{"gene":"ANLN","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1995,"finding":"Anillin (Drosophila) directly binds actin filaments and bundles them through a defined 244-amino-acid domain; it localizes to the nucleus during interphase and becomes enriched in the cleavage furrow with myosin II during anaphase-telophase, suggesting a role in organizing/stabilizing contractile domains of the actin cytoskeleton.","method":"Actin filament chromatography, cDNA cloning, bacterial expression of protein fragments for domain mapping, in vitro actin binding/bundling assays, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro actin binding reconstituted with defined domain mapping, replicated by subsequent studies","pmids":["7559773"],"is_preprint":false},{"year":2004,"finding":"Anillin directly interacts with nonmuscle myosin II, and this interaction is regulated by myosin light chain phosphorylation; depletion of anillin in Drosophila or human cells causes cytokinesis failure with loss of spatial regulation of myosin II contraction and failure of abscission.","method":"Direct binding assays, RNAi depletion in Drosophila and human cultured cells, immunofluorescence, time-lapse microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay with phosphorylation-dependent regulation, RNAi phenotype in two organisms","pmids":["15496454"],"is_preprint":false},{"year":2005,"finding":"Anillin is a substrate of the APC/C ubiquitin ligase activated by Cdh1; anillin contains a destruction-box, is ubiquitinated in a Cdh1-dependent manner, and its levels peak in mitosis and drop during mitotic exit. APC/C-mediated degradation controls spatial contractility of myosin during late cytokinesis.","method":"In vitro expression screen for APC/C substrates, ubiquitination assay, Cdh1 overexpression and APC/C inactivation experiments, cell biology assays, knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination with defined destruction-box, Cdh1-dependency demonstrated with overexpression and inactivation","pmids":["16040610"],"is_preprint":false},{"year":2005,"finding":"Drosophila anillin (encoded by the scraps gene) is required for septin recruitment to the furrow canal and contractile ring; PH domain mutations cause defects in septin localization, membrane stabilization, and cellularization; a more N-terminal mutation blocks pole cell separation.","method":"Genetic analysis of Drosophila anillin alleles (maternal effect and zygotic), immunofluorescence, characterization of cellularization and cytokinesis phenotypes","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic allele series with multiple orthogonal phenotypic readouts, demonstrates domain-specific functions","pmids":["15930114"],"is_preprint":false},{"year":2005,"finding":"Human ANLN interacts with RhoA and induces actin stress fibers; PI3K/AKT activity regulates ANLN stability and nuclear localization; siRNA knockdown of ANLN in NSCLC cells causes multinucleation and cell death.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, PI3K inhibitor treatment, immunofluorescence","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for RhoA interaction, pharmacologic inhibition for PI3K/AKT link, supported by knockdown phenotype","pmids":["16357138"],"is_preprint":false},{"year":2007,"finding":"Human anillin contains a conserved C-terminal domain homologous to the RhoA-binding protein Rhotekin that directly interacts with RhoA; anillin functions as a scaffold linking RhoA to actin and myosin at the equatorial cortex; furrows can initiate without anillin but require anillin when the central spindle is also disrupted.","method":"Sequence homology analysis, direct binding assays, RNAi depletion, epistasis with central spindle perturbation, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct RhoA binding demonstrated with defined domain, epistasis analysis with orthogonal perturbations","pmids":["18158243"],"is_preprint":false},{"year":2007,"finding":"Anillin and septins promote asymmetric furrow ingression in C. elegans; anillin and septins promote coalescence of contractile ring components on one side of the ring, and disruption of this asymmetry makes cytokinesis sensitive to partial contractility inhibition.","method":"RNAi depletion in C. elegans, time-lapse microscopy, quantification of furrow ingression asymmetry","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic depletion with quantitative functional readout, demonstrates mechanistic role of anillin-septin interaction in furrow mechanics","pmids":["17488632"],"is_preprint":false},{"year":2007,"finding":"Drosophila RacGAP50C directly