at 2.0 Å resolution, biochemical competition assays with ALIX and TSG101 peptides","pmids":["18948538"],"confidence":"High","gaps":["How full-length CEP55 oligomerizes at the midbody ring to provide multiple binding sites was not resolved","No structure of the N-terminal or central coiled-coil regions"]},{"year":2009,"claim":"Pin1 was identified as a co-factor that promotes Plk1-mediated phosphorylation and post-translational stabilization of CEP55 during mitosis, placing Pin1 in the same cytokinesis pathway as CEP55 through genetic epistasis.","evidence":"Pin1 KO MEFs, double-knockdown epistasis in HeLa, phosphorylation-site mutagenesis","pmids":["19638580","19855176"],"confidence":"High","gaps":["Specific isomerization event (cis/trans conversion) on CEP55 was not demonstrated biochemically","Whether Pin1 acts catalytically or as a scaffold was unclear"]},{"year":2010,"claim":"Two studies resolved complementary aspects of CEP55 timing: Plk1 phosphorylation acts as a negative gate preventing premature CEP55 midbody recruitment until Plk1 is degraded at mitotic exit, while in male germ cells TEX14 hijacks the EABR binding site to permanently block ESCRT recruitment and maintain intercellular bridges.","evidence":"Plk1 phosphomutant expression and Plk1 inhibitor live imaging (abscission); TEX14 competitive binding assay and Tex14 KO mice (intercellular bridges)","pmids":["21079244","20176808"],"confidence":"High","gaps":["How Plk1 degradation kinetics differ between cell types was not explored","Whether TEX14 competition is regulated during spermatogenesis was unknown"]},{"year":2011,"claim":"A p53–Plk1–CEP55 regulatory axis was defined: p53 suppresses both CEP55 transcription and Plk1-dependent CEP55 protein stability, linking tumor suppressor loss to CEP55 overexpression in cancer.","evidence":"p53 overexpression/siRNA, Plk1 inhibitor BI2356, luciferase promoter assay, immunoblotting in HCC cells","pmids":["22184120"],"confidence":"Medium","gaps":["Whether p53 directly binds the CEP55 promoter or acts indirectly was not resolved","Contribution of transcriptional vs. post-translational regulation in vivo not quantified"]},{"year":2012,"claim":"BRCA2 was shown to facilitate CEP55–ALIX and CEP55–TSG101 complex formation at the midbody, establishing that cancer-associated BRCA2 mutations disrupt cytokinesis independently of homologous recombination.","evidence":"Reciprocal Co-IP, siRNA knockdown, cancer mutation analysis, immunofluorescence in HeLa cells","pmids":["22771033"],"confidence":"High","gaps":["Mechanism by which BRCA2 promotes CEP55–ESCRT interaction (scaffolding vs. conformational) unresolved","Whether BRCA2-dependent abscission defects contribute to tumorigenesis in vivo was not tested"]},{"year":2015,"claim":"Zebrafish cep55 mutants demonstrated that CEP55 stabilizes AKT protein against proteasomal degradation in vivo, with constitutively active PI3K/AKT or proteasome inhibition partially rescuing the mutant phenotype.","evidence":"Zebrafish cep55 nonsense mutant, MG132 and constitutively active PIK3CA/AKT1 mRNA rescue","pmids":["25667221"],"confidence":"High","gaps":["Direct physical mechanism by which CEP55 shields AKT from ubiquitin-proteasome degradation not defined","Which E3 ligase targets AKT in the absence of CEP55 was unknown"]},{"year":2017,"claim":"Identification of a causative CEP55 truncation in MARCH syndrome patients proved that human CEP55 is essential for brain development; the truncated protein fails to reach the midbody and causes multinucleation.","evidence":"Exome sequencing of affected families, patient-derived cell immunofluorescence, zebrafish cep55l morpholino rescue with full-length vs. truncated CEP55","pmids":["28264986"],"confidence":"High","gaps":["Whether partial CEP55 function persists in heterozygous carriers was not assessed","Genotype–phenotype correlation across different CEP55 mutations not established"]},{"year":2018,"claim":"Multiple discoveries in 2018 expanded the regulatory and signaling landscape: iASPP-PP1 dephosphorylates CEP55 S436 to enable midbody recruitment; CEP55 signals through JAK2–STAT3 and interacts with SPAG5 to activate AKT; and CEP55 is a downstream effector of MEK1/2–MYC influencing mitotic cell fate in breast cancer.","evidence":"iASPP–PP1 Co-IP and phospho-specific blotting; JAK2 and SPAG5 Co-IP with inhibitor rescue; CEP55 KD/overexpression in breast cancer syngeneic models with MEK/PLK1 epistasis","pmids":["29743530","30096813","30089483","30108112"],"confidence":"Medium","gaps":["JAK2 and SPAG5 interactions each rely on single Co-IP studies","Whether iASPP-PP1 specificity for CEP55 S436 extends to other Plk1 substrates was untested","Relative contribution of PI3K/AKT vs. JAK2/STAT3 arms to CEP55 oncogenic function unclear"]},{"year":2019,"claim":"Structure–function analysis identified two NEMO-like ubiquitin-binding domains (NOA and ZF) in CEP55 that are essential for abscission, establishing that CEP55 participates in non-degradative ubiquitin signaling at the midbody.","evidence":"In vitro domain characterization, structure-guided mutagenesis, CEP55 KD reconstitution with abscission readout","pmids":["31605944"],"confidence":"Medium","gaps":["Identity of the ubiquitinated target(s) recognized by CEP55 UBDs at the midbody is unknown","Structural model of full-length CEP55 including both UBDs and EABR not available"]},{"year":2020,"claim":"Cep55 knockout mice revealed that CEP55 is dispensable for most somatic cell divisions but essential in neural progenitor cells, where abscission failure triggers a cell-type-specific p53-dependent apoptosis that drives microcephaly.","evidence":"Cep55 KO and Cep55/p53 double-KO mice, quantitative live abscission assays in NSCs vs. fibroblasts, ESCRT localization","pmids":["32269212","33622776"],"confidence":"High","gaps":["Why NPCs but not fibroblasts require CEP55 for abscission is mechanistically unexplained","Alternative abscission machinery compensating in fibroblasts not identified"]},{"year":2021,"claim":"A cilia-regulatory function was uncovered: CEP55 stabilizes Aurora A kinase by facilitating its association with the CCT chaperonin complex, and Cep55-null mice display elongated cilia and Meckel–Gruber syndrome features, linking CEP55 to ciliopathy.","evidence":"Cep55 KO mice, Co-IP of CEP55 with Aurora A and CCT subunits, cilia length quantification","pmids":["33475699"],"confidence":"High","gaps":["Whether CEP55 directly contacts CCT or acts as an adaptor bringing Aurora A to CCT is not resolved","How CEP55 subcellular pool at centrosomes vs. midbody differentially controls cilia vs. abscission is unclear"]},{"year":2022,"claim":"NEDD4L was identified as an E3 ubiquitin ligase targeting CEP55 for degradation, with the miR-342-3p/NEDD4L axis regulating CEP55 protein levels and downstream PI3K/AKT/mTOR signaling in renal cell carcinoma.","evidence":"Ubiquitination assay, miR-342-3p/NEDD4L luciferase reporter, xenograft rescue","pmids":["37305161"],"confidence":"Medium","gaps":["Specific lysine residues on CEP55 ubiquitinated by NEDD4L not mapped","Whether NEDD4L-mediated degradation is cell-cycle-regulated was not tested"]},{"year":2025,"claim":"Recent work identified USP8 as a deubiquitinase stabilizing CEP55 and showed CEP55 binds CHMP6 (ESCRT-III) to promote ferroptosis resistance, while ILF3 stabilizes CEP55 mRNA, broadening the regulatory inputs controlling CEP55 abundance.","evidence":"USP8 deubiquitination assay, CEP55–CHMP6 Co-IP, xenograft rescue; ILF3 RIP and mRNA stability assay in breast cancer cells","pmids":["40925844","39871389"],"confidence":"Medium","gaps":["CEP55–CHMP6 interaction confirmed by single Co-IP only","Whether ferroptosis resistance is a direct consequence of ESCRT function or PI3K/AKT signaling is undetermined","ILF3-CEP55 mRNA interaction site not mapped"]},{"year":null,"claim":"Key open questions include why neural progenitor cells uniquely depend on CEP55 for abscission while most somatic cells do not, what the ubiquitinated substrates recognized by CEP55's UBDs are, and how CEP55's cytokinetic and PI3K/AKT signaling functions are coordinated in space and time.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of full-length CEP55 exists","Alternative abscission machinery in CEP55-independent cells not identified","Ubiquitin targets of CEP55 UBDs at the midbody unknown","Spatial segregation of cytokinetic vs. signaling pools of CEP55 not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,9,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,12,17]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,3,8,14,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,12,16,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[23]}],"complexes":["centralspindlin (MKLP1–MgcRacGAP)","ESCRT-I (via TSG101)","ESCRT-III (via CHMP6)"],"partners":["MKLP1","TSG101","ALIX","PLK1","TEX14","AURKA","PIK3CA","IASPP"],"other_free_text":[]},"mechanistic_narrative":"CEP55 is a coiled-coil centrosomal and midbody protein that serves as the master recruiter of the ESCRT membrane-scission machinery during cytokinetic abscission and additionally functions in PI3K/AKT signaling and cilia disassembly. During interphase CEP55 resides at the mother centriole; sequential phosphorylation by Erk2/Cdk1 (S425/S428) and Plk1 (S436), modulated by Pin1-dependent isomerization and iASPP-PP1-mediated dephosphorylation, controls its timely release from centrosomes and recruitment to the midbody via the centralspindlin complex (MKLP1–MgcRacGAP), where its dimeric EABR domain competitively binds ALIX and TSG101 through GPPX3Y motifs to nucleate ESCRT-III–dependent membrane abscission [PMID:16198290, PMID:18948538, PMID:21079244, PMID:29743530, PMID:16790497]. Cep55 knockout mice reveal that most somatic cells complete abscission without CEP55, but neural progenitor cells are uniquely dependent on it—binucleate NPCs activate p53-dependent apoptosis—and Cep55-null mice also display abnormally elongated cilia owing to impaired Aurora A stabilization via the CCT chaperonin complex [PMID:32269212, PMID:33475699]. Loss-of-function mutations in CEP55 cause MARCH syndrome (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, hydranencephaly), attributable to failed midbody localization and abscission [PMID:28264986]."},"prefetch_data":{"uniprot":{"accession":"Q53EZ4","full_name":"Centrosomal protein of 55 kDa","aliases":["Up-regulated in colon cancer 6"],"length_aa":464,"mass_kda":54.2,"function":"Plays a role in mitotic exit and cytokinesis (PubMed:16198290, PubMed:17853893). Recruits PDCD6IP and TSG101 to midbody during cytokinesis. Required for successful completion of cytokinesis (PubMed:17853893). Not required for microtubule nucleation (PubMed:16198290). Plays a role in the development of the brain and kidney (PubMed:28264986)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cleavage furrow; Midbody, Midbody ring; Midbody","url":"https://www.uniprot.org/uniprotkb/Q53EZ4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP55","classification":"Not Classified","n_dependent_lines":324,"n_total_lines":1208,"dependency_fraction":0.2682119205298013},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CKAP2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"MVB12A","stoichiometry":0.2},{"gene":"PDCD6IP","stoichiometry":0.2},{"gene":"TSG101","stoichiometry":0.2},{"gene":"VPS28","stoichiometry":0.2},{"gene":"VPS37B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CEP55","total_profiled":1310},"omim":[{"mim_id":"610000","title":"CENTROSOMAL PROTEIN, 55-KD; CEP55","url":"https://www.omim.org/entry/610000"},{"mim_id":"608074","title":"PROGRAMMED CELL DEATH 6-INTERACTING PROTEIN; PDCD6IP","url":"https://www.omim.org/entry/608074"},{"mim_id":"605792","title":"TESTIS-EXPRESSED GENE 14; TEX14","url":"https://www.omim.org/entry/605792"},{"mim_id":"605064","title":"KINESIN FAMILY MEMBER 23; KIF23","url":"https://www.omim.org/entry/605064"},{"mim_id":"601387","title":"TUMOR SUSCEPTIBILITY GENE 101; TSG101","url":"https://www.omim.org/entry/601387"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Centriolar satellite","reliability":"Uncertain"},{"location":"Midbody","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":25.5},{"tissue":"testis","ntpm":20.3}],"url":"https://www.proteinatlas.org/search/CEP55"},"hgnc":{"alias_symbol":["FLJ10540","CT111"],"prev_symbol":["C10orf3"]},"alphafold":{"accession":"Q53EZ4","domains":[{"cath_id":"-","chopping":"107-152_166-214_228-350","consensus_level":"medium","plddt":93.5715,"start":107,"end":350},{"cath_id":"1.10.287","chopping":"29-96","consensus_level":"medium","plddt":85.7994,"start":29,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EZ4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EZ4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EZ4-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP55","jax_strain_url":"https://www.jax.org/strain/search?query=CEP55"},"sequence":{"accession":"Q53EZ4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EZ4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EZ4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EZ4"}},"corpus_meta":[{"pmid":"16198290","id":"PMC_16198290","title":"Cdk1/Erk2- 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targets of FOXM1: CEP55 and HELLS are cancer progression markers of head and neck squamous cell carcinoma.","date":"2010","source":"Oral oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20400365","citation_count":79,"is_preprint":false},{"pmid":"19609239","id":"PMC_19609239","title":"Cep55/c10orf3, a tumor antigen derived from a centrosome residing protein in breast carcinoma.","date":"2009","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/19609239","citation_count":78,"is_preprint":false},{"pmid":"16406728","id":"PMC_16406728","title":"The novel centrosomal associated protein CEP55 is present in the spindle midzone and the midbody.","date":"2006","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/16406728","citation_count":72,"is_preprint":false},{"pmid":"19525975","id":"PMC_19525975","title":"Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31920335","citation_count":60,"is_preprint":false},{"pmid":"30607788","id":"PMC_30607788","title":"CEP55 promotes epithelial-mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway.","date":"2019","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/30607788","citation_count":55,"is_preprint":false},{"pmid":"28264986","id":"PMC_28264986","title":"A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28264986","citation_count":51,"is_preprint":false},{"pmid":"26902787","id":"PMC_26902787","title":"Lentivirus-mediated knockdown of CEP55 suppresses cell proliferation of breast cancer cells.","date":"2016","source":"Bioscience 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Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29800603","citation_count":45,"is_preprint":false},{"pmid":"29683733","id":"PMC_29683733","title":"Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29683733","citation_count":45,"is_preprint":false},{"pmid":"30096813","id":"PMC_30096813","title":"CEP55 Promotes Cell Motility via JAK2⁻STAT3⁻MMPs Cascade in Hepatocellular Carcinoma.","date":"2018","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30096813","citation_count":44,"is_preprint":false},{"pmid":"32269212","id":"PMC_32269212","title":"Cep55 promotes cytokinesis of neural progenitors but is dispensable for most mammalian cell divisions.","date":"2020","source":"Nature 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Erk2/Cdk1-dependent phosphorylation at S425 and S428 triggers centrosome dissociation at mitotic entry. S425/428 phosphorylation enables interaction with Plk1, which then phosphorylates CEP55 at S436. This phosphorylation cascade is required for CEP55 recruitment to the midbody and completion of cytokinesis; phosphorylation-deficient mutants cause cytokinesis failure.\",\n      \"method\": \"Site-directed mutagenesis, in vitro kinase assays, Co-IP, siRNA knockdown with cytokinesis readout, immunofluorescence localization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assays and mutagenesis combined with cellular phenotype, foundational paper with 271 citations\",\n      \"pmids\": [\"16198290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CEP55 directly binds MKLP1 in vitro and associates with the MKLP1-MgcRacGAP centralspindlin complex in vivo. CEP55 is a microtubule-bundling protein. Knockdown of centralspindlin abolishes CEP55 localization to the spindle midzone, placing CEP55 downstream of centralspindlin. CEP55 depletion causes absence of the Flemming body and mislocalization of midbody components, and controls endobrevin (v-SNARE) localization for membrane fusion during abscission.\",\n      \"method\": \"In vitro binding assay, Co-IP, siRNA knockdown, immunofluorescence, microtubule-bundling assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay plus epistasis (centralspindlin→CEP55) and functional KD phenotype; 196 citations\",\n      \"pmids\": [\"16790497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CEP55 homodimerizes (detected by co-immunoprecipitation) and localizes to the centrosome throughout mitosis and to the midbody during cytokinesis via coiled-coil domains. Overexpression does not affect microtubule nucleation.\",\n      \"method\": \"Co-immunoprecipitation, EGFP-fusion live imaging, immunofluorescence, nocodazole/taxol treatment\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP for homodimerization, localization well documented; moderate evidence\",\n      \"pmids\": [\"16406728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CEP55 recruits both ESCRT-I (via TSG101) and ALIX to the midbody through its EABR (ESCRT and ALIX-binding region). Crystal structure at 2.0 Å shows EABR forms an asymmetric dimeric parallel coiled coil with a single binding site for ALIX or TSG101 GPPX3Y peptides that compete with each other. Both ALIX and ESCRT-I are required for cytokinesis, implying multiple CEP55 dimers are needed.\",\n      \"method\": \"X-ray crystallography (2.0 Å), biochemical competition assays, peptide binding\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical reconstitution; 219 citations, strong evidence\",\n      \"pmids\": [\"18948538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Pin1 (peptidyl-prolyl isomerase) binds to CEP55 at the midbody ring and promotes Plk1-mediated phosphorylation of CEP55, which is critical for cytokinesis. Pin1 KO MEFs show cytokinesis delay; Pin1 knockdown does not further worsen cytokinesis in CEP55-depleted cells, indicating they act in the same pathway.\",\n      \"method\": \"Pin1 KO mouse embryonic fibroblasts, HeLa siRNA depletion, epistasis analysis, immunofluorescence, Co-IP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (double KD) plus Co-IP and KO cell phenotype\",\n      \"pmids\": [\"19638580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CEP55 (FLJ10540) forms a complex with the p110-alpha catalytic subunit of PI3K and activates PI3K kinase activity, driving AKT phosphorylation and oncogenic cell transformation. Knockdown of CEP55 destabilizes the PI3K p110/p85 complex.\",\n      \"method\": \"Co-immunoprecipitation, PI3K kinase activity assay, siRNA knockdown, nude mouse tumorigenicity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vitro kinase assay, single lab but multiple methods\",\n      \"pmids\": [\"19337377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEP55 (FLJ10540) forms a complex with PI3K and activates PI3K activity, mediating oncogenic cell transformation via the PI3K/AKT pathway in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, PI3K kinase activity assay, anchorage-independent growth, nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vitro kinase assay; independent replication of PI3K binding finding\",\n      \"pmids\": [\"17237822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Pin1 promotes post-translational stabilization of CEP55 during mitosis; mutation of Pin1 binding sites or Plk1 phosphorylation site in CEP55 reduces its mitotic stability. Plk1 overexpression increases CEP55 levels, linking Pin1/Plk1 to CEP55 protein stability required for cytokinesis.\",\n      \"method\": \"siRNA knockdown, phosphorylation-site mutagenesis, immunoblotting for protein stability, Pin1 KO MEFs\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus Pin1 KO validation, single lab\",\n      \"pmids\": [\"19855176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Plk1 phosphorylates CEP55 in trans during mitotic exit, preventing premature recruitment of CEP55 to the anaphase spindle. Only after Plk1 degradation can CEP55 target the midbody to promote abscission. A Plk1-site mutant of CEP55 is prematurely recruited to the anaphase spindle and fails to support abscission. Blocking Plk1 degradation prevents CEP55 midbody recruitment.\",\n      \"method\": \"Phosphomutant expression, Plk1 inhibitor treatment (BI2536, GW842862), live-cell imaging, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic manipulation with defined cellular phenotype; 126 citations\",\n      \"pmids\": [\"21079244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TEX14 uses a conserved GPPX3Y motif to bind strongly to CEP55 and block the same GPPX3Y motifs of ALIX and TSG101 from binding CEP55, thereby preventing abscission and establishing stable intercellular bridges in male germ cells. CEP55 is a stable component of the intercellular bridge in testes.\",\n      \"method\": \"Biochemical enrichment of intercellular bridges, Co-IP, competitive binding assay, TEX14 KO mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding biochemistry plus genetic model; 68 citations\",\n      \"pmids\": [\"20176808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p53 negatively regulates CEP55 protein stability and promoter activity through suppression of Plk1; Plk1 is a positive regulator of CEP55 post-translational stability. Overexpression of Plk1 or knockdown of p53 enhances CEP55 stability; the Plk1 inhibitor BI2356 prevents CEP55 accumulation in p53-depleted cells, defining a p53–Plk1–CEP55 regulatory axis.\",\n      \"method\": \"p53 overexpression/siRNA knockdown, Plk1 inhibitor, luciferase promoter assay, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological interventions, single lab\",\n      \"pmids\": [\"22184120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BRCA2 localizes to the midbody through interaction with Filamin A, where it facilitates formation of CEP55-ALIX and CEP55-TSG101 complexes and proper recruitment of ESCRT-associated proteins during abscission. Cancer-associated BRCA2 mutations disrupt these interactions and increase cytokinetic defects without affecting homologous recombination.\",\n      \"method\": \"Co-IP, siRNA knockdown, immunofluorescence, cancer mutation analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional KD phenotype, 71 citations\",\n      \"pmids\": [\"22771033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In zebrafish, cep55 loss-of-function causes destabilization of Akt protein; constitutively active PIK3CA or AKT1 partially rescues cep55 mutant phenotype. Proteasome inhibitor MG132 also partially rescues, indicating CEP55 promotes Akt stability by protecting it from proteasomal degradation.\",\n      \"method\": \"Zebrafish cep55 nonsense mutant, morpholino knockdown, mRNA rescue, pharmacological rescue (MG132), constitutively active PI3K/AKT expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic model plus multiple orthogonal rescue experiments\",\n      \"pmids\": [\"25667221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A truncating mutation in CEP55 causes MARCH syndrome. The truncated protein fails to localize to the midbody, leading to abscission failure and multinucleated daughter cells. Full-length but not truncated CEP55 rescues zebrafish cep55l knockdown phenotypes.\",\n      \"method\": \"Exome sequencing, patient-derived cell immunofluorescence, zebrafish morpholino knockdown, mRNA rescue with full-length vs. truncated CEP55\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human mutation + cellular localization defect + zebrafish rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28264986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"iASPP acts as a PP1-targeting subunit that facilitates PP1-CEP55 interaction to remove Plk1-mediated Ser436 phosphorylation from CEP55 during late mitosis, enabling timely CEP55 recruitment to the midbody. iASPP depletion results in abnormal midbody structure and failed cytokinesis.\",\n      \"method\": \"Protein affinity purification, Co-IP, phospho-specific immunoblotting, siRNA knockdown with cytokinesis readout\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical Co-IP plus phosphorylation analysis and KD phenotype, single lab\",\n      \"pmids\": [\"29743530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP55 overexpression dictates cell fate during perturbed mitosis; it is a downstream effector of the MEK1/2-MYC axis. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and caspase-dependent mitotic death. Blocking MEK1/2-PLK1 signaling reduces breast tumor outgrowth in vivo.\",\n      \"method\": \"CEP55 KD/overexpression in breast cancer cells and syngeneic mouse models, CDK1 activity assays, epistasis (MEK inhibitors, PLK1 inhibition)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tumor models plus mechanistic signaling pathway epistasis, single lab\",\n      \"pmids\": [\"30108112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG5 interacts with CEP55 (detected by Co-IP) to trigger phosphorylation of AKT at Ser473 and activate PI3K/AKT signaling in hepatocellular carcinoma. Inhibition of PI3K/AKT markedly attenuates SPAG5-mediated cell growth.\",\n      \"method\": \"Co-immunoprecipitation, AKT phosphorylation assay, in vitro/in vivo tumor models, PI3K/AKT inhibitor treatment\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional follow-up, PI3K/AKT inhibitor rescue\",\n      \"pmids\": [\"30089483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP55 overexpression in mice causes hyperactivation of PI3K/Akt signaling in testis, increased phosphorylation of FoxO1 suppressing its nuclear retention, enrichment of PLZF-positive undifferentiated spermatogonia, and progressive germ cell loss causing male sterility.\",\n      \"method\": \"Ubiquitous Cep55 transgenic mice, phospho-Akt/FoxO1 immunoblotting, immunofluorescence, gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with defined signaling mechanism, single lab\",\n      \"pmids\": [\"29683733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP55 physically interacts with JAK2 and promotes its phosphorylation, activating downstream STAT3 signaling and target genes MMP2/9, thereby promoting HCC cell migration and invasion. Blocking JAK2 or STAT3 blunts the migration/invasion stimulated by CEP55 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, phospho-JAK2/STAT3 immunoblotting, JAK2/STAT3 inhibitor rescue, transwell migration assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"30096813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP55 contains two NEMO-like ubiquitin-binding domains (NOA, a dimeric coiled coil; ZF, a UBZ scaffold). Structure-guided mutations in either domain cause severe abscission defects in reconstituted CEP55-KD cells. The ZF domain's ubiquitin-receptor function can be replaced by other UBZ-family domains, indicating CEP55 participates in non-degradative ubiquitin signaling during cytokinetic abscission.\",\n      \"method\": \"In vitro domain characterization, structure-guided mutagenesis, CEP55 KD reconstitution assays, abscission phenotype readout\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structural characterization plus functional mutagenesis and cellular reconstitution, single lab\",\n      \"pmids\": [\"31605944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP55 depletion during meiotic anaphase I in mouse oocytes causes persistent Cdk1 activity due to inadequate inhibitory Cdk1 phosphorylation consequent on failure to suppress Cdc25 phosphatase, identifying a proteolysis-independent step required for anaphase I exit.\",\n      \"method\": \"siRNA injection in mouse oocytes, Cdk1 kinase activity assay, Cdc25 analysis, live imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with biochemical readout in primary oocytes, single lab\",\n      \"pmids\": [\"31427428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cep55 knockout mice show that Cep55 is dispensable for most somatic cell divisions but required specifically for neural progenitor cell (NPC) abscission and survival. Cep55 facilitates ESCRT recruitment and timely microtubule disassembly during abscission in NPCs. Binucleate NPCs (but not fibroblasts) elevate p53 and undergo apoptosis; double KO of p53 and Cep55 blocks apoptosis but only partially rescues brain size.\",\n      \"method\": \"Cep55 and p53/Cep55 double-KO mice, quantitative abscission assays in fixed and live NSCs, ESCRT localization, p53/apoptosis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with quantitative cellular assays and genetic epistasis (double KO), multiple orthogonal methods\",\n      \"pmids\": [\"32269212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cep55 overexpression in MEFs compromises the Chk1-dependent S-phase checkpoint, causing increased replication speed and DNA damage, and a prolonged aberrant mitosis. PI3K/Akt inhibition or expression of Akt-insensitive Chk1 (S280A) rescues this phenotype, placing Cep55→Pi3k/Akt→Chk1 in a pathway regulating genomic stability. Cep55 overexpression also causes microtubule stabilization.\",\n      \"method\": \"Cep55 transgenic MEFs, Chk1 phosphorylation assay, DNA fiber assay, pharmacological PI3K/Akt inhibition, Chk1 S280A mutant rescue\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic model with multiple mechanistic readouts and rescue experiments, single lab\",\n      \"pmids\": [\"33087841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase through facilitation of the chaperonin CCT complex to Aurora A. Cep55-/- mice exhibit abnormally elongated cilia and Meckel-Gruber syndrome features. CEP55 mutations in MKS cause failure of cilia disassembly.\",\n      \"method\": \"Cep55 KO mice, Co-IP of CEP55 with Aurora A and CCT complex, cilia length measurement, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO plus Co-IP and mechanistic dissection with CCT chaperonin, multiple methods\",\n      \"pmids\": [\"33475699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Cep55 in mouse cortical NSCs causes abscission defects (increased failure rate and slowed abscission), and binucleate NSCs activate p53-dependent apoptosis. Most NSCs complete abscission without Cep55, but failures trigger a cell-type-specific p53 response not seen in fibroblasts.\",\n      \"method\": \"Cep55 KO and p53/Cep55 double-KO mice, quantitative live and fixed abscission assays, p53/apoptosis immunostaining\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO model with quantitative cellular analysis and genetic epistasis\",\n      \"pmids\": [\"33622776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Integrin-mediated FAK-Src signaling decelerates PLK1 degradation at the midbody, thereby controlling the timing of CEP55 accumulation and subsequent ALIX/TSG101/CHMP4B (ESCRT-III) recruitment. In non-adherent cells, PLK1 disappears more rapidly and CEP55 cannot efficiently recruit ESCRT components, causing abscission failure.\",\n      \"method\": \"FAK/Src inhibitor treatment, PLK1 inhibition, immunofluorescence of midbody proteins, adherent vs. non-adherent cell comparison\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis plus localization analysis, single lab\",\n      \"pmids\": [\"27127172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NEDD4L ubiquitinates CEP55 and promotes its degradation; M2-macrophage-derived exosomal miR-342-3p suppresses NEDD4L, thereby elevating CEP55 protein via reduced ubiquitination and activating the PI3K/AKT/mTOR pathway in renal cell carcinoma.\",\n      \"method\": \"Ubiquitination assay, miR-342-3p/NEDD4L luciferase reporter, Co-IP, in vivo xenograft\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ubiquitination assay with regulatory pathway delineation, single lab\",\n      \"pmids\": [\"37305161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP55 loading into exosomes does not occur via canonical early-to-late endosome trafficking but instead through Alix-mediated recruitment to secretory CD63-positive late endosomes. Mutation of the CEP55-Alix interaction site strongly reduces CEP55 dot formation and CEP55 presence in extracellular vesicles.\",\n      \"method\": \"High-resolution microscopy, EGFP-CEP55 trafficking analysis, Rab5/Rab7/CD63 marker co-localization, CEP55-Alix interaction-site mutagenesis\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging plus mutagenesis of interaction site, single lab\",\n      \"pmids\": [\"39976236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UXT is a novel TSG101-interacting protein; CEP55 is recruited to TSG101-containing cytoplasmic vesicles and degraded via the lysosome pathway. UXT depletion promotes TSG101 vesicle-lysosome association and enhances CEP55 degradation upon TSG101 overexpression.\",\n      \"method\": \"Co-IP, lysosome inhibitor treatment, immunofluorescence, siRNA depletion\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/localization study, single lab\",\n      \"pmids\": [\"33486193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"α-catenin physically interacts with CEP55 in the cytoplasm of HCC cells (identified by BioID mass spectrometry and confirmed by Co-IP and proximity ligation), stabilizing CEP55 protein. CEP55 is also transcriptionally induced by a FoxM1/TEAD/YAP complex. CEP55 supports HCC cell migration in conjunction with α-catenin but does not affect proliferation.\",\n      \"method\": \"BioID proximity labeling + mass spectrometry, Co-IP, proximity ligation assay, chromatin immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — BioID discovery plus Co-IP/PLA validation and ChIP for transcriptional regulation, single lab\",\n      \"pmids\": [\"37381005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP8 deubiquitinates CEP55 to maintain its protein stability; CEP55 binds to CHMP6 (confirmed by Co-IP) and promotes its expression, thereby facilitating ferroptosis resistance and macrophage M2 polarization in TNBC. USP8 knockdown effects on tumor growth are reversed by CEP55 overexpression.\",\n      \"method\": \"Ubiquitination/deubiquitination assay, Co-IP, siRNA knockdown, flow cytometry (ferroptosis markers, macrophage polarization), xenograft model\",\n      \"journal\": \"Clinical breast cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination assay plus Co-IP and in vivo rescue, single lab\",\n      \"pmids\": [\"40925844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ILF3 stabilizes CEP55 mRNA (confirmed by RIP and mRNA stability assay), maintaining CEP55 protein levels in breast cancer cells. ILF3 depletion reduces CEP55 expression, impairs cell growth and invasion, and promotes ferroptosis; CEP55 restoration rescues these effects.\",\n      \"method\": \"RNA immunoprecipitation (RIP), CEP55 mRNA stability assay, siRNA knockdown, xenograft model\",\n      \"journal\": \"Hereditas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP plus mRNA stability assay and functional rescue, single lab\",\n      \"pmids\": [\"39871389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP55 promotes resistance to cisplatin in prostate cancer by regulating CDK1 phosphorylation at Tyr15, driving neuroendocrine differentiation. CEP55 overexpression enhances NEPC biomarker expression; knockdown reduces proliferation and invasiveness.\",\n      \"method\": \"scRNA-seq analysis, in vitro/in vivo CEP55 KD/overexpression, CDK1 Tyr15 phosphorylation immunoblot, clinical sample validation\",\n      \"journal\": \"Cancer pathogenesis and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — CDK1 phosphorylation readout without direct kinase-CEP55 mechanistic assay, single lab\",\n      \"pmids\": [\"41403895\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP55 is a coiled-coil centrosomal protein that, upon mitotic entry, is phosphorylated by Erk2/Cdk1 (at S425/428) enabling Plk1 interaction and subsequent S436 phosphorylation, which is then dephosphorylated by iASPP-PP1; this phosphorylation cycle—kept in check by Pin1 and negatively regulated by p53 via Plk1—controls the precise timing of CEP55 recruitment to the midbody, where its dimeric EABR domain sequentially recruits ALIX and ESCRT-I (TSG101) in a competitive manner to drive ESCRT-III-mediated membrane abscission; in male germ cells, TEX14 competes with ALIX/TSG101 for the same CEP55 binding site to arrest abscission and form stable intercellular bridges; beyond cytokinesis, CEP55 activates PI3K/AKT signaling by forming a complex with PI3K and stabilizing AKT against proteasomal degradation, and promotes cilia disassembly by stabilizing Aurora A kinase through the CCT chaperonin complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CEP55 is a coiled-coil centrosomal and midbody protein that serves as the master recruiter of the ESCRT membrane-scission machinery during cytokinetic abscission and additionally functions in PI3K/AKT signaling and cilia disassembly. During interphase CEP55 resides at the mother centriole; sequential phosphorylation by Erk2/Cdk1 (S425/S428) and Plk1 (S436), modulated by Pin1-dependent isomerization and iASPP-PP1-mediated dephosphorylation, controls its timely release from centrosomes and recruitment to the midbody via the centralspindlin complex (MKLP1–MgcRacGAP), where its dimeric EABR domain competitively binds ALIX and TSG101 through GPPX3Y motifs to nucleate ESCRT-III–dependent membrane abscission [PMID:16198290, PMID:18948538, PMID:21079244, PMID:29743530, PMID:16790497]. Cep55 knockout mice reveal that most somatic cells complete abscission without CEP55, but neural progenitor cells are uniquely dependent on it—binucleate NPCs activate p53-dependent apoptosis—and Cep55-null mice also display abnormally elongated cilia owing to impaired Aurora A stabilization via the CCT chaperonin complex [PMID:32269212, PMID:33475699]. Loss-of-function mutations in CEP55 cause MARCH syndrome (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia, hydranencephaly), attributable to failed midbody localization and abscission [PMID:28264986].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The first mechanistic study established that CEP55 is a centrosomal protein whose sequential phosphorylation by Erk2/Cdk1 and Plk1 drives its mitotic redistribution to the midbody and is essential for cytokinesis, answering how CEP55 dynamics are controlled across the cell cycle.\",\n      \"evidence\": \"Site-directed mutagenesis of S425/S428/S436, in vitro kinase assays, siRNA knockdown with cytokinesis readout in HeLa cells\",\n      \"pmids\": [\"16198290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering Erk2/Cdk1 phosphorylation of CEP55 at mitotic entry was not defined\", \"No structural basis for how phosphorylation alters CEP55 centrosome association\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of centralspindlin (MKLP1–MgcRacGAP) as the midbody-targeting platform for CEP55 established the epistatic hierarchy: centralspindlin recruits CEP55, which in turn organizes the Flemming body and v-SNARE trafficking for abscission.\",\n      \"evidence\": \"Direct in vitro binding of CEP55 to MKLP1, siRNA epistasis (centralspindlin KD abolishes CEP55 midbody localization), microtubule-bundling assay\",\n      \"pmids\": [\"16790497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CEP55 microtubule-bundling activity is required for abscission was not tested\", \"Structural basis of CEP55–MKLP1 interaction unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that CEP55 forms a complex with PI3K p110α and activates PI3K/AKT signaling revealed a cytokinesis-independent oncogenic function, later validated in multiple cancer types.\",\n      \"evidence\": \"Co-IP of CEP55 with PI3K, in vitro PI3K kinase assay, nude mouse xenograft in HCC cells\",\n      \"pmids\": [\"17237822\", \"19337377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding domain on CEP55 for PI3K not mapped\", \"Whether PI3K activation requires CEP55 midbody localization or occurs independently was not determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The crystal structure of the CEP55 EABR domain revealed the structural basis for ESCRT recruitment: an asymmetric dimeric coiled coil presents a single GPPX3Y-binding groove that competitively accommodates ALIX or TSG101, explaining why multiple CEP55 dimers are needed for abscission.\",\n      \"evidence\": \"X-ray crystallography at 2.0 Å resolution, biochemical competition assays with ALIX and TSG101 peptides\",\n      \"pmids\": [\"18948538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How full-length CEP55 oligomerizes at the midbody ring to provide multiple binding sites was not resolved\", \"No structure of the N-terminal or central coiled-coil regions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Pin1 was identified as a co-factor that promotes Plk1-mediated phosphorylation and post-translational stabilization of CEP55 during mitosis, placing Pin1 in the same cytokinesis pathway as CEP55 through genetic epistasis.\",\n      \"evidence\": \"Pin1 KO MEFs, double-knockdown epistasis in HeLa, phosphorylation-site mutagenesis\",\n      \"pmids\": [\"19638580\", \"19855176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific isomerization event (cis/trans conversion) on CEP55 was not demonstrated biochemically\", \"Whether Pin1 acts catalytically or as a scaffold was unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two studies resolved complementary aspects of CEP55 timing: Plk1 phosphorylation acts as a negative gate preventing premature CEP55 midbody recruitment until Plk1 is degraded at mitotic exit, while in male germ cells TEX14 hijacks the EABR binding site to permanently block ESCRT recruitment and maintain intercellular bridges.\",\n      \"evidence\": \"Plk1 phosphomutant expression and Plk1 inhibitor live imaging (abscission); TEX14 competitive binding assay and Tex14 KO mice (intercellular bridges)\",\n      \"pmids\": [\"21079244\", \"20176808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Plk1 degradation kinetics differ between cell types was not explored\", \"Whether TEX14 competition is regulated during spermatogenesis was unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A p53–Plk1–CEP55 regulatory axis was defined: p53 suppresses both CEP55 transcription and Plk1-dependent CEP55 protein stability, linking tumor suppressor loss to CEP55 overexpression in cancer.\",\n      \"evidence\": \"p53 overexpression/siRNA, Plk1 inhibitor BI2356, luciferase promoter assay, immunoblotting in HCC cells\",\n      \"pmids\": [\"22184120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 directly binds the CEP55 promoter or acts indirectly was not resolved\", \"Contribution of transcriptional vs. post-translational regulation in vivo not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"BRCA2 was shown to facilitate CEP55–ALIX and CEP55–TSG101 complex formation at the midbody, establishing that cancer-associated BRCA2 mutations disrupt cytokinesis independently of homologous recombination.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, cancer mutation analysis, immunofluorescence in HeLa cells\",\n      \"pmids\": [\"22771033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BRCA2 promotes CEP55–ESCRT interaction (scaffolding vs. conformational) unresolved\", \"Whether BRCA2-dependent abscission defects contribute to tumorigenesis in vivo was not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Zebrafish cep55 mutants demonstrated that CEP55 stabilizes AKT protein against proteasomal degradation in vivo, with constitutively active PI3K/AKT or proteasome inhibition partially rescuing the mutant phenotype.\",\n      \"evidence\": \"Zebrafish cep55 nonsense mutant, MG132 and constitutively active PIK3CA/AKT1 mRNA rescue\",\n      \"pmids\": [\"25667221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical mechanism by which CEP55 shields AKT from ubiquitin-proteasome degradation not defined\", \"Which E3 ligase targets AKT in the absence of CEP55 was unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of a causative CEP55 truncation in MARCH syndrome patients proved that human CEP55 is essential for brain development; the truncated protein fails to reach the midbody and causes multinucleation.\",\n      \"evidence\": \"Exome sequencing of affected families, patient-derived cell immunofluorescence, zebrafish cep55l morpholino rescue with full-length vs. truncated CEP55\",\n      \"pmids\": [\"28264986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether partial CEP55 function persists in heterozygous carriers was not assessed\", \"Genotype–phenotype correlation across different CEP55 mutations not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple discoveries in 2018 expanded the regulatory and signaling landscape: iASPP-PP1 dephosphorylates CEP55 S436 to enable midbody recruitment; CEP55 signals through JAK2–STAT3 and interacts with SPAG5 to activate AKT; and CEP55 is a downstream effector of MEK1/2–MYC influencing mitotic cell fate in breast cancer.\",\n      \"evidence\": \"iASPP–PP1 Co-IP and phospho-specific blotting; JAK2 and SPAG5 Co-IP with inhibitor rescue; CEP55 KD/overexpression in breast cancer syngeneic models with MEK/PLK1 epistasis\",\n      \"pmids\": [\"29743530\", \"30096813\", \"30089483\", \"30108112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK2 and SPAG5 interactions each rely on single Co-IP studies\", \"Whether iASPP-PP1 specificity for CEP55 S436 extends to other Plk1 substrates was untested\", \"Relative contribution of PI3K/AKT vs. JAK2/STAT3 arms to CEP55 oncogenic function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structure–function analysis identified two NEMO-like ubiquitin-binding domains (NOA and ZF) in CEP55 that are essential for abscission, establishing that CEP55 participates in non-degradative ubiquitin signaling at the midbody.\",\n      \"evidence\": \"In vitro domain characterization, structure-guided mutagenesis, CEP55 KD reconstitution with abscission readout\",\n      \"pmids\": [\"31605944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the ubiquitinated target(s) recognized by CEP55 UBDs at the midbody is unknown\", \"Structural model of full-length CEP55 including both UBDs and EABR not available\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cep55 knockout mice revealed that CEP55 is dispensable for most somatic cell divisions but essential in neural progenitor cells, where abscission failure triggers a cell-type-specific p53-dependent apoptosis that drives microcephaly.\",\n      \"evidence\": \"Cep55 KO and Cep55/p53 double-KO mice, quantitative live abscission assays in NSCs vs. fibroblasts, ESCRT localization\",\n      \"pmids\": [\"32269212\", \"33622776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why NPCs but not fibroblasts require CEP55 for abscission is mechanistically unexplained\", \"Alternative abscission machinery compensating in fibroblasts not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A cilia-regulatory function was uncovered: CEP55 stabilizes Aurora A kinase by facilitating its association with the CCT chaperonin complex, and Cep55-null mice display elongated cilia and Meckel–Gruber syndrome features, linking CEP55 to ciliopathy.\",\n      \"evidence\": \"Cep55 KO mice, Co-IP of CEP55 with Aurora A and CCT subunits, cilia length quantification\",\n      \"pmids\": [\"33475699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CEP55 directly contacts CCT or acts as an adaptor bringing Aurora A to CCT is not resolved\", \"How CEP55 subcellular pool at centrosomes vs. midbody differentially controls cilia vs. abscission is unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"NEDD4L was identified as an E3 ubiquitin ligase targeting CEP55 for degradation, with the miR-342-3p/NEDD4L axis regulating CEP55 protein levels and downstream PI3K/AKT/mTOR signaling in renal cell carcinoma.\",\n      \"evidence\": \"Ubiquitination assay, miR-342-3p/NEDD4L luciferase reporter, xenograft rescue\",\n      \"pmids\": [\"37305161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific lysine residues on CEP55 ubiquitinated by NEDD4L not mapped\", \"Whether NEDD4L-mediated degradation is cell-cycle-regulated was not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work identified USP8 as a deubiquitinase stabilizing CEP55 and showed CEP55 binds CHMP6 (ESCRT-III) to promote ferroptosis resistance, while ILF3 stabilizes CEP55 mRNA, broadening the regulatory inputs controlling CEP55 abundance.\",\n      \"evidence\": \"USP8 deubiquitination assay, CEP55–CHMP6 Co-IP, xenograft rescue; ILF3 RIP and mRNA stability assay in breast cancer cells\",\n      \"pmids\": [\"40925844\", \"39871389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CEP55–CHMP6 interaction confirmed by single Co-IP only\", \"Whether ferroptosis resistance is a direct consequence of ESCRT function or PI3K/AKT signaling is undetermined\", \"ILF3-CEP55 mRNA interaction site not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include why neural progenitor cells uniquely depend on CEP55 for abscission while most somatic cells do not, what the ubiquitinated substrates recognized by CEP55's UBDs are, and how CEP55's cytokinetic and PI3K/AKT signaling functions are coordinated in space and time.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of full-length CEP55 exists\", \"Alternative abscission machinery in CEP55-independent cells not identified\", \"Ubiquitin targets of CEP55 UBDs at the midbody unknown\", \"Spatial segregation of cytokinetic vs. signaling pools of CEP55 not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 9, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 12, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 3, 8, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 12, 16, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"centralspindlin (MKLP1–MgcRacGAP)\",\n      \"ESCRT-I (via TSG101)\",\n      \"ESCRT-III (via CHMP6)\"\n    ],\n    \"partners\": [\n      \"MKLP1\",\n      \"TSG101\",\n      \"ALIX\",\n      \"PLK1\",\n      \"TEX14\",\n      \"AURKA\",\n      \"PIK3CA\",\n      \"IASPP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}