{"gene":"NUMA1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1996,"finding":"NuMA forms a complex with cytoplasmic dynein and dynactin; immunodepletion of NuMA from frog egg extracts prevents normal mitotic spindle assembly, producing chromatin-associated irregular microtubule arrays lacking spindle poles. A subdomain of the NuMA tail mediates microtubule bundling and aster formation.","method":"Immunodepletion from Xenopus egg extracts, Co-IP, microtubule aster assembly assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in cell-free system, immunodepletion with rescue, multiple orthogonal methods, replicated by subsequent studies","pmids":["8898198"],"is_preprint":false},{"year":2000,"finding":"NuMA is transported toward microtubule minus-ends at spindle poles via cytoplasmic dynein and dynactin. GFP-NuMA streams poleward in association with dynactin Arp1 subunit; disruption of dynactin (dynamitin overexpression) or dynein (antibody) blocks NuMA translocation and spindle pole assembly. NuMA-dynein-dynactin complex is mitosis-specific and reversible.","method":"GFP live imaging, immunoprecipitation, gel filtration, dominant-negative dynamitin overexpression, antibody inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, reciprocal co-IP, live imaging, functional perturbation, replicated across labs","pmids":["10811826"],"is_preprint":false},{"year":1995,"finding":"NuMA is required for organization of microtubules into mitotic asters: immunodepletion from mammalian mitotic extracts abolishes aster formation, and addition of purified recombinant NuMA rescues aster assembly. NuMA is phosphorylated upon aster assembly and is required only in late stages of aster formation.","method":"Cell-free mitotic extract, immunodepletion, recombinant protein add-back, in vitro aster assembly assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified protein, immunodepletion with rescue, in vitro assay","pmids":["7593190"],"is_preprint":false},{"year":1992,"finding":"NuMA encodes a 236-kDa protein with a large central coiled-coil domain (~1,485 aa) flanked by globular N- and C-terminal domains. NuMA dissociates from chromatin in early prophase before nuclear lamina breakdown, and reassociates with telophase chromosomes before lamins, defining a novel pathway for nuclear protein segregation at mitosis.","method":"cDNA cloning, sequence analysis, double immunofluorescence with anti-NuMA and anti-lamin antibodies","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary structure determination combined with cell biological localization, single lab but multiple methods","pmids":["1541630","1541636"],"is_preprint":false},{"year":1993,"finding":"Expression of NuMA lacking its globular head domain causes failure of cytokinesis and micronucleation. Expression of NuMA lacking its globular tail domain prevents targeting to interphase nuclei and mitotic spindle; cells transit mitosis normally but assemble micronuclei in daughter cells. Wild-type NuMA overexpression rescues nuclear assembly defects in RCC1-mutant tsBN2 cells.","method":"Dominant-negative mutant expression, cell cycle analysis, immunofluorescence, rescue experiment in temperature-sensitive cell line","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-deletion mutagenesis, rescue experiments, multiple phenotypic readouts, replicated across constructs","pmids":["8432734"],"is_preprint":false},{"year":1995,"finding":"Mutation of threonine 2040 (a predicted p34cdc2 phosphorylation site) in NuMA abolishes its ability to associate with the mitotic spindle; instead, the mutant concentrates at the plasma membrane. Cells expressing these mutants have disorganized spindles and fail cytokinesis. NuMA is phosphorylated in a mitosis-specific manner in vivo.","method":"Site-directed mutagenesis, transient expression in tissue culture cells, immunofluorescence, in vivo phosphorylation labeling","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific phosphorylation sites with defined functional phenotype, in vivo phosphorylation confirmed","pmids":["7769006"],"is_preprint":false},{"year":2004,"finding":"LGN (mammalian Pins) acts as a conformational switch linking NuMA to Gαi at the cell cortex. In its closed state, LGN N- and C-termini interact; NuMA or Gαi disrupts this, allowing simultaneous binding to both and cortical localization. NuMA binding to LGN is required for metaphase spindle oscillations.","method":"FRET biosensor, overexpression, dominant-negative analysis, live cell imaging","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRET conformational analysis, genetic rescue, live imaging, multiple orthogonal methods","pmids":["15537540"],"is_preprint":false},{"year":2001,"finding":"LGN binds directly to the C-terminal tail of NuMA. LGN associates with spindle poles during mitosis; ectopic expression or siRNA knockdown of LGN disrupts spindle-pole organization. Anti-LGN antibodies and LGN-binding domain of NuMA trigger microtubule aster formation in Xenopus egg extracts.","method":"Co-immunoprecipitation, RNAi, Xenopus egg extract aster assay, immunofluorescence","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay, cell-free system, siRNA loss-of-function, multiple orthogonal methods","pmids":["11781568"],"is_preprint":false},{"year":2002,"finding":"LGN blocks NuMA's ability to stabilize microtubules. NuMA C-terminus directly binds microtubules and stabilizes them; the LGN-binding domain on NuMA overlaps by 10 residues with the MT-binding domain. LGN exerts its inhibitory effect on spindle organization through steric exclusion of NuMA-MT interaction.","method":"In vitro microtubule stabilization assay, in vitro binding assay, Xenopus egg extracts, mammalian cell expression","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding and functional assay, domain mapping, multiple systems tested","pmids":["12445386"],"is_preprint":false},{"year":2005,"finding":"NuMA is a major acceptor of poly(ADP-ribosyl)ation (PARsylation) by tankyrase 1 in mitosis. Association between tankyrase 1 and NuMA dramatically increases at mitotic onset, coincident with NuMA PARsylation. Tankyrase 1 siRNA knockdown eliminates NuMA PARsylation. NuMA siRNA knockdown causes complete loss of tankyrase 1 from spindle poles (NuMA is required for tankyrase 1 spindle pole localization).","method":"Immunoprecipitation, immunofluorescence, siRNA knockdown","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal knockdown experiments, co-IP, immunofluorescence, single lab","pmids":["16076287"],"is_preprint":false},{"year":2002,"finding":"NuMA contains an RXXPDG motif that mediates its binding to the ankyrin repeat domain of tankyrase 1 and tankyrase 2. NuMA was identified as a tankyrase partner by yeast two-hybrid and verified by direct binding assay.","method":"Yeast two-hybrid screen, in vitro binding assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid plus direct binding verification, single lab, limited functional follow-up","pmids":["12080061"],"is_preprint":false},{"year":2009,"finding":"Poly(ADP-ribose) (pADPr) from tankyrase 1 (PARP-5a) contributes to spindle pole assembly. The rod domain of NuMA binds directly to pADPr chains in vitro. pADPr-coated beads trigger aster assembly in mitotic lysates, suggesting pADPr provides dynamic cross-linking at spindle poles by binding NuMA non-covalently.","method":"Immunoelectron microscopy, concentrated mitotic lysate system, in vitro pADPr binding assay, pADPr-coated magnetic bead aster assembly","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of binding, functional aster assay, domain mapping, single lab","pmids":["19759176"],"is_preprint":false},{"year":1999,"finding":"NuMA self-assembles in vitro into multiarm oligomers (up to 10–12 arms) via interaction of its C-terminal globular domains; each arm corresponds to a NuMA dimer. Computer modeling suggests 12-arm oligomers are structural units of the NuMA nuclear scaffold observed by EM in transfected cells.","method":"In vitro assembly of recombinant NuMA, electron microscopy, domain deletion analysis, computer modeling","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution, EM visualization, domain-deletion mapping, single lab","pmids":["10075938"],"is_preprint":false},{"year":1999,"finding":"A 135-kDa nonerythroid isoform of protein 4.1R interacts directly with NuMA. The interaction is mediated by exons 20–21 of 4.1R and residues 1788–1810 of NuMA. 4.1R colocalizes with NuMA in interphase nuclei and at spindle poles; overexpression of 135-kDa 4.1R alters NuMA distribution in interphase nuclei.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, co-immunolocalization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal co-IP plus in vitro binding, domain mapping, functional consequence shown","pmids":["10189366"],"is_preprint":false},{"year":2009,"finding":"NuMA is an essential mitotic component with distinct contributions to spindle pole establishment and maintenance. When NuMA mitotic function is disrupted using a conditional knockout in primary mouse cells, centrosomes provide initial focusing but centrosome attachment under tension is defective and kinetochore fiber maintenance at poles fails. Without both centrosomes and NuMA, spindle microtubule focusing completely fails.","method":"Conditional knockout allele in mice and primary cultured cells, immunofluorescence, live cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in primary cells and mice, epistasis with centrosome pathway, clean loss-of-function phenotype, rigorous genetic approach","pmids":["19255246"],"is_preprint":false},{"year":2013,"finding":"CDK1-mediated phosphorylation of NuMA at T2055 negatively regulates NuMA cortical localization during metaphase; PPP2CA phosphatase activity counteracts this. CDK1 inactivation in anaphase leads to rise in dephosphorylated NuMA at cortex, increasing cortical dynein and promoting spindle elongation.","method":"Phosphomutant expression, CDK1 inhibitor experiments, siRNA, immunofluorescence, quantitative imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphosite mutagenesis with functional readout, pharmacological inhibition, phosphatase manipulation, multiple orthogonal approaches","pmids":["23921553"],"is_preprint":false},{"year":2014,"finding":"NuMA directly associates with PtdInsP (PIP) and PtdInsP2 (PIP2) phosphoinositides in vitro, providing a LGN/Gαi-independent mechanism for cortical localization. Chemical or enzymatic depletion of PIP/PIP2 prevents NuMA cortical localization during mitosis; increasing PIP2 augments cortical NuMA. During anaphase, LGN/Gαi are dispensable for NuMA-dependent cortical dynein enrichment.","method":"In vitro lipid-binding assay, chemical/enzymatic PIP depletion, immunofluorescence, genetic knockdown","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding assay, pharmacological and enzymatic depletion, multiple orthogonal methods, single lab","pmids":["24996901"],"is_preprint":false},{"year":2016,"finding":"Aurora-A directly phosphorylates NuMA C-terminus on three serine residues including Ser1969, controlling dynamic exchange of NuMA between cytoplasm and spindle poles. Partial Aurora-A inhibition causes NuMA/dynein accumulation at spindle poles without reaching cortex while LGN cortical distribution is unperturbed. A new microtubule-binding domain of NuMA was identified that does not overlap with the LGN-binding motif, allowing simultaneous binding to LGN and microtubules.","method":"In vitro kinase assay, FRAP, phosphomutant expression, Aurora-A partial inhibition, immunofluorescence","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay, FRAP dynamics, phosphosite mutagenesis with functional readouts, domain mapping","pmids":["26832443"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of LGN/NuMA and LGN/mInsc complexes show that NuMA and Inscuteable bind the same TPR repeats of LGN in a mutually exclusive manner, with mInsc binding with higher affinity. The Par3/mInsc/LGN and NuMA/LGN/Gαi complexes play sequential and overlapping roles in asymmetric cell division.","method":"X-ray crystallography, in vitro competition binding assay, cell biology","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at high resolution with biochemical validation and functional cell biology studies","pmids":["21816348"],"is_preprint":false},{"year":2005,"finding":"Ric-8A GEF activity catalytically dissociates Gαi-GDP/LGN/NuMA complexes in vitro, releasing activated Gαi-GTP and concomitantly liberating NuMA from LGN. Ric-8A efficiently uses GoLoco/Gαi-GDP complexes as substrates.","method":"In vitro GEF assay with purified proteins, biochemical dissociation experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified components, GEF activity directly measured, single lab","pmids":["16275912"],"is_preprint":false},{"year":2010,"finding":"Ric-8A and Gαi function to recruit LGN, NuMA, and dynein to the cell cortex for mitotic spindle orientation. Pertussis toxin (blocking Ric-8A GEF activity for Gαi), Ric-8A knockdown, or Gαi knockdown each impair cortical localization of LGN, NuMA, and dynein, and disturb integrin-dependent spindle orientation.","method":"Pertussis toxin treatment, siRNA knockdown, immunofluorescence, live cell imaging of GFP-tubulin","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, cortical localization readout, single lab with orthogonal approaches","pmids":["20479129"],"is_preprint":false},{"year":2017,"finding":"NuMA targets dynactin to microtubule minus-ends, localizing dynein activity there. NuMA is recruited to new minus-ends independently of dynein and faster than dynactin; both NuMA and dynactin show steady-state minus-end binding. NuMA localization to minus-ends requires a C-terminal region outside its canonical MT-binding domain. Both NuMA's minus-end-binding and dynein-dynactin-binding modules are required for focused bipolar spindle organization.","method":"Quantitative live imaging, laser ablation to generate new minus-ends, domain-deletion analysis, siRNA rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — laser ablation plus quantitative imaging, domain-deletion rescue, multiple orthogonal approaches, mechanistic epistasis established","pmids":["29185983"],"is_preprint":false},{"year":2018,"finding":"Cortical NuMA assembles specialized focal structures that cluster multiple dynein-dynactin force-generating modules (DDN clusters) to produce cooperative spindle-pulling forces. Induced cortical targeting of NuMA alone (not dynein) is sufficient for spindle pulling. This clustering activity is required for spindle positioning but not spindle-pole focusing.","method":"Light-induced cortical reconstitution system in human cells, live imaging, domain-deletion analysis, siRNA","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — optogenetic reconstitution, domain-separation of clustering vs. pole-focusing function, quantitative imaging, rigorous controls","pmids":["29848445"],"is_preprint":false},{"year":2013,"finding":"NuMA is required to recruit dynactin to the keratinocyte cell cortex. The 4.1-binding domain of NuMA stabilizes its cortical interaction (shown by FRAP); loss of 4.1/NuMA interaction causes spindle orientation defects. CDK1 inhibition or mutation of a single NuMA residue increases cortical NuMA localization in anaphase via an LGN- and 4.1-independent mechanism.","method":"siRNA, FRAP, phosphomutant expression, immunofluorescence, spindle orientation assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP dynamics, multiple mutant analyses, functional spindle orientation readout, single lab","pmids":["24109598"],"is_preprint":false},{"year":2016,"finding":"NuMA's microtubule-binding domain, which targets microtubule tips, is required for spindle orientation in keratinocytes in addition to dynein/dynactin. Loss of NuMA-MT interactions in skin causes spindle orientation defects, epidermal differentiation defects, and neonatal lethality in mice. NuMA-MT interactions are also required in adult hair follicle matrix cells for proper differentiation.","method":"Conditional knockout/knock-in mice, MT-binding domain mutation, in vivo histology and immunofluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional mouse models, domain-specific separation-of-function mutations, multiple tissue contexts validated","pmids":["26765568"],"is_preprint":false},{"year":2006,"finding":"Rae1 interacts with NuMA in a mitosis-specific manner. A specific binding site for Rae1 on NuMA was mapped that would convert a NuMA dimer into a tetravalent MT crosslinker. Overexpression of Rae1 Rac binding domain of NuMA in HeLa cells leads to aberrant spindle formation; coupling Rae1 overexpression to NuMA overexpression or co-depleting both prevents aberrant spindles.","method":"Co-immunoprecipitation, domain mapping, overexpression and knockdown epistasis, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site mapping, genetic epistasis by double perturbation, functional spindle readout, single lab","pmids":["17172455"],"is_preprint":false},{"year":1999,"finding":"NuMA forms an insoluble matrix at spindle poles distinct from pericentriolar material. Once incorporated into this matrix in vivo or in vitro, NuMA's insolubility is no longer dependent on microtubules. Immunodepletion of NuMA from mitotic extracts prevents formation of this insoluble matrix at aster cores.","method":"Immunogold electron microscopy, solubility fractionation, immunodepletion from mitotic extracts","journal":"Cell motility and the cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoelectron microscopy, biochemical fractionation, immunodepletion, single lab","pmids":["10098933"],"is_preprint":false},{"year":1997,"finding":"The NuMA-RARA fusion protein from APL t(11;17) variant forms sheet-like nuclear aggregates with which normal NuMA partly co-localizes, while PML organization remains normal. This establishes that RARα dysregulation rather than PML disruption is essential for APL.","method":"Characterization of patient-derived fusion gene, immunofluorescence co-localization","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and characterization of fusion protein in patient cells, functional inference, single study","pmids":["9288109"],"is_preprint":false},{"year":2013,"finding":"Cell cycle-regulated membrane binding of NuMA via a Gαi/LGN-independent lipid/membrane-binding domain at the NuMA C-terminus underlies anaphase-specific cortical NuMA enrichment. CDK1 phosphorylation inhibits this membrane binding during prophase/metaphase; CDK1 inactivation at anaphase onset enables membrane binding. Membrane-binding-deficient NuMA specifically reduces anaphase cortical dynein, impairing chromosome separation.","method":"Domain mapping, phosphomutant expression, CDK1 inhibition, endogenous NuMA replacement by RNAi + rescue, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous replacement strategy, phosphosite-specific mutants, CDK1 epistasis, functional chromosome separation readout","pmids":["24371089"],"is_preprint":false},{"year":2004,"finding":"Cyclin B degradation in anaphase leads to NuMA dephosphorylation and release from dynein/dynactin and from spindle poles in Xenopus egg extracts. Non-degradable cyclin B (Δ90) keeps NuMA phosphorylated, associated with dynein/dynactin, and locked at stable spindle poles that fail to disassemble.","method":"Xenopus egg extract, non-degradable cyclin B expression, immunoprecipitation, immunofluorescence","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-free system with defined biochemical perturbation, phosphorylation state analysis, functional spindle readout","pmids":["14710193"],"is_preprint":false},{"year":1997,"finding":"NuMA is phosphorylated during nuclear breakdown (G2/M transition) in a mitosis-specific manner. This phosphorylation occurs before spindle formation (present in nocodazole-treated cells) and does not require microtubule assembly. Dephosphorylation occurs in two distinct steps in early G1 and at end of G1.","method":"32P-orthophosphate labeling of synchronized cells, phosphatase treatment, nocodazole arrest","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — radiolabeling in synchronized cells, phosphatase validation, drug perturbation, single lab","pmids":["9202389"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of Importin-α/NuMA-C-terminus complex reveals a novel NLS binding pattern. Importin-β, in the presence of Importin-α, inhibits the microtubule-binding function of NuMA by sterically masking a high-affinity MT-binding region C-terminal to the NLS.","method":"X-ray crystallography, in vitro microtubule-binding assay, domain mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical functional validation, in vitro MT-binding inhibition assay, mechanistic model directly tested","pmids":["28939615"],"is_preprint":false},{"year":2020,"finding":"NuMA contains two LIC (light intermediate chain)-binding sites: a hook domain contacting LIC1 and LIC2 via a conserved hydrophobic patch, and a CC1-box homologous motif in the coiled-coil region. Both LIC-binding sites are essential for correct spindle placement and cell division, establishing NuMA as a dynein-activating adaptor.","method":"Structural studies (crystal/biochemical), mitotic cell functional assays, domain mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination of interaction interface, mutagenesis of both binding sites with mitotic functional readout","pmids":["32413290"],"is_preprint":false},{"year":2014,"finding":"NuMA accumulates at DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner and directly interacts with ISWI ATPase SNF2h. NuMA co-immunoprecipitates with SNF2h, regulates its nucleoplasmic diffusion, and controls its accumulation at DNA breaks. NuMA knockdown reduces chromatin decompaction after DNA cleavage, impairs recruitment of homologous recombination factors, and impairs DSB repair in chromosomal contexts.","method":"Co-immunoprecipitation, FRAP, siRNA knockdown, DNA damage assays, HR factor recruitment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, FRAP dynamics, functional DNA repair assay, multiple orthogonal methods, single lab","pmids":["24753406"],"is_preprint":false},{"year":2013,"finding":"NuMA binds to p53 and is required for selective induction of p21 (but not PUMA) following DNA damage. NuMA knockdown attenuates p21 induction and impairs cell cycle arrest. NuMA is required for recruitment of CDK8 (Mediator complex component) to the p21 promoter.","method":"Co-immunoprecipitation, siRNA knockdown, gene expression analysis, ChIP (CDK8 recruitment)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding (co-IP), functional transcription assay, chromatin recruitment assay, single lab","pmids":["23589328"],"is_preprint":false},{"year":2017,"finding":"NuMA is present in the nucleolus and co-immunoprecipitates with RNA polymerase I, ribosomal proteins RPL26 and RPL24, and B-WICH chromatin remodeling complex components. NuMA binds 18S and 28S rRNAs and localizes to rDNA promoter regions. NuMA downregulation triggers nucleolar stress with decreased pre-rRNA synthesis and p27kip1 upregulation independent of p53.","method":"Co-immunoprecipitation, RNA immunoprecipitation, ChIP at rDNA promoters, siRNA knockdown, nascent RNA synthesis assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays (co-IP, RNA-IP, ChIP), functional loss-of-function, single lab","pmids":["28981686"],"is_preprint":false},{"year":2019,"finding":"NuMA interacts with 53BP1 and constrains 53BP1 diffusion throughout the nucleoplasm in the absence of DNA damage. This interaction is reduced after DNA damage. NuMA prevents 53BP1 accumulation at DNA breaks; NuMA knockdown enhances NHEJ and 53BP1-dependent activities.","method":"Co-immunoprecipitation, single-molecule tracking/FRAP, siRNA knockdown, NHEJ assay, immunoglobulin class switching","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct co-IP, diffusion dynamics measurement, functional repair assay, single lab","pmids":["30812030"],"is_preprint":false},{"year":2000,"finding":"GAS41 binds in vitro to the C-terminal part of the NuMA rod region with Kd of 2×10⁻⁷ M. GAS41 shows a dotted nuclear staining in interphase. Interaction identified by yeast two-hybrid and confirmed by dot overlay and surface plasmon resonance.","method":"Yeast two-hybrid, dot overlay assay, surface plasmon resonance","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by SPR with Kd measurement, biochemical binding, single lab","pmids":["10913114"],"is_preprint":false},{"year":2018,"finding":"Plk1 directly interacts with and phosphorylates NuMA, reducing NuMA's cortical localization. Acute Plk1 inhibition during metaphase enriches cortical NuMA/dynein/LGN levels and alters NuMA dynamics at the cortex. This Plk1-NuMA phosphorylation is required for precise spindle orientation.","method":"In vitro kinase assay, Plk1 inhibitor (acute inactivation), phosphomutant expression, immunofluorescence, FRAP","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, pharmacological inhibition, phosphomutant functional analysis, single lab","pmids":["30456393"],"is_preprint":false},{"year":2021,"finding":"NuMA undergoes liquid-liquid phase separation during mitotic entry; this is mediated by its C-terminus and facilitated by its dynein-dynactin binding motif. KifC1 promotes NuMA condensate concentration at spindle poles. Phase-separated NuMA droplets concentrate tubulins, bind microtubules, and enrich Kif2A, which depolymerizes spindle MTs for poleward flux. Aurora-A phosphorylation regulates NuMA phase separation.","method":"In vitro phase separation assay, live cell imaging, Aurora-A inhibition, siRNA knockdown, domain mutagenesis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phase separation demonstration, Aurora-A regulation tested, functional consequences measured, single lab","pmids":["34887424"],"is_preprint":false},{"year":2016,"finding":"C-terminal tail of NuMA directly binds the C-terminus of Astrin, helping to recruit Astrin to microtubules. NuMA knockdown dramatically impairs Astrin spindle localization. Cytoplasmic dynein is required for spindle pole accumulation of Astrin. Reduced Astrin levels impair NuMA concentration at spindle poles (reciprocal dependency).","method":"In vitro direct binding assay, co-immunoprecipitation, RNAi knockdown, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro direct binding, reciprocal siRNA epistasis, co-IP, single lab","pmids":["27462074"],"is_preprint":false},{"year":2014,"finding":"CYLD deubiquitinase deubiquitinates the cortical polarity protein Dishevelled, which enhances Dishevelled's interaction with NuMA, stimulating cortical localization of NuMA and dynein/dynactin. This is required for generating pulling forces on astral microtubules for spindle orientation.","method":"Deubiquitination assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, spindle orientation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical deubiquitination assay, co-IP of Dishevelled-NuMA, functional spindle orientation readout, single lab","pmids":["24469800"],"is_preprint":false},{"year":2021,"finding":"NUMA1 is downregulated in Huntington's disease neural progenitor growth cones by miR-124. NUMA1 regulates microtubule organization in axonal growth cones; suppressing NUMA1 recapitulates HD microtubule bundling defects and impairs axonal growth. Raising NUMA1 levels with antagomiR-124 or stabilizing microtubules rescues axonal growth defects.","method":"Proteomic analysis of growth cones, shRNA knockdown, antagomiR-124, epothilone B treatment, microtubule imaging in growth cones","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and rescue experiments in neurons, multiple perturbations, proteomic discovery confirmed functionally, single lab","pmids":["34793694"],"is_preprint":false},{"year":2020,"finding":"NuMA1 is transiently localized at the axon initial segment (AIS) during development where it interacts with scaffolding protein 4.1B and dynein regulator Lis1. NuMA1 silencing disrupts AIS assembly (not maintenance). NuMA1 inhibits endocytosis of AIS protein neurofascin-186 by impeding Lis1's interaction with doublecortin.","method":"Differential proteomics, shRNA knockdown, overexpression, co-immunoprecipitation, endocytosis assay, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of binding partners, functional endocytosis assay, shRNA phenotype, single lab","pmids":["31727776"],"is_preprint":false},{"year":2017,"finding":"Katanin p80 regulates microtubule remodeling in combination with NuMA and cytoplasmic dynein. Depletion of p80 and/or NuMA induces abnormal mitotic phenotypes in mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in mouse embryonic brain, placing p80 and NuMA in a common pathway for MT organization at spindle poles.","method":"siRNA knockdown, in utero electroporation in mouse brain, patient-derived iPSCs and brain organoids, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown, in vivo neural phenotype, iPSC validation, single lab","pmids":["28079116"],"is_preprint":false},{"year":1995,"finding":"Electron microscopy of recombinant full-length NuMA reveals a tripartite structure: a 207-nm long central rod domain that is a double-stranded parallel coiled-coil (the longest known at the time), flanked by globular N- and C-terminal domains. Chemical cross-linking and circular dichroism confirm the coiled-coil structure.","method":"Electron microscopy of purified recombinant NuMA, chemical cross-linking, circular dichroism spectroscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural visualization of purified recombinant protein, multiple biophysical methods, precise domain dimensions established","pmids":["7781599"],"is_preprint":false},{"year":1997,"finding":"NuMA is cleaved in apoptosis between residues 1701 and 1725 to produce a stable 180–200 kDa fragment. TPCK protease inhibitor retards both apoptotic morphology and NuMA cleavage, whereas ICE inhibitor II does not, suggesting a serine-type protease involvement. NuMA redistribution and cleavage are early nuclear events in apoptosis.","method":"Apoptosis induction, immunoblotting, protease inhibitor panel, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage site mapped, protease inhibitor panel, immunoblot confirmation, single lab","pmids":["9184071"],"is_preprint":false},{"year":2003,"finding":"NuMA is preferentially cleaved by caspase-3 in vivo during Fas-mediated apoptosis (not cleaved in caspase-3-null MCF-7 cells). NuMA is cleaved coincidently with PARP-1 and lamin B; cleavage is inhibited by z-DEVD-FMK, z-VEID-FMK, and z-IETD-FMK caspase inhibitors.","method":"Caspase-3-null cell line, caspase inhibitors, immunoblotting, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null cell line used to identify responsible caspase, inhibitor panel, single lab","pmids":["12508117"],"is_preprint":false},{"year":2004,"finding":"NuMA undergoes continuous exchange between soluble and spindle-associated pools at spindle poles with ~3-minute half-time in living cells (FRAP). Protein kinase activity and LGN binding regulate NuMA dynamics: kinase inhibition increases, and LGN modulates the rate of NuMA exchange at spindle poles.","method":"FRAP in living cells, GFP-NuMA, in vitro aster displacement assay, kinase inhibitors","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP in vivo combined with in vitro aster assay, pharmacological perturbations, single lab","pmids":["15561764"],"is_preprint":false},{"year":2019,"finding":"NuMA assembles microtubule asters at nuclear envelope breakdown in acentrosomal human cells, and these asters are assembled via dynein and NuMA's clustering activity. NuMA-mediated asters incorporate Eg5 and facilitate spindle bipolarization. In cells with centrosomes, NuMA also promotes the initial step of spindle bipolarization in early mitosis.","method":"Acentrosomal human cell system, siRNA, immunofluorescence, live cell imaging","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acentrosomal cell model, siRNA loss-of-function, functional spindle bipolarization readout, single lab","pmids":["31782546"],"is_preprint":false}],"current_model":"NuMA is a large coiled-coil nuclear/spindle protein that during mitosis is released from the nucleus via CDK1/Aurora-A phosphorylation, transported to spindle microtubule minus-ends by cytoplasmic dynein/dynactin (to which it binds via two distinct LIC-interaction sites, functioning as a dynein-activating adaptor), where it self-assembles into an insoluble matrix that cross-links and anchors microtubule minus-ends at spindle poles; at the cell cortex, NuMA is recruited via the LGN/Gαi/Ric-8A pathway and direct phosphoinositide binding to form clustered DDN (Dynein-Dynactin-NuMA) complexes that generate cooperative spindle-pulling forces for spindle positioning, with its cortical levels regulated by CDK1 (negative), Aurora-A (negative at poles/promoting cortical mobility), and Plk1 (negative), while during interphase NuMA contributes to nuclear architecture, rDNA transcription regulation, p53-selective target gene activation, homologous recombination repair via SNF2h chromatin remodeling, and 53BP1 sequestration, and in post-mitotic neurons regulates axonal microtubule organization and AIS assembly."},"narrative":{"mechanistic_narrative":"NUMA1 (NuMA) is a large coiled-coil protein that serves as the principal organizer of microtubule minus-ends at mitotic spindle poles and as the cortical force-transducer for spindle positioning [PMID:8898198, PMID:19255246]. Structurally it is a 236-kDa molecule with a ~207-nm central parallel coiled-coil rod flanked by globular N- and C-terminal domains [PMID:1541630, PMID:1541636, PMID:7781599], the C-terminal globular domains driving self-assembly into multiarm oligomers that build an insoluble, microtubule-independent matrix at spindle poles [PMID:10075938, PMID:10098933]. NuMA acts together with cytoplasmic dynein and dynactin, streaming poleward toward microtubule minus-ends in a mitosis-specific manner; this transport and pole assembly require intact dynein/dynactin [PMID:8898198, PMID:10811826], and NuMA functions as a dynein-activating adaptor through two LIC-binding sites [PMID:32413290] while also targeting dynactin and dynein activity directly to minus-ends via a dedicated C-terminal minus-end-binding module distinct from its microtubule-binding domain [PMID:29185983]. At the cell cortex NuMA is recruited through the Gαi/LGN/Ric-8A pathway—LGN acting as a conformational switch that simultaneously engages NuMA and Gαi, with Ric-8A GEF activity dissociating the complex—to assemble clustered dynein–dynactin–NuMA modules that generate cooperative spindle-pulling forces [PMID:15537540, PMID:16275912, PMID:29848445]; cortical targeting of NuMA alone suffices to pull the spindle [PMID:29848445]. A parallel LGN/Gαi-independent route uses direct binding of NuMA to PtdInsP/PtdInsP2 and a C-terminal membrane-binding domain for anaphase cortical enrichment [PMID:24996901, PMID:24371089]. NuMA's localization is gated by mitotic phosphorylation: CDK1 phosphorylation at T2055/T2040 and Plk1 phosphorylation restrain cortical binding, Aurora-A phosphorylation controls cytoplasm-to-pole exchange, and CDK1 inactivation/cyclin B degradation at anaphase releases NuMA from poles and promotes cortical accumulation [PMID:7769006, PMID:23921553, PMID:26832443, PMID:24371089, PMID:14710193, PMID:30456393]. In vivo, NuMA is essential for spindle-pole focusing and kinetochore-fiber maintenance and for spindle orientation in epithelial tissues, where its microtubule-binding function controls epidermal differentiation [PMID:19255246, PMID:26765568]. Beyond mitosis, NuMA contributes to interphase nuclear functions including PARsylation-dependent recruitment to DNA breaks and SNF2h-mediated homologous recombination [PMID:24753406], p53-selective p21 induction [PMID:23589328], rDNA transcription in the nucleolus [PMID:28981686], and 53BP1 sequestration [PMID:30812030], and in neurons it organizes axonal growth-cone microtubules and axon-initial-segment assembly [PMID:34793694, PMID:31727776]. The NUMA1-RARA fusion underlies a variant of acute promyelocytic leukemia, establishing RARα dysregulation as the essential lesion [PMID:9288109].","teleology":[{"year":1992,"claim":"Establishing NuMA's primary structure as a tripartite coiled-coil protein and its distinctive mitotic redistribution defined it as a candidate nuclear/spindle scaffold rather than a typical lamina component.","evidence":"cDNA cloning, sequence analysis, and dual immunofluorescence with anti-lamin antibodies","pmids":["1541630","1541636"],"confidence":"Medium","gaps":["Function of the globular domains not yet assigned","No mechanism for how segregation pathway differs from lamins"]},{"year":1995,"claim":"Direct structural visualization confirmed the central rod as the longest known parallel coiled-coil flanked by globular heads, providing the architectural basis for self-assembly and microtubule cross-linking.","evidence":"Electron microscopy of recombinant NuMA with cross-linking and circular dichroism","pmids":["7781599"],"confidence":"High","gaps":["Atomic structure of globular domains not resolved","Oligomerization state in cells not addressed"]},{"year":1995,"claim":"Immunodepletion and recombinant rescue in mitotic extracts established NuMA as functionally required for microtubule aster organization, settling whether it was merely a marker or an active organizer.","evidence":"Cell-free mitotic extract immunodepletion with recombinant add-back and in vitro aster assay","pmids":["7593190"],"confidence":"High","gaps":["Molecular partners mediating aster assembly not identified","Phosphorylation requirement not yet mapped"]},{"year":1996,"claim":"Identifying NuMA in a complex with dynein/dynactin and showing its depletion abolishes spindle poles connected NuMA to the minus-end transport machinery.","evidence":"Xenopus egg extract immunodepletion, Co-IP, and aster assembly assays","pmids":["8898198"],"confidence":"High","gaps":["Direct vs. indirect dynein binding not distinguished","Site of NuMA-dynein contact unknown"]},{"year":2000,"claim":"Live imaging of poleward NuMA streaming dependent on functional dynein/dynactin established that minus-end transport delivers NuMA to spindle poles.","evidence":"GFP live imaging, gel filtration, dominant-negative dynamitin, and dynein antibody inhibition","pmids":["10811826"],"confidence":"High","gaps":["Whether NuMA activates dynein motility not yet tested","Minus-end recognition mechanism unknown"]},{"year":2001,"claim":"Discovery that LGN binds the NuMA C-terminal tail and controls spindle-pole organization opened the cortical/spindle-orientation arm of NuMA function.","evidence":"Co-IP, RNAi, and Xenopus egg extract aster assays","pmids":["11781568"],"confidence":"High","gaps":["How LGN couples NuMA to the cortex not yet defined","Regulation of the interaction unknown"]},{"year":2002,"claim":"Mapping the tankyrase-binding RXXPDG motif and showing LGN sterically blocks NuMA's microtubule-stabilizing activity revealed competing C-terminal interactions controlling NuMA output.","evidence":"Yeast two-hybrid, in vitro binding, microtubule stabilization assays in extracts and cells","pmids":["12080061","12445386"],"confidence":"High","gaps":["Physiological balance of competing interactions not quantified","In vivo consequence of tankyrase binding unresolved at this stage"]},{"year":2004,"claim":"FRET and biochemical work defined LGN as a Gαi-regulated conformational switch linking NuMA to the cortex, and cyclin B degradation as the trigger releasing NuMA from poles in anaphase.","evidence":"FRET biosensor, live imaging, and Xenopus extract with non-degradable cyclin B","pmids":["15537540","14710193"],"confidence":"High","gaps":["Phosphatases reversing NuMA phosphorylation not identified here","Quantitative force output not measured"]},{"year":2005,"claim":"Demonstration that Ric-8A GEF activity catalytically dissociates Gαi/LGN/NuMA complexes and that NuMA is a major tankyrase-1 PARsylation acceptor added enzymatic regulators of cortical and spindle-pole NuMA.","evidence":"In vitro GEF assay with purified proteins; co-IP and siRNA for tankyrase-1/NuMA","pmids":["16275912","16076287"],"confidence":"Medium","gaps":["Functional consequence of NuMA PARsylation for force generation untested here","In vivo timing of Ric-8A action not resolved"]},{"year":2009,"claim":"Conditional knockout and pADPr-binding studies separated NuMA's roles in pole establishment versus maintenance and showed poly(ADP-ribose) provides non-covalent cross-linking at poles.","evidence":"Mouse conditional knockout in primary cells; in vitro pADPr binding and bead aster assays","pmids":["19255246","19759176"],"confidence":"High","gaps":["Relative contribution of pADPr vs. NuMA self-assembly to matrix not quantified","Centrosome-NuMA cooperation mechanism incomplete"]},{"year":2011,"claim":"Crystal structures of LGN/NuMA and LGN/mInsc complexes showed mutually exclusive TPR-repeat binding, defining the molecular logic by which polarity and spindle-tethering complexes are switched during asymmetric division.","evidence":"X-ray crystallography and in vitro competition binding","pmids":["21816348"],"confidence":"High","gaps":["Temporal handoff between mInsc and NuMA in cells not directly visualized","Affinity regulation by phosphorylation not addressed"]},{"year":2013,"claim":"Phosphosite-specific work established CDK1 (T2055) as a negative regulator of cortical NuMA counteracted by PPP2CA, and identified a Gαi/LGN-independent membrane-binding domain enabling anaphase cortical enrichment.","evidence":"Phosphomutant expression, CDK1 inhibition, RNAi rescue, FRAP, and spindle orientation assays","pmids":["23921553","24371089","24109598"],"confidence":"High","gaps":["Identity of the membrane lipid ligand not yet defined at this stage","Crosstalk between LGN and membrane routes unquantified"]},{"year":2014,"claim":"Identifying direct NuMA binding to phosphoinositides and DNA-damage-site recruitment via PARsylation/SNF2h extended NuMA function to a defined cortical lipid anchor and to homologous recombination.","evidence":"In vitro lipid-binding and PIP depletion assays; co-IP, FRAP, and DSB repair assays with CYLD/Dishevelled deubiquitination link","pmids":["24996901","24753406","24469800"],"confidence":"High","gaps":["Structural basis of lipid recognition unresolved","Mechanism of NuMA's interphase nuclear-to-damage redistribution incomplete"]},{"year":2016,"claim":"Aurora-A was shown to directly phosphorylate the NuMA C-terminus to control cytoplasm-pole exchange, and a non-overlapping microtubule-binding domain was found required for spindle orientation in vivo.","evidence":"In vitro kinase assay, FRAP, phosphomutants, conditional mouse models, and Astrin binding mapping","pmids":["26832443","26765568","27462074"],"confidence":"High","gaps":["Integration of Aurora-A with CDK1/Plk1 phosphoregulation not unified","How MT-binding controls differentiation mechanistically unclear"]},{"year":2017,"claim":"Defining NuMA as the factor that delivers dynactin to minus-ends, plus structural work on the Importin-α NLS and nucleolar/rDNA roles, refined both its spindle adaptor mechanism and its interphase nuclear functions.","evidence":"Laser-ablation minus-end assays, Importin-α/NuMA crystallography, and nucleolar co-IP/RNA-IP/ChIP","pmids":["29185983","28939615","28981686","28079116"],"confidence":"High","gaps":["How importin masking is relieved at NEBD not fully detailed","Direct rDNA transcriptional mechanism of NuMA undefined"]},{"year":2018,"claim":"Optogenetic reconstitution demonstrated cortical NuMA clusters dynein-dynactin into cooperative force modules sufficient for spindle pulling, and Plk1 was added as a phosphoregulator of cortical NuMA.","evidence":"Light-induced cortical targeting, domain-deletion, FRAP, and Plk1 kinase/inhibitor assays","pmids":["29848445","30456393"],"confidence":"Medium","gaps":["Stoichiometry of DDN clusters in vivo unmeasured","How clustering distinguishes pole-focusing from positioning unresolved"]},{"year":2019,"claim":"Acentrosomal-aster work and 53BP1/AIS studies broadened NuMA's role to spindle-independent aster nucleation, 53BP1 sequestration controlling repair pathway choice, and neuronal axon-initial-segment assembly.","evidence":"Acentrosomal cell system with live imaging; co-IP, single-molecule tracking, NHEJ assays; neuronal proteomics and shRNA","pmids":["31782546","30812030","31727776"],"confidence":"Medium","gaps":["Mechanism linking nuclear NuMA pools to repair choice incomplete","Neuronal NuMA partners beyond 4.1B/Lis1 not fully mapped"]},{"year":2020,"claim":"Structural identification of two LIC-binding sites confirmed NuMA as a bona fide dynein-activating adaptor required for spindle placement.","evidence":"Structural/biochemical interface determination and mitotic functional mutagenesis","pmids":["32413290"],"confidence":"High","gaps":["How both LIC sites cooperate during transport not resolved","Adaptor activity in interphase contexts untested"]},{"year":2021,"claim":"Phase-separation and neuronal-disease studies revealed NuMA forms condensates that concentrate spindle factors and that its loss recapitulates Huntington's disease growth-cone defects, extending NuMA into biophysical assembly and neuropathology.","evidence":"In vitro phase separation, Aurora-A regulation; neuronal proteomics, shRNA, antagomiR and microtubule-stabilizer rescue","pmids":["34887424","34793694"],"confidence":"Medium","gaps":["Whether phase separation underlies the in vivo pole matrix not established","Direct molecular link between miR-124/NuMA and HD pathology incomplete"]},{"year":null,"claim":"How the multiple phosphoregulatory inputs (CDK1, Aurora-A, Plk1), competing C-terminal interactions, lipid binding, and phase separation are integrated to switch NuMA between its nuclear, spindle-pole, and cortical activities in space and time remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of NuMA phosphoregulation","Structure of the full-length NuMA matrix/condensate unknown","Relationship between interphase nuclear roles and mitotic functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,17,21,24,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[21,22,32]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[12,26,45]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[16,28]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[35]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[33,36]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,21,26]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[16,22,28]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[35]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[42,43]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,14,15,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[33,36]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[34,35]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[46,47]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24,44]}],"complexes":["Dynein-Dynactin-NuMA (DDN) cortical cluster","Gαi/LGN/NuMA cortical complex","spindle pole matrix"],"partners":["DCTN1","LGN","GNAI1","TNKS","SNF2H","TP53","TP53BP1","EPB41"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14980","full_name":"Nuclear mitotic apparatus protein 1","aliases":["Nuclear matrix protein-22","NMP-22","Nuclear mitotic apparatus protein","NuMA protein","SP-H antigen"],"length_aa":2115,"mass_kda":238.3,"function":"Microtubule (MT)-binding protein that plays a role in the formation and maintenance of the spindle poles and the alignement and the segregation of chromosomes during mitotic cell division (PubMed:17172455, PubMed:19255246, PubMed:24996901, PubMed:26195665, PubMed:27462074, PubMed:7769006). Functions to tether the minus ends of MTs at the spindle poles, which is critical for the establishment and maintenance of the spindle poles (PubMed:11956313, PubMed:12445386). Plays a role in the establishment of the mitotic spindle orientation during metaphase and elongation during anaphase in a dynein-dynactin-dependent manner (PubMed:23870127, PubMed:24109598, PubMed:24996901, PubMed:26765568). In metaphase, part of a ternary complex composed of GPSM2 and G(i) alpha proteins, that regulates the recruitment and anchorage of the dynein-dynactin complex in the mitotic cell cortex regions situated above the two spindle poles, and hence regulates the correct oritentation of the mitotic spindle (PubMed:22327364, PubMed:23027904, PubMed:23921553). During anaphase, mediates the recruitment and accumulation of the dynein-dynactin complex at the cell membrane of the polar cortical region through direct association with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), and hence participates in the regulation of the spindle elongation and chromosome segregation (PubMed:22327364, PubMed:23921553, PubMed:24371089, PubMed:24996901). Also binds to other polyanionic phosphoinositides, such as phosphatidylinositol 3-phosphate (PIP), lysophosphatidic acid (LPA) and phosphatidylinositol triphosphate (PIP3), in vitro (PubMed:24371089, PubMed:24996901). Also required for proper orientation of the mitotic spindle during asymmetric cell divisions (PubMed:21816348). Plays a role in mitotic MT aster assembly (PubMed:11163243, PubMed:11229403, PubMed:12445386). Involved in anastral spindle assembly (PubMed:25657325). Positively regulates TNKS protein localization to spindle poles in mitosis (PubMed:16076287). Highly abundant component of the nuclear matrix where it may serve a non-mitotic structural role, occupies the majority of the nuclear volume (PubMed:10075938). Required for epidermal differentiation and hair follicle morphogenesis (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q14980/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUMA1","classification":"Common Essential","n_dependent_lines":700,"n_total_lines":1208,"dependency_fraction":0.5794701986754967},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000137497","cell_line_id":"CID001100","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"H1F0","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"HIST1H1D","stoichiometry":10.0},{"gene":"H1FX","stoichiometry":10.0},{"gene":"HIST1H2AC","stoichiometry":10.0},{"gene":"H2AFY2","stoichiometry":10.0},{"gene":"HIST2H2AB","stoichiometry":10.0},{"gene":"HIST3H2BB","stoichiometry":10.0},{"gene":"HMGN5","stoichiometry":4.0},{"gene":"MYO1E","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001100","total_profiled":1310},"omim":[{"mim_id":"616919","title":"FERM AND PDZ DOMAINS-CONTAINING PROTEIN 1; FRMPD1","url":"https://www.omim.org/entry/616919"},{"mim_id":"613529","title":"CENTROSOMAL PROTEIN, 152-KD; CEP152","url":"https://www.omim.org/entry/613529"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"612376","title":"ACUTE PROMYELOCYTIC LEUKEMIA; APL","url":"https://www.omim.org/entry/612376"},{"mim_id":"604260","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B; STAT5B","url":"https://www.omim.org/entry/604260"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUMA1"},"hgnc":{"alias_symbol":["NUMA"],"prev_symbol":[]},"alphafold":{"accession":"Q14980","domains":[{"cath_id":"1.10.418.10","chopping":"6-152","consensus_level":"high","plddt":72.8283,"start":6,"end":152},{"cath_id":"-","chopping":"497-533_566-824","consensus_level":"medium","plddt":76.0592,"start":497,"end":824},{"cath_id":"1.20.5","chopping":"826-887","consensus_level":"medium","plddt":71.3695,"start":826,"end":887},{"cath_id":"1.10.287","chopping":"1036-1101_1122-1327","consensus_level":"medium","plddt":76.9103,"start":1036,"end":1327},{"cath_id":"1.20.5","chopping":"1423-1559","consensus_level":"high","plddt":78.7312,"start":1423,"end":1559}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14980","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14980-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14980-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUMA1","jax_strain_url":"https://www.jax.org/strain/search?query=NUMA1"},"sequence":{"accession":"Q14980","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14980.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14980/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14980"}},"corpus_meta":[{"pmid":"8898198","id":"PMC_8898198","title":"A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly.","date":"1996","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8898198","citation_count":488,"is_preprint":false},{"pmid":"15537540","id":"PMC_15537540","title":"Mammalian Pins is a conformational switch that links NuMA to heterotrimeric G proteins.","date":"2004","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15537540","citation_count":321,"is_preprint":false},{"pmid":"10811826","id":"PMC_10811826","title":"Formation of spindle poles by dynein/dynactin-dependent transport of NuMA.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10811826","citation_count":280,"is_preprint":false},{"pmid":"16648843","id":"PMC_16648843","title":"The NuMA-related Mud protein binds Pins and regulates spindle orientation in Drosophila neuroblasts.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16648843","citation_count":267,"is_preprint":false},{"pmid":"16740476","id":"PMC_16740476","title":"The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division.","date":"2006","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/16740476","citation_count":251,"is_preprint":false},{"pmid":"11781568","id":"PMC_11781568","title":"A mammalian Partner of inscuteable binds NuMA and regulates mitotic spindle organization.","date":"2001","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11781568","citation_count":223,"is_preprint":false},{"pmid":"1541630","id":"PMC_1541630","title":"NuMA: an unusually long coiled-coil related protein in the mammalian nucleus.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1541630","citation_count":220,"is_preprint":false},{"pmid":"7593190","id":"PMC_7593190","title":"NuMA is required for the organization of microtubules into aster-like mitotic arrays.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7593190","citation_count":220,"is_preprint":false},{"pmid":"9288109","id":"PMC_9288109","title":"Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia.","date":"1997","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9288109","citation_count":211,"is_preprint":false},{"pmid":"1541636","id":"PMC_1541636","title":"Primary structure of NuMA, an intranuclear protein that defines a novel pathway for segregation of proteins at mitosis.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1541636","citation_count":207,"is_preprint":false},{"pmid":"8432734","id":"PMC_8432734","title":"NuMA is required for the proper completion of mitosis.","date":"1993","source":"The Journal of cell 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IRAP, TAB182, and human TRF1 but not mouse TRF1. 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A subdomain of the NuMA tail mediates microtubule bundling and aster formation.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, Co-IP, microtubule aster assembly assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in cell-free system, immunodepletion with rescue, multiple orthogonal methods, replicated by subsequent studies\",\n      \"pmids\": [\"8898198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NuMA is transported toward microtubule minus-ends at spindle poles via cytoplasmic dynein and dynactin. GFP-NuMA streams poleward in association with dynactin Arp1 subunit; disruption of dynactin (dynamitin overexpression) or dynein (antibody) blocks NuMA translocation and spindle pole assembly. NuMA-dynein-dynactin complex is mitosis-specific and reversible.\",\n      \"method\": \"GFP live imaging, immunoprecipitation, gel filtration, dominant-negative dynamitin overexpression, antibody inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, reciprocal co-IP, live imaging, functional perturbation, replicated across labs\",\n      \"pmids\": [\"10811826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NuMA is required for organization of microtubules into mitotic asters: immunodepletion from mammalian mitotic extracts abolishes aster formation, and addition of purified recombinant NuMA rescues aster assembly. NuMA is phosphorylated upon aster assembly and is required only in late stages of aster formation.\",\n      \"method\": \"Cell-free mitotic extract, immunodepletion, recombinant protein add-back, in vitro aster assembly assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified protein, immunodepletion with rescue, in vitro assay\",\n      \"pmids\": [\"7593190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"NuMA encodes a 236-kDa protein with a large central coiled-coil domain (~1,485 aa) flanked by globular N- and C-terminal domains. NuMA dissociates from chromatin in early prophase before nuclear lamina breakdown, and reassociates with telophase chromosomes before lamins, defining a novel pathway for nuclear protein segregation at mitosis.\",\n      \"method\": \"cDNA cloning, sequence analysis, double immunofluorescence with anti-NuMA and anti-lamin antibodies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary structure determination combined with cell biological localization, single lab but multiple methods\",\n      \"pmids\": [\"1541630\", \"1541636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Expression of NuMA lacking its globular head domain causes failure of cytokinesis and micronucleation. Expression of NuMA lacking its globular tail domain prevents targeting to interphase nuclei and mitotic spindle; cells transit mitosis normally but assemble micronuclei in daughter cells. Wild-type NuMA overexpression rescues nuclear assembly defects in RCC1-mutant tsBN2 cells.\",\n      \"method\": \"Dominant-negative mutant expression, cell cycle analysis, immunofluorescence, rescue experiment in temperature-sensitive cell line\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-deletion mutagenesis, rescue experiments, multiple phenotypic readouts, replicated across constructs\",\n      \"pmids\": [\"8432734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Mutation of threonine 2040 (a predicted p34cdc2 phosphorylation site) in NuMA abolishes its ability to associate with the mitotic spindle; instead, the mutant concentrates at the plasma membrane. Cells expressing these mutants have disorganized spindles and fail cytokinesis. NuMA is phosphorylated in a mitosis-specific manner in vivo.\",\n      \"method\": \"Site-directed mutagenesis, transient expression in tissue culture cells, immunofluorescence, in vivo phosphorylation labeling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific phosphorylation sites with defined functional phenotype, in vivo phosphorylation confirmed\",\n      \"pmids\": [\"7769006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LGN (mammalian Pins) acts as a conformational switch linking NuMA to Gαi at the cell cortex. In its closed state, LGN N- and C-termini interact; NuMA or Gαi disrupts this, allowing simultaneous binding to both and cortical localization. NuMA binding to LGN is required for metaphase spindle oscillations.\",\n      \"method\": \"FRET biosensor, overexpression, dominant-negative analysis, live cell imaging\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRET conformational analysis, genetic rescue, live imaging, multiple orthogonal methods\",\n      \"pmids\": [\"15537540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LGN binds directly to the C-terminal tail of NuMA. LGN associates with spindle poles during mitosis; ectopic expression or siRNA knockdown of LGN disrupts spindle-pole organization. Anti-LGN antibodies and LGN-binding domain of NuMA trigger microtubule aster formation in Xenopus egg extracts.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, Xenopus egg extract aster assay, immunofluorescence\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay, cell-free system, siRNA loss-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"11781568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"LGN blocks NuMA's ability to stabilize microtubules. NuMA C-terminus directly binds microtubules and stabilizes them; the LGN-binding domain on NuMA overlaps by 10 residues with the MT-binding domain. LGN exerts its inhibitory effect on spindle organization through steric exclusion of NuMA-MT interaction.\",\n      \"method\": \"In vitro microtubule stabilization assay, in vitro binding assay, Xenopus egg extracts, mammalian cell expression\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding and functional assay, domain mapping, multiple systems tested\",\n      \"pmids\": [\"12445386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NuMA is a major acceptor of poly(ADP-ribosyl)ation (PARsylation) by tankyrase 1 in mitosis. Association between tankyrase 1 and NuMA dramatically increases at mitotic onset, coincident with NuMA PARsylation. Tankyrase 1 siRNA knockdown eliminates NuMA PARsylation. NuMA siRNA knockdown causes complete loss of tankyrase 1 from spindle poles (NuMA is required for tankyrase 1 spindle pole localization).\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal knockdown experiments, co-IP, immunofluorescence, single lab\",\n      \"pmids\": [\"16076287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NuMA contains an RXXPDG motif that mediates its binding to the ankyrin repeat domain of tankyrase 1 and tankyrase 2. NuMA was identified as a tankyrase partner by yeast two-hybrid and verified by direct binding assay.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid plus direct binding verification, single lab, limited functional follow-up\",\n      \"pmids\": [\"12080061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Poly(ADP-ribose) (pADPr) from tankyrase 1 (PARP-5a) contributes to spindle pole assembly. The rod domain of NuMA binds directly to pADPr chains in vitro. pADPr-coated beads trigger aster assembly in mitotic lysates, suggesting pADPr provides dynamic cross-linking at spindle poles by binding NuMA non-covalently.\",\n      \"method\": \"Immunoelectron microscopy, concentrated mitotic lysate system, in vitro pADPr binding assay, pADPr-coated magnetic bead aster assembly\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of binding, functional aster assay, domain mapping, single lab\",\n      \"pmids\": [\"19759176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NuMA self-assembles in vitro into multiarm oligomers (up to 10–12 arms) via interaction of its C-terminal globular domains; each arm corresponds to a NuMA dimer. Computer modeling suggests 12-arm oligomers are structural units of the NuMA nuclear scaffold observed by EM in transfected cells.\",\n      \"method\": \"In vitro assembly of recombinant NuMA, electron microscopy, domain deletion analysis, computer modeling\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution, EM visualization, domain-deletion mapping, single lab\",\n      \"pmids\": [\"10075938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A 135-kDa nonerythroid isoform of protein 4.1R interacts directly with NuMA. The interaction is mediated by exons 20–21 of 4.1R and residues 1788–1810 of NuMA. 4.1R colocalizes with NuMA in interphase nuclei and at spindle poles; overexpression of 135-kDa 4.1R alters NuMA distribution in interphase nuclei.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, co-immunolocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal co-IP plus in vitro binding, domain mapping, functional consequence shown\",\n      \"pmids\": [\"10189366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NuMA is an essential mitotic component with distinct contributions to spindle pole establishment and maintenance. When NuMA mitotic function is disrupted using a conditional knockout in primary mouse cells, centrosomes provide initial focusing but centrosome attachment under tension is defective and kinetochore fiber maintenance at poles fails. Without both centrosomes and NuMA, spindle microtubule focusing completely fails.\",\n      \"method\": \"Conditional knockout allele in mice and primary cultured cells, immunofluorescence, live cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in primary cells and mice, epistasis with centrosome pathway, clean loss-of-function phenotype, rigorous genetic approach\",\n      \"pmids\": [\"19255246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK1-mediated phosphorylation of NuMA at T2055 negatively regulates NuMA cortical localization during metaphase; PPP2CA phosphatase activity counteracts this. CDK1 inactivation in anaphase leads to rise in dephosphorylated NuMA at cortex, increasing cortical dynein and promoting spindle elongation.\",\n      \"method\": \"Phosphomutant expression, CDK1 inhibitor experiments, siRNA, immunofluorescence, quantitative imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphosite mutagenesis with functional readout, pharmacological inhibition, phosphatase manipulation, multiple orthogonal approaches\",\n      \"pmids\": [\"23921553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NuMA directly associates with PtdInsP (PIP) and PtdInsP2 (PIP2) phosphoinositides in vitro, providing a LGN/Gαi-independent mechanism for cortical localization. Chemical or enzymatic depletion of PIP/PIP2 prevents NuMA cortical localization during mitosis; increasing PIP2 augments cortical NuMA. During anaphase, LGN/Gαi are dispensable for NuMA-dependent cortical dynein enrichment.\",\n      \"method\": \"In vitro lipid-binding assay, chemical/enzymatic PIP depletion, immunofluorescence, genetic knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding assay, pharmacological and enzymatic depletion, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24996901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aurora-A directly phosphorylates NuMA C-terminus on three serine residues including Ser1969, controlling dynamic exchange of NuMA between cytoplasm and spindle poles. Partial Aurora-A inhibition causes NuMA/dynein accumulation at spindle poles without reaching cortex while LGN cortical distribution is unperturbed. A new microtubule-binding domain of NuMA was identified that does not overlap with the LGN-binding motif, allowing simultaneous binding to LGN and microtubules.\",\n      \"method\": \"In vitro kinase assay, FRAP, phosphomutant expression, Aurora-A partial inhibition, immunofluorescence\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay, FRAP dynamics, phosphosite mutagenesis with functional readouts, domain mapping\",\n      \"pmids\": [\"26832443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of LGN/NuMA and LGN/mInsc complexes show that NuMA and Inscuteable bind the same TPR repeats of LGN in a mutually exclusive manner, with mInsc binding with higher affinity. The Par3/mInsc/LGN and NuMA/LGN/Gαi complexes play sequential and overlapping roles in asymmetric cell division.\",\n      \"method\": \"X-ray crystallography, in vitro competition binding assay, cell biology\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at high resolution with biochemical validation and functional cell biology studies\",\n      \"pmids\": [\"21816348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ric-8A GEF activity catalytically dissociates Gαi-GDP/LGN/NuMA complexes in vitro, releasing activated Gαi-GTP and concomitantly liberating NuMA from LGN. Ric-8A efficiently uses GoLoco/Gαi-GDP complexes as substrates.\",\n      \"method\": \"In vitro GEF assay with purified proteins, biochemical dissociation experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified components, GEF activity directly measured, single lab\",\n      \"pmids\": [\"16275912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ric-8A and Gαi function to recruit LGN, NuMA, and dynein to the cell cortex for mitotic spindle orientation. Pertussis toxin (blocking Ric-8A GEF activity for Gαi), Ric-8A knockdown, or Gαi knockdown each impair cortical localization of LGN, NuMA, and dynein, and disturb integrin-dependent spindle orientation.\",\n      \"method\": \"Pertussis toxin treatment, siRNA knockdown, immunofluorescence, live cell imaging of GFP-tubulin\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, cortical localization readout, single lab with orthogonal approaches\",\n      \"pmids\": [\"20479129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NuMA targets dynactin to microtubule minus-ends, localizing dynein activity there. NuMA is recruited to new minus-ends independently of dynein and faster than dynactin; both NuMA and dynactin show steady-state minus-end binding. NuMA localization to minus-ends requires a C-terminal region outside its canonical MT-binding domain. Both NuMA's minus-end-binding and dynein-dynactin-binding modules are required for focused bipolar spindle organization.\",\n      \"method\": \"Quantitative live imaging, laser ablation to generate new minus-ends, domain-deletion analysis, siRNA rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — laser ablation plus quantitative imaging, domain-deletion rescue, multiple orthogonal approaches, mechanistic epistasis established\",\n      \"pmids\": [\"29185983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cortical NuMA assembles specialized focal structures that cluster multiple dynein-dynactin force-generating modules (DDN clusters) to produce cooperative spindle-pulling forces. Induced cortical targeting of NuMA alone (not dynein) is sufficient for spindle pulling. This clustering activity is required for spindle positioning but not spindle-pole focusing.\",\n      \"method\": \"Light-induced cortical reconstitution system in human cells, live imaging, domain-deletion analysis, siRNA\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — optogenetic reconstitution, domain-separation of clustering vs. pole-focusing function, quantitative imaging, rigorous controls\",\n      \"pmids\": [\"29848445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NuMA is required to recruit dynactin to the keratinocyte cell cortex. The 4.1-binding domain of NuMA stabilizes its cortical interaction (shown by FRAP); loss of 4.1/NuMA interaction causes spindle orientation defects. CDK1 inhibition or mutation of a single NuMA residue increases cortical NuMA localization in anaphase via an LGN- and 4.1-independent mechanism.\",\n      \"method\": \"siRNA, FRAP, phosphomutant expression, immunofluorescence, spindle orientation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP dynamics, multiple mutant analyses, functional spindle orientation readout, single lab\",\n      \"pmids\": [\"24109598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NuMA's microtubule-binding domain, which targets microtubule tips, is required for spindle orientation in keratinocytes in addition to dynein/dynactin. Loss of NuMA-MT interactions in skin causes spindle orientation defects, epidermal differentiation defects, and neonatal lethality in mice. NuMA-MT interactions are also required in adult hair follicle matrix cells for proper differentiation.\",\n      \"method\": \"Conditional knockout/knock-in mice, MT-binding domain mutation, in vivo histology and immunofluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional mouse models, domain-specific separation-of-function mutations, multiple tissue contexts validated\",\n      \"pmids\": [\"26765568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rae1 interacts with NuMA in a mitosis-specific manner. A specific binding site for Rae1 on NuMA was mapped that would convert a NuMA dimer into a tetravalent MT crosslinker. Overexpression of Rae1 Rac binding domain of NuMA in HeLa cells leads to aberrant spindle formation; coupling Rae1 overexpression to NuMA overexpression or co-depleting both prevents aberrant spindles.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, overexpression and knockdown epistasis, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site mapping, genetic epistasis by double perturbation, functional spindle readout, single lab\",\n      \"pmids\": [\"17172455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NuMA forms an insoluble matrix at spindle poles distinct from pericentriolar material. Once incorporated into this matrix in vivo or in vitro, NuMA's insolubility is no longer dependent on microtubules. Immunodepletion of NuMA from mitotic extracts prevents formation of this insoluble matrix at aster cores.\",\n      \"method\": \"Immunogold electron microscopy, solubility fractionation, immunodepletion from mitotic extracts\",\n      \"journal\": \"Cell motility and the cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoelectron microscopy, biochemical fractionation, immunodepletion, single lab\",\n      \"pmids\": [\"10098933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The NuMA-RARA fusion protein from APL t(11;17) variant forms sheet-like nuclear aggregates with which normal NuMA partly co-localizes, while PML organization remains normal. This establishes that RARα dysregulation rather than PML disruption is essential for APL.\",\n      \"method\": \"Characterization of patient-derived fusion gene, immunofluorescence co-localization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and characterization of fusion protein in patient cells, functional inference, single study\",\n      \"pmids\": [\"9288109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cell cycle-regulated membrane binding of NuMA via a Gαi/LGN-independent lipid/membrane-binding domain at the NuMA C-terminus underlies anaphase-specific cortical NuMA enrichment. CDK1 phosphorylation inhibits this membrane binding during prophase/metaphase; CDK1 inactivation at anaphase onset enables membrane binding. Membrane-binding-deficient NuMA specifically reduces anaphase cortical dynein, impairing chromosome separation.\",\n      \"method\": \"Domain mapping, phosphomutant expression, CDK1 inhibition, endogenous NuMA replacement by RNAi + rescue, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous replacement strategy, phosphosite-specific mutants, CDK1 epistasis, functional chromosome separation readout\",\n      \"pmids\": [\"24371089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Cyclin B degradation in anaphase leads to NuMA dephosphorylation and release from dynein/dynactin and from spindle poles in Xenopus egg extracts. Non-degradable cyclin B (Δ90) keeps NuMA phosphorylated, associated with dynein/dynactin, and locked at stable spindle poles that fail to disassemble.\",\n      \"method\": \"Xenopus egg extract, non-degradable cyclin B expression, immunoprecipitation, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-free system with defined biochemical perturbation, phosphorylation state analysis, functional spindle readout\",\n      \"pmids\": [\"14710193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NuMA is phosphorylated during nuclear breakdown (G2/M transition) in a mitosis-specific manner. This phosphorylation occurs before spindle formation (present in nocodazole-treated cells) and does not require microtubule assembly. Dephosphorylation occurs in two distinct steps in early G1 and at end of G1.\",\n      \"method\": \"32P-orthophosphate labeling of synchronized cells, phosphatase treatment, nocodazole arrest\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — radiolabeling in synchronized cells, phosphatase validation, drug perturbation, single lab\",\n      \"pmids\": [\"9202389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of Importin-α/NuMA-C-terminus complex reveals a novel NLS binding pattern. Importin-β, in the presence of Importin-α, inhibits the microtubule-binding function of NuMA by sterically masking a high-affinity MT-binding region C-terminal to the NLS.\",\n      \"method\": \"X-ray crystallography, in vitro microtubule-binding assay, domain mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical functional validation, in vitro MT-binding inhibition assay, mechanistic model directly tested\",\n      \"pmids\": [\"28939615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NuMA contains two LIC (light intermediate chain)-binding sites: a hook domain contacting LIC1 and LIC2 via a conserved hydrophobic patch, and a CC1-box homologous motif in the coiled-coil region. Both LIC-binding sites are essential for correct spindle placement and cell division, establishing NuMA as a dynein-activating adaptor.\",\n      \"method\": \"Structural studies (crystal/biochemical), mitotic cell functional assays, domain mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination of interaction interface, mutagenesis of both binding sites with mitotic functional readout\",\n      \"pmids\": [\"32413290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NuMA accumulates at DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner and directly interacts with ISWI ATPase SNF2h. NuMA co-immunoprecipitates with SNF2h, regulates its nucleoplasmic diffusion, and controls its accumulation at DNA breaks. NuMA knockdown reduces chromatin decompaction after DNA cleavage, impairs recruitment of homologous recombination factors, and impairs DSB repair in chromosomal contexts.\",\n      \"method\": \"Co-immunoprecipitation, FRAP, siRNA knockdown, DNA damage assays, HR factor recruitment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, FRAP dynamics, functional DNA repair assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24753406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NuMA binds to p53 and is required for selective induction of p21 (but not PUMA) following DNA damage. NuMA knockdown attenuates p21 induction and impairs cell cycle arrest. NuMA is required for recruitment of CDK8 (Mediator complex component) to the p21 promoter.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, gene expression analysis, ChIP (CDK8 recruitment)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding (co-IP), functional transcription assay, chromatin recruitment assay, single lab\",\n      \"pmids\": [\"23589328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NuMA is present in the nucleolus and co-immunoprecipitates with RNA polymerase I, ribosomal proteins RPL26 and RPL24, and B-WICH chromatin remodeling complex components. NuMA binds 18S and 28S rRNAs and localizes to rDNA promoter regions. NuMA downregulation triggers nucleolar stress with decreased pre-rRNA synthesis and p27kip1 upregulation independent of p53.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, ChIP at rDNA promoters, siRNA knockdown, nascent RNA synthesis assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays (co-IP, RNA-IP, ChIP), functional loss-of-function, single lab\",\n      \"pmids\": [\"28981686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NuMA interacts with 53BP1 and constrains 53BP1 diffusion throughout the nucleoplasm in the absence of DNA damage. This interaction is reduced after DNA damage. NuMA prevents 53BP1 accumulation at DNA breaks; NuMA knockdown enhances NHEJ and 53BP1-dependent activities.\",\n      \"method\": \"Co-immunoprecipitation, single-molecule tracking/FRAP, siRNA knockdown, NHEJ assay, immunoglobulin class switching\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct co-IP, diffusion dynamics measurement, functional repair assay, single lab\",\n      \"pmids\": [\"30812030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"GAS41 binds in vitro to the C-terminal part of the NuMA rod region with Kd of 2×10⁻⁷ M. GAS41 shows a dotted nuclear staining in interphase. Interaction identified by yeast two-hybrid and confirmed by dot overlay and surface plasmon resonance.\",\n      \"method\": \"Yeast two-hybrid, dot overlay assay, surface plasmon resonance\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by SPR with Kd measurement, biochemical binding, single lab\",\n      \"pmids\": [\"10913114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plk1 directly interacts with and phosphorylates NuMA, reducing NuMA's cortical localization. Acute Plk1 inhibition during metaphase enriches cortical NuMA/dynein/LGN levels and alters NuMA dynamics at the cortex. This Plk1-NuMA phosphorylation is required for precise spindle orientation.\",\n      \"method\": \"In vitro kinase assay, Plk1 inhibitor (acute inactivation), phosphomutant expression, immunofluorescence, FRAP\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, pharmacological inhibition, phosphomutant functional analysis, single lab\",\n      \"pmids\": [\"30456393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NuMA undergoes liquid-liquid phase separation during mitotic entry; this is mediated by its C-terminus and facilitated by its dynein-dynactin binding motif. KifC1 promotes NuMA condensate concentration at spindle poles. Phase-separated NuMA droplets concentrate tubulins, bind microtubules, and enrich Kif2A, which depolymerizes spindle MTs for poleward flux. Aurora-A phosphorylation regulates NuMA phase separation.\",\n      \"method\": \"In vitro phase separation assay, live cell imaging, Aurora-A inhibition, siRNA knockdown, domain mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phase separation demonstration, Aurora-A regulation tested, functional consequences measured, single lab\",\n      \"pmids\": [\"34887424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C-terminal tail of NuMA directly binds the C-terminus of Astrin, helping to recruit Astrin to microtubules. NuMA knockdown dramatically impairs Astrin spindle localization. Cytoplasmic dynein is required for spindle pole accumulation of Astrin. Reduced Astrin levels impair NuMA concentration at spindle poles (reciprocal dependency).\",\n      \"method\": \"In vitro direct binding assay, co-immunoprecipitation, RNAi knockdown, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro direct binding, reciprocal siRNA epistasis, co-IP, single lab\",\n      \"pmids\": [\"27462074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CYLD deubiquitinase deubiquitinates the cortical polarity protein Dishevelled, which enhances Dishevelled's interaction with NuMA, stimulating cortical localization of NuMA and dynein/dynactin. This is required for generating pulling forces on astral microtubules for spindle orientation.\",\n      \"method\": \"Deubiquitination assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, spindle orientation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical deubiquitination assay, co-IP of Dishevelled-NuMA, functional spindle orientation readout, single lab\",\n      \"pmids\": [\"24469800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUMA1 is downregulated in Huntington's disease neural progenitor growth cones by miR-124. NUMA1 regulates microtubule organization in axonal growth cones; suppressing NUMA1 recapitulates HD microtubule bundling defects and impairs axonal growth. Raising NUMA1 levels with antagomiR-124 or stabilizing microtubules rescues axonal growth defects.\",\n      \"method\": \"Proteomic analysis of growth cones, shRNA knockdown, antagomiR-124, epothilone B treatment, microtubule imaging in growth cones\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and rescue experiments in neurons, multiple perturbations, proteomic discovery confirmed functionally, single lab\",\n      \"pmids\": [\"34793694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NuMA1 is transiently localized at the axon initial segment (AIS) during development where it interacts with scaffolding protein 4.1B and dynein regulator Lis1. NuMA1 silencing disrupts AIS assembly (not maintenance). NuMA1 inhibits endocytosis of AIS protein neurofascin-186 by impeding Lis1's interaction with doublecortin.\",\n      \"method\": \"Differential proteomics, shRNA knockdown, overexpression, co-immunoprecipitation, endocytosis assay, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of binding partners, functional endocytosis assay, shRNA phenotype, single lab\",\n      \"pmids\": [\"31727776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Katanin p80 regulates microtubule remodeling in combination with NuMA and cytoplasmic dynein. Depletion of p80 and/or NuMA induces abnormal mitotic phenotypes in mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in mouse embryonic brain, placing p80 and NuMA in a common pathway for MT organization at spindle poles.\",\n      \"method\": \"siRNA knockdown, in utero electroporation in mouse brain, patient-derived iPSCs and brain organoids, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown, in vivo neural phenotype, iPSC validation, single lab\",\n      \"pmids\": [\"28079116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Electron microscopy of recombinant full-length NuMA reveals a tripartite structure: a 207-nm long central rod domain that is a double-stranded parallel coiled-coil (the longest known at the time), flanked by globular N- and C-terminal domains. Chemical cross-linking and circular dichroism confirm the coiled-coil structure.\",\n      \"method\": \"Electron microscopy of purified recombinant NuMA, chemical cross-linking, circular dichroism spectroscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural visualization of purified recombinant protein, multiple biophysical methods, precise domain dimensions established\",\n      \"pmids\": [\"7781599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NuMA is cleaved in apoptosis between residues 1701 and 1725 to produce a stable 180–200 kDa fragment. TPCK protease inhibitor retards both apoptotic morphology and NuMA cleavage, whereas ICE inhibitor II does not, suggesting a serine-type protease involvement. NuMA redistribution and cleavage are early nuclear events in apoptosis.\",\n      \"method\": \"Apoptosis induction, immunoblotting, protease inhibitor panel, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage site mapped, protease inhibitor panel, immunoblot confirmation, single lab\",\n      \"pmids\": [\"9184071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NuMA is preferentially cleaved by caspase-3 in vivo during Fas-mediated apoptosis (not cleaved in caspase-3-null MCF-7 cells). NuMA is cleaved coincidently with PARP-1 and lamin B; cleavage is inhibited by z-DEVD-FMK, z-VEID-FMK, and z-IETD-FMK caspase inhibitors.\",\n      \"method\": \"Caspase-3-null cell line, caspase inhibitors, immunoblotting, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null cell line used to identify responsible caspase, inhibitor panel, single lab\",\n      \"pmids\": [\"12508117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NuMA undergoes continuous exchange between soluble and spindle-associated pools at spindle poles with ~3-minute half-time in living cells (FRAP). Protein kinase activity and LGN binding regulate NuMA dynamics: kinase inhibition increases, and LGN modulates the rate of NuMA exchange at spindle poles.\",\n      \"method\": \"FRAP in living cells, GFP-NuMA, in vitro aster displacement assay, kinase inhibitors\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP in vivo combined with in vitro aster assay, pharmacological perturbations, single lab\",\n      \"pmids\": [\"15561764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NuMA assembles microtubule asters at nuclear envelope breakdown in acentrosomal human cells, and these asters are assembled via dynein and NuMA's clustering activity. NuMA-mediated asters incorporate Eg5 and facilitate spindle bipolarization. In cells with centrosomes, NuMA also promotes the initial step of spindle bipolarization in early mitosis.\",\n      \"method\": \"Acentrosomal human cell system, siRNA, immunofluorescence, live cell imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acentrosomal cell model, siRNA loss-of-function, functional spindle bipolarization readout, single lab\",\n      \"pmids\": [\"31782546\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NuMA is a large coiled-coil nuclear/spindle protein that during mitosis is released from the nucleus via CDK1/Aurora-A phosphorylation, transported to spindle microtubule minus-ends by cytoplasmic dynein/dynactin (to which it binds via two distinct LIC-interaction sites, functioning as a dynein-activating adaptor), where it self-assembles into an insoluble matrix that cross-links and anchors microtubule minus-ends at spindle poles; at the cell cortex, NuMA is recruited via the LGN/Gαi/Ric-8A pathway and direct phosphoinositide binding to form clustered DDN (Dynein-Dynactin-NuMA) complexes that generate cooperative spindle-pulling forces for spindle positioning, with its cortical levels regulated by CDK1 (negative), Aurora-A (negative at poles/promoting cortical mobility), and Plk1 (negative), while during interphase NuMA contributes to nuclear architecture, rDNA transcription regulation, p53-selective target gene activation, homologous recombination repair via SNF2h chromatin remodeling, and 53BP1 sequestration, and in post-mitotic neurons regulates axonal microtubule organization and AIS assembly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUMA1 (NuMA) is a large coiled-coil protein that serves as the principal organizer of microtubule minus-ends at mitotic spindle poles and as the cortical force-transducer for spindle positioning [#0, #14]. Structurally it is a 236-kDa molecule with a ~207-nm central parallel coiled-coil rod flanked by globular N- and C-terminal domains [#3, #45], the C-terminal globular domains driving self-assembly into multiarm oligomers that build an insoluble, microtubule-independent matrix at spindle poles [#12, #26]. NuMA acts together with cytoplasmic dynein and dynactin, streaming poleward toward microtubule minus-ends in a mitosis-specific manner; this transport and pole assembly require intact dynein/dynactin [#0, #1], and NuMA functions as a dynein-activating adaptor through two LIC-binding sites [#32] while also targeting dynactin and dynein activity directly to minus-ends via a dedicated C-terminal minus-end-binding module distinct from its microtubule-binding domain [#21]. At the cell cortex NuMA is recruited through the Gαi/LGN/Ric-8A pathway—LGN acting as a conformational switch that simultaneously engages NuMA and Gαi, with Ric-8A GEF activity dissociating the complex—to assemble clustered dynein–dynactin–NuMA modules that generate cooperative spindle-pulling forces [#6, #19, #22]; cortical targeting of NuMA alone suffices to pull the spindle [#22]. A parallel LGN/Gαi-independent route uses direct binding of NuMA to PtdInsP/PtdInsP2 and a C-terminal membrane-binding domain for anaphase cortical enrichment [#16, #28]. NuMA's localization is gated by mitotic phosphorylation: CDK1 phosphorylation at T2055/T2040 and Plk1 phosphorylation restrain cortical binding, Aurora-A phosphorylation controls cytoplasm-to-pole exchange, and CDK1 inactivation/cyclin B degradation at anaphase releases NuMA from poles and promotes cortical accumulation [#5, #15, #17, #28, #29, #38]. In vivo, NuMA is essential for spindle-pole focusing and kinetochore-fiber maintenance and for spindle orientation in epithelial tissues, where its microtubule-binding function controls epidermal differentiation [#14, #24]. Beyond mitosis, NuMA contributes to interphase nuclear functions including PARsylation-dependent recruitment to DNA breaks and SNF2h-mediated homologous recombination [#33], p53-selective p21 induction [#34], rDNA transcription in the nucleolus [#35], and 53BP1 sequestration [#36], and in neurons it organizes axonal growth-cone microtubules and axon-initial-segment assembly [#42, #43]. The NUMA1-RARA fusion underlies a variant of acute promyelocytic leukemia, establishing RARα dysregulation as the essential lesion [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing NuMA's primary structure as a tripartite coiled-coil protein and its distinctive mitotic redistribution defined it as a candidate nuclear/spindle scaffold rather than a typical lamina component.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and dual immunofluorescence with anti-lamin antibodies\",\n      \"pmids\": [\"1541630\", \"1541636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the globular domains not yet assigned\", \"No mechanism for how segregation pathway differs from lamins\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Direct structural visualization confirmed the central rod as the longest known parallel coiled-coil flanked by globular heads, providing the architectural basis for self-assembly and microtubule cross-linking.\",\n      \"evidence\": \"Electron microscopy of recombinant NuMA with cross-linking and circular dichroism\",\n      \"pmids\": [\"7781599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of globular domains not resolved\", \"Oligomerization state in cells not addressed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Immunodepletion and recombinant rescue in mitotic extracts established NuMA as functionally required for microtubule aster organization, settling whether it was merely a marker or an active organizer.\",\n      \"evidence\": \"Cell-free mitotic extract immunodepletion with recombinant add-back and in vitro aster assay\",\n      \"pmids\": [\"7593190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating aster assembly not identified\", \"Phosphorylation requirement not yet mapped\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying NuMA in a complex with dynein/dynactin and showing its depletion abolishes spindle poles connected NuMA to the minus-end transport machinery.\",\n      \"evidence\": \"Xenopus egg extract immunodepletion, Co-IP, and aster assembly assays\",\n      \"pmids\": [\"8898198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect dynein binding not distinguished\", \"Site of NuMA-dynein contact unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Live imaging of poleward NuMA streaming dependent on functional dynein/dynactin established that minus-end transport delivers NuMA to spindle poles.\",\n      \"evidence\": \"GFP live imaging, gel filtration, dominant-negative dynamitin, and dynein antibody inhibition\",\n      \"pmids\": [\"10811826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NuMA activates dynein motility not yet tested\", \"Minus-end recognition mechanism unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that LGN binds the NuMA C-terminal tail and controls spindle-pole organization opened the cortical/spindle-orientation arm of NuMA function.\",\n      \"evidence\": \"Co-IP, RNAi, and Xenopus egg extract aster assays\",\n      \"pmids\": [\"11781568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LGN couples NuMA to the cortex not yet defined\", \"Regulation of the interaction unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping the tankyrase-binding RXXPDG motif and showing LGN sterically blocks NuMA's microtubule-stabilizing activity revealed competing C-terminal interactions controlling NuMA output.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, microtubule stabilization assays in extracts and cells\",\n      \"pmids\": [\"12080061\", \"12445386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance of competing interactions not quantified\", \"In vivo consequence of tankyrase binding unresolved at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"FRET and biochemical work defined LGN as a Gαi-regulated conformational switch linking NuMA to the cortex, and cyclin B degradation as the trigger releasing NuMA from poles in anaphase.\",\n      \"evidence\": \"FRET biosensor, live imaging, and Xenopus extract with non-degradable cyclin B\",\n      \"pmids\": [\"15537540\", \"14710193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatases reversing NuMA phosphorylation not identified here\", \"Quantitative force output not measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that Ric-8A GEF activity catalytically dissociates Gαi/LGN/NuMA complexes and that NuMA is a major tankyrase-1 PARsylation acceptor added enzymatic regulators of cortical and spindle-pole NuMA.\",\n      \"evidence\": \"In vitro GEF assay with purified proteins; co-IP and siRNA for tankyrase-1/NuMA\",\n      \"pmids\": [\"16275912\", \"16076287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of NuMA PARsylation for force generation untested here\", \"In vivo timing of Ric-8A action not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Conditional knockout and pADPr-binding studies separated NuMA's roles in pole establishment versus maintenance and showed poly(ADP-ribose) provides non-covalent cross-linking at poles.\",\n      \"evidence\": \"Mouse conditional knockout in primary cells; in vitro pADPr binding and bead aster assays\",\n      \"pmids\": [\"19255246\", \"19759176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of pADPr vs. NuMA self-assembly to matrix not quantified\", \"Centrosome-NuMA cooperation mechanism incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystal structures of LGN/NuMA and LGN/mInsc complexes showed mutually exclusive TPR-repeat binding, defining the molecular logic by which polarity and spindle-tethering complexes are switched during asymmetric division.\",\n      \"evidence\": \"X-ray crystallography and in vitro competition binding\",\n      \"pmids\": [\"21816348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal handoff between mInsc and NuMA in cells not directly visualized\", \"Affinity regulation by phosphorylation not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Phosphosite-specific work established CDK1 (T2055) as a negative regulator of cortical NuMA counteracted by PPP2CA, and identified a Gαi/LGN-independent membrane-binding domain enabling anaphase cortical enrichment.\",\n      \"evidence\": \"Phosphomutant expression, CDK1 inhibition, RNAi rescue, FRAP, and spindle orientation assays\",\n      \"pmids\": [\"23921553\", \"24371089\", \"24109598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the membrane lipid ligand not yet defined at this stage\", \"Crosstalk between LGN and membrane routes unquantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying direct NuMA binding to phosphoinositides and DNA-damage-site recruitment via PARsylation/SNF2h extended NuMA function to a defined cortical lipid anchor and to homologous recombination.\",\n      \"evidence\": \"In vitro lipid-binding and PIP depletion assays; co-IP, FRAP, and DSB repair assays with CYLD/Dishevelled deubiquitination link\",\n      \"pmids\": [\"24996901\", \"24753406\", \"24469800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of lipid recognition unresolved\", \"Mechanism of NuMA's interphase nuclear-to-damage redistribution incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Aurora-A was shown to directly phosphorylate the NuMA C-terminus to control cytoplasm-pole exchange, and a non-overlapping microtubule-binding domain was found required for spindle orientation in vivo.\",\n      \"evidence\": \"In vitro kinase assay, FRAP, phosphomutants, conditional mouse models, and Astrin binding mapping\",\n      \"pmids\": [\"26832443\", \"26765568\", \"27462074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of Aurora-A with CDK1/Plk1 phosphoregulation not unified\", \"How MT-binding controls differentiation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining NuMA as the factor that delivers dynactin to minus-ends, plus structural work on the Importin-α NLS and nucleolar/rDNA roles, refined both its spindle adaptor mechanism and its interphase nuclear functions.\",\n      \"evidence\": \"Laser-ablation minus-end assays, Importin-α/NuMA crystallography, and nucleolar co-IP/RNA-IP/ChIP\",\n      \"pmids\": [\"29185983\", \"28939615\", \"28981686\", \"28079116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How importin masking is relieved at NEBD not fully detailed\", \"Direct rDNA transcriptional mechanism of NuMA undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Optogenetic reconstitution demonstrated cortical NuMA clusters dynein-dynactin into cooperative force modules sufficient for spindle pulling, and Plk1 was added as a phosphoregulator of cortical NuMA.\",\n      \"evidence\": \"Light-induced cortical targeting, domain-deletion, FRAP, and Plk1 kinase/inhibitor assays\",\n      \"pmids\": [\"29848445\", \"30456393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of DDN clusters in vivo unmeasured\", \"How clustering distinguishes pole-focusing from positioning unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Acentrosomal-aster work and 53BP1/AIS studies broadened NuMA's role to spindle-independent aster nucleation, 53BP1 sequestration controlling repair pathway choice, and neuronal axon-initial-segment assembly.\",\n      \"evidence\": \"Acentrosomal cell system with live imaging; co-IP, single-molecule tracking, NHEJ assays; neuronal proteomics and shRNA\",\n      \"pmids\": [\"31782546\", \"30812030\", \"31727776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking nuclear NuMA pools to repair choice incomplete\", \"Neuronal NuMA partners beyond 4.1B/Lis1 not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structural identification of two LIC-binding sites confirmed NuMA as a bona fide dynein-activating adaptor required for spindle placement.\",\n      \"evidence\": \"Structural/biochemical interface determination and mitotic functional mutagenesis\",\n      \"pmids\": [\"32413290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How both LIC sites cooperate during transport not resolved\", \"Adaptor activity in interphase contexts untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Phase-separation and neuronal-disease studies revealed NuMA forms condensates that concentrate spindle factors and that its loss recapitulates Huntington's disease growth-cone defects, extending NuMA into biophysical assembly and neuropathology.\",\n      \"evidence\": \"In vitro phase separation, Aurora-A regulation; neuronal proteomics, shRNA, antagomiR and microtubule-stabilizer rescue\",\n      \"pmids\": [\"34887424\", \"34793694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether phase separation underlies the in vivo pole matrix not established\", \"Direct molecular link between miR-124/NuMA and HD pathology incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple phosphoregulatory inputs (CDK1, Aurora-A, Plk1), competing C-terminal interactions, lipid binding, and phase separation are integrated to switch NuMA between its nuclear, spindle-pole, and cortical activities in space and time remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of NuMA phosphoregulation\", \"Structure of the full-length NuMA matrix/condensate unknown\", \"Relationship between interphase nuclear roles and mitotic functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 17, 21, 24, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [21, 22, 32]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [12, 26, 45]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [16, 28]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [35]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [33, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 21, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16, 22, 28]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [35]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [42, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 14, 15, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [33, 36]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [34, 35]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [46, 47]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24, 44]}\n    ],\n    \"complexes\": [\n      \"Dynein-Dynactin-NuMA (DDN) cortical cluster\",\n      \"Gαi/LGN/NuMA cortical complex\",\n      \"spindle pole matrix\"\n    ],\n    \"partners\": [\n      \"DCTN1\",\n      \"LGN\",\n      \"GNAI1\",\n      \"TNKS\",\n      \"SNF2h\",\n      \"TP53\",\n      \"TP53BP1\",\n      \"EPB41\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}