interacts with Anillin; both proteins depend on this interaction for their localization; in the absence of anillin, spindle-associated RacGAP50C loses equatorial cortex association and cytokinesis fails, establishing a direct molecular link between spindle microtubules and the actomyosin contractile ring.","method":"Genetic analysis, co-localization in vivo, in vitro interaction assay, RNAi depletion","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated in vitro and confirmed by co-localization in vivo, reciprocal genetic dependency shown","pmids":["18158242"],"is_preprint":false},{"year":2008,"finding":"Affinity-purification/MS of Anillin interactors in Drosophila cells identified actin, myosin, three septins, and RacGAP50C (Tum); F-actin is essential for cortical Anillin localization in prometaphase but not for furrow accumulation; septins travel along microtubules to interact with Anillin at the furrow; RacGAP50C is necessary for Anillin accumulation at the furrow and the two proteins interact in vitro.","method":"Affinity purification coupled with mass spectrometry, RNAi, drug treatments, in vitro binding, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — AP-MS interactome with multiple orthogonal validations (RNAi, drug, in vitro binding)","pmids":["18349071"],"is_preprint":false},{"year":2008,"finding":"Ran regulates anillin-dependent targeting of the septin Peanut to pseudocleavage furrows in Drosophila; importin-α and importin-β directly bind anillin and prevent its interaction with Peanut; RanGTP reverses this inhibition; a mutant anillin lacking the importin binding site renders furrow ingression insensitive to Ran pathway disruption.","method":"In vitro biochemical binding assays, importin pulldown, dominant-negative Ran expression, immunofluorescence in Drosophila syncytial embryos","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical binding demonstrated and confirmed by functional rescue with mutant anillin","pmids":["18579688"],"is_preprint":false},{"year":2010,"finding":"mDia2 interacts with anillin via its diaphanous-inhibitory domain (DID); anillin binding is competitive with the diaphanous autoregulatory domain (DAD) autoinhibitory interaction; both Rho GTPase-mediated activation and anillin interaction are required for mDia2 localization and function in cytokinesis.","method":"Pulldown assays, RNAi, functional rescue experiments in NIH 3T3 cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown identifies interaction, competition assay and RNAi rescue define functional requirement, single lab","pmids":["20660154"],"is_preprint":false},{"year":2011,"finding":"The PH domain of anillin directly binds PI(4,5)P2; reduction of cellular PI(4,5)P2 or PH domain mutations that disrupt PI(4,5)P2 binding impair anillin localization to the furrow; the PH domain has two functions: PI(4,5)P2-mediated furrow targeting and septin recruitment to the furrow.","method":"PIP binding assays, site-directed mutagenesis of PH domain, PI(4,5)P2 depletion, RNAi rescue experiments, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct lipid binding assay combined with mutagenesis and cellular rescue experiments defining two PH domain functions","pmids":["22197245"],"is_preprint":false},{"year":2011,"finding":"Citron kinase (CIT-K) physically and functionally interacts with anillin; CIT-K is an upstream regulator (not effector) of RhoA during late cytokinesis; active RhoA and anillin are displaced from the midbody in CIT-K-depleted cells; overexpression of anillin alone delays abscission independently of RhoA.","method":"Co-immunoprecipitation, RNAi depletion, RhoA inactivation, overexpression in mammalian cells, immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and epistasis by RhoA inactivation, single lab","pmids":["21849473"],"is_preprint":false},{"year":2011,"finding":"Anillin (ANI-1) promotes astral microtubule-directed cortical myosin polarization in C. elegans embryos; microtubule-directed myosin II polarization is aberrant without ANI-1; anillin interacts with microtubules providing an inhibitory mechanism to promote cell cortex polarization for cytokinesis.","method":"RNAi depletion, time-lapse microscopy in C. elegans embryos, microtubule binding assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with clear polarization phenotype and microtubule interaction assay, single lab","pmids":["21737681"],"is_preprint":false},{"year":2012,"finding":"Anillin acts as a bifunctional linker coordinating midbody ring biogenesis: the N-terminus connects with the actomyosin contractile ring and supports midbody ring formation; the C-terminus (via septin Peanut) ensures stable anchoring of the plasma membrane; loss of either function prevents complete cytokinesis.","method":"RNAi depletion, truncation analysis, time-lapse microscopy in Drosophila S2 cells","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic domain truncation analysis with functional readout, defines two mechanistically distinct roles","pmids":["22226749"],"is_preprint":false},{"year":2012,"finding":"Anillin interacts with the PH domain of Ect2 (RhoGEF) in human cells; the anillin-Ect2 complex stabilizes central spindle microtubules at the cortex during cytokinesis; a PH domain mutation disrupting phospholipid association weakens the anillin-Ect2 interaction.","method":"Co-immunoprecipitation, PH domain mutagenesis, immunofluorescence in cultured human cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP with mutagenesis support, functional model supported but not fully reconstituted, single lab","pmids":["22514687"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of human anillin C-terminal region reveal a cryptic C2 domain and a Rho-binding domain; together with the PH domain, three membrane-associating elements (C2, RBD, PH) synergistically bind RhoA and phospholipids to anchor anillin at the cleavage furrow.","method":"X-ray crystallography, functional mutagenesis, lipid binding assays, cell biological validation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis validating mechanistic model of membrane anchorage","pmids":["25959226"],"is_preprint":false},{"year":2014,"finding":"Anillin localizes to epithelial cell-cell junctions throughout the cell cycle in Xenopus embryos and regulates junction integrity; anillin knockdown disrupts tight and adherens junctions, increases dynamic RhoA-GTP flares at junctions, and reduces junctional F-actin and myosin II accumulation.","method":"Morpholino knockdown in Xenopus laevis embryos, live imaging of RhoA-GTP biosensor, immunofluorescence, laser ablation","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with quantitative RhoA-GTP biosensor and multiple junctional readouts","pmids":["24835458"],"is_preprint":false},{"year":2014,"finding":"Mutations in ANLN (R431C and G618C) cause familial FSGS; the R431C mutant displays reduced binding to the slit-diaphragm scaffold protein CD2AP, enhanced podocyte motility, and loss-of-function in zebrafish glomerular filtration; anillin is required for podocyte actin cytoskeleton integrity.","method":"Whole-exome sequencing, family linkage, Co-IP for CD2AP interaction, overexpression in human podocytes, zebrafish morpholino knockdown","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay showing reduced CD2AP interaction with mutant, in vivo zebrafish functional validation, human genetic evidence","pmids":["24676636"],"is_preprint":false},{"year":2014,"finding":"Human anillin interacts with astral microtubules; astral and central spindle microtubules independently control contractile protein localization; RhoA-GTP binding to anillin competes with its microtubule interaction; anillin restricts myosin to the equatorial cortex and NuMA to the polar cortex.","method":"Microtubule binding assays, RNAi, immunofluorescence in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct microtubule binding assay, RNAi competition experiment, single lab","pmids":["24994938"],"is_preprint":false},{"year":2014,"finding":"A complex of p190RhoGAP-A and anillin modulates RhoA-GTP levels at the cytokinetic furrow; p190RhoGAP-A mutants that cannot bind anillin or inactivate RhoA fail to rescue cytokinesis defects; excess RhoA-GTP from p190RhoGAP-A depletion prevents progression to abscission.","method":"Co-immunoprecipitation, RNAi, mutant rescue experiments, blebbistatin pharmacology in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutant rescue establishing functional requirement, single lab","pmids":["25359885"],"is_preprint":false},{"year":2015,"finding":"Anillin (Drosophila and C. elegans) directly links RhoG/MIG-2 signaling to the actin cytoskeleton during neuronal migration and neurite growth: the active form of RhoG directly binds anillin and recruits it to the leading edge, where the anillin actin-binding domain stabilizes F-actin by antagonizing cofilin-mediated severing.","method":"Somatic CRISPR-Cas9 conditional mutagenesis in C. elegans, biochemical pulldown of RhoG-anillin interaction, in vitro F-actin severing assays, live imaging","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct RhoG binding demonstrated biochemically, F-actin stabilization mechanistically defined by severing assay, in vivo validation","pmids":["25843030"],"is_preprint":false},{"year":2015,"finding":"Importin-β2 targets anillin to the nucleus during interphase via a noncanonical PY-NLS; nuclear sequestration restricts anillin's membrane function to mitosis; importin-β2 binding does not regulate mitotic function but prevents cytosolic accumulation that disrupts interphase architecture.","method":"NLS mapping, importin-β2 binding assays, Ran-dependent nuclear import assays, immunofluorescence in human cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct importin binding with defined NLS motif and Ran dependency, functional consequences demonstrated, single lab","pmids":["25829492"],"is_preprint":false},{"year":2015,"finding":"Anillin knockdown disrupts tight and adherens junctions in human epithelial cells; this is accompanied by disorganization of the perijunctional actomyosin belt, decreased γ-adducin expression, and cytoplasmic aggregation of αII-spectrin; JNK activation mediates the junctional defects, and JNK inhibition restores junction integrity in anillin-depleted cells.","method":"siRNA knockdown in human epithelial cell lines, immunofluorescence, JNK inhibitor rescue, western blotting","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with pharmacologic rescue defining JNK pathway placement, multiple junctional readouts, single lab","pmids":["25809162"],"is_preprint":false},{"year":2015,"finding":"Active Ran/importin gradient spatially restricts anillin to the equatorial cortex; anillin contains a conserved NLS that binds importin-β; RhoA-GTP binding to anillin's RBD domain autoinhibits the NLS and nearby microtubule-binding domain; importin-β binding stabilizes a conformation favoring cortical recruitment during cytokinesis.","method":"Ran-GTP manipulation, importin binding assays, NLS mutagenesis, live-cell imaging in human cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct importin binding with NLS mutants and Ran manipulation, functional cortical localization assay, single lab","pmids":["28931593"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of anillin at S635 (adjacent to the AH domain) by mitotic kinases is required for efficient recruitment to the equatorial membrane at anaphase onset; a S635A mutant shows impaired cortical recruitment and cytokinesis failure; a phosphomimetic S635D partially restores localization.","method":"Systematic phosphomutant screen (46 sites), phosphospecific antibody, time-lapse videomicroscopy, rescue assays in human cells","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with phosphospecific antibody and live-cell imaging, single lab","pmids":["28081137"],"is_preprint":false},{"year":2017,"finding":"Anillin actin-binding domain harbors three distinct actin-binding sites (ABS1–3); ABS1 and ABS3 bind F-actin in a mutually exclusive fashion; ABS2 and ABS3 are each required and together sufficient for cortical localization during cytokinesis; anillin can cross-link actin filaments in parallel and antiparallel orientations and promotes 3D F-actin bundle formation.","method":"In vitro binding assays, electron microscopy on recombinant fragments, depletion-rescue in Drosophila S2 cells, immunofluorescence","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural EM with defined actin binding sites, mutagenesis rescue in cells, orthogonal in vitro and in vivo validation","pmids":["28147230"],"is_preprint":false},{"year":2018,"finding":"The ANLN R431C FSGS mutation causes hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling and mTOR-driven ER stress in podocytes; inhibition of mTOR, GSK-3β, Rac1, or calcineurin ameliorates R431C effects; calcineurin/NFAT pathway inhibition reduces endogenous ANLN and mTOR expression.","method":"In vivo zebrafish complementation, stable human podocyte cell lines, western blotting, pharmacologic inhibition","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacologic interventions with biochemical readouts, in vivo zebrafish validation, single lab","pmids":["30002222"],"is_preprint":false},{"year":2019,"finding":"Anillin directly binds GTP-RhoA and concentrates PIP2 at the cortex to promote effector recruitment; a sequential kinetic scaffolding pathway is proposed and tested where GTP-RhoA first binds anillin, is then retained at the membrane by PIP2 after disengaging from anillin, and repeated binding cycles increase GTP-RhoA dwell time to enhance effector recruitment.","method":"Direct binding assays, live-cell FRAP/single-molecule imaging, PIP2 manipulation, anillin mutants, quantitative kinetic modeling in Xenopus and mammalian epithelial cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding, single-molecule imaging, PIP2 manipulation, kinetic modeling with multiple orthogonal validations","pmids":["31105010"],"is_preprint":false},{"year":2019,"finding":"Anillin regulates medial-apical actomyosin in Xenopus epithelial cells; anillin overexpression increases mechano-sensitive vinculin recruitment to junctions (increased tension) but slows junctional recoil after laser ablation; medial-apical laser ablation reveals tensile forces stored across the apical surface that depend on anillin; anillin's effects on cellular mechanics impact tissue-wide mechanics.","method":"Laser ablation, vinculin mechanosensor, morpholino knockdown and overexpression in Xenopus embryos, traction force microscopy","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biophysical methods (laser ablation, mechanosensor, traction microscopy), gain- and loss-of-function in vivo","pmids":["30702429"],"is_preprint":false},{"year":2019,"finding":"ANLN knockdown in pancreatic cancer cells inhibits LASP1 expression via upregulation of miR-218-5p; ANLN-induced EZH2 upregulation suppresses miR-218-5p to maintain LASP1 levels; this ANLN→EZH2→miR-218-5p→LASP1 axis promotes pancreatic cancer cell proliferation, migration, and invasion.","method":"siRNA knockdown, gene expression microarray, luciferase reporter assays, rescue experiments in vitro and xenograft in vivo","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter confirms direct miR-218-5p/LASP1 targeting, EZH2 link supported by expression assays and rescue, single lab","pmids":["31395079"],"is_preprint":false},{"year":2020,"finding":"Importin-β binding to anillin's NLS promotes a conformation that increases accessibility of the C2 domain; active RhoA binding to the RBD initially opens the C2 domain, and subsequent importin binding stabilizes the conformation required for cortical recruitment; this reveals importin-mediated positive regulation (not just nuclear sequestration) of a cortical protein.","method":"Binding assays with RhoA and importin-β, domain mutant analysis, live-cell localization assays in human cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays with domain mutants defining sequential conformational regulation, single lab","pmids":["32238082"],"is_preprint":false},{"year":2020,"finding":"The Rho guanine nucleotide exchange factor Bud3 and anillin-like Bud4 form a RhoGEF-anillin module essential for septin architectural remodeling from hourglass to double ring in budding yeast; Bud3 stabilizes single septin filaments and Bud4 strengthens interactions between filament types at outer zones of the transitional hourglass.","method":"Genetic deletion analysis, fluorescence microscopy, polarization microscopy for filament orientation in S. cerevisiae","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection with domain deletions and quantitative microscopy, yeast ortholog","pmids":["32197082"],"is_preprint":false},{"year":2020,"finding":"ANLN is required for cell migration, invasion, and anchorage-independent growth in breast cancer cells; ANLN knockout triggers transcriptional reprogramming suppressing stemness and inducing mesenchymal-to-epithelial trans-differentiation with upregulation of E-cadherin; E-cadherin knockdown restores migration in anillin-deficient cells.","method":"CRISPR/Cas9 knockout, wound healing and Matrigel invasion assays, mammosphere formation, xenograft mouse models, RNA-seq, immunofluorescence","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with rescue experiment (E-cadherin KD), in vivo xenograft, transcriptomics, single lab","pmids":["31910867"],"is_preprint":false},{"year":2021,"finding":"Anillin, as a non-motor actin crosslinker, autonomously propels contractility of actin bundles and rings: it generates contractile forces of tens of picoNewtons to maximize overlap lengths between bundled antiparallel actin filaments; contractility is enhanced by actin disassembly and leads to ring constriction in the absence of myosin activity.","method":"In vitro reconstitution with purified anillin and actin, optical trap force measurements, TIRF microscopy, actin ring formation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with quantitative force measurements, myosin-independent mechanism definitively demonstrated","pmids":["34321459"],"is_preprint":false},{"year":2021,"finding":"ANLN directly interacts with RhoA (demonstrated by Co-IP) and promotes RhoA activation; ANLN overexpression enhances expression of multidrug resistance proteins MDR1 and BCRP, promoting doxorubicin resistance; C3 transferase (RhoA inhibitor) abolishes ANLN overexpression effects on drug resistance.","method":"Co-immunoprecipitation, overexpression, RNAi knockdown, C3 transferase pharmacology, flow cytometry, western blotting in breast cancer cells","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct Co-IP for RhoA interaction, pharmacologic RhoA inhibition for epistasis, single lab","pmids":["33116832"],"is_preprint":false},{"year":2022,"finding":"USP10 deubiquitinase interacts with ANLN and removes K11- and K63-linked ubiquitin chains to prevent APC/C-Cdh1-mediated degradation; USP10 and Cdh1 form a non-competitive complex with ANLN to balance its protein levels; USP10-stabilized ANLN promotes contractile ring assembly and cytokinesis.","method":"Co-immunoprecipitation, ubiquitin chain linkage analysis, USP10 knockdown/inhibition, APC/C-Cdh1 complex assays, cell biology in ESCC cells","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Co-IP, specific ubiquitin chain type identification, non-competitive complex formation, functional rescue assays","pmids":["36526897"],"is_preprint":false},{"year":2022,"finding":"CIN85 interacts directly with the N-terminal region of anillin and with SEPT9; this anillin-CIN85-SEPT9 complex facilitates SEPT9-containing septin filament localization to the intercellular bridge plasma membrane during cytokinesis; the anillin PH domain separately binds septin units lacking SEPT9 but enriched in SEPT11.","method":"Direct binding assays, Co-immunoprecipitation, RNAi knockdown, immunofluorescence in human cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay defining domain specificity for two septin complexes, functional RNAi readout, single lab","pmids":["36044846"],"is_preprint":false},{"year":2022,"finding":"ANLN acts as a scaffold that strengthens the interaction between RACGAP1 and PLK1; ANLN promotes PLK1-mediated RACGAP1 phosphorylation and RhoA activation to ensure cytokinesis fidelity; hepatic Anln ablation in mice enhances polyploidization and impairs c-Myc/NRAS-driven hepatocarcinogenesis.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, kinase assay for PLK1-mediated phosphorylation, Anln knockout mouse model with hydrodynamic transfection of oncogenes, flow cytometry for polyploidy","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for scaffold role, kinase assay for PLK1-RACGAP1-ANLN axis, in vivo mouse model, single lab","pmids":["35477750"],"is_preprint":false},{"year":2023,"finding":"Nuclear ANLN forms a transcriptional complex with SP1, which enhances KIF2C transcriptional activity to activate the mTORC1 pathway; increased RANKL and disproportionate RANKL-OPG expression in the bone microenvironment drives HCC bone metastasis; ANLN mRNA stability is enhanced via m6A modification by METTL3/YTHDF1.","method":"METTL3/YTHDF1 knockdown, m6A assays, ChIP, nuclear ANLN co-immunoprecipitation with SP1, luciferase reporter, xenograft bone metastasis models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — nuclear complex Co-IP and ChIP demonstrated, m6A modification defined, in vivo model, but single lab study","pmids":["36923927"],"is_preprint":false},{"year":2023,"finding":"TAZ and TEAD2 transcriptionally upregulate ANLN as a target gene to promote HCC cell proliferation; CRISPRi knockdown of ANLN in a dCas9 knock-in mouse model reduces TAZ-driven and MET/CTNNB1-driven HCC growth in vivo.","method":"RNA-seq, ChIP, CRISPRi screen in dCas9 mice, genetic deletion of TAZ in floxed mice via AAV-Cre, in vivo HCC models","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms TEAD2 binding to ANLN, in vivo CRISPRi demonstrates functional requirement, single lab","pmids":["36894036"],"is_preprint":false}],"current_model":"Anillin (ANLN) is a multidomain scaffold protein that organizes the cytokinetic contractile ring by directly binding F-actin (via three distinct actin-binding sites that bundle filaments and generate myosin-independent contractile forces), nonmuscle myosin II (in a phosphorylation-regulated manner), septins (through its C-terminal PH domain via PI(4,5)P2), and active GTP-RhoA (through a cryptic C2 domain and a Rhotekin-homologous RBD revealed by crystal structure); it links these ring components to RhoGEFs (Ect2), RacGAP/centralspindlin, and the mDia2 formin, physically connecting spindle microtubules to the actomyosin ring; its membrane association is anchored by PI(4,5)P2 binding via the PH domain; anillin enhances RhoA cortical signaling by kinetic scaffolding—stabilizing GTP-RhoA membrane dwell time cooperatively with PIP2; its abundance is cell-cycle regulated by APC/C-Cdh1-mediated ubiquitin degradation (counterbalanced by USP10 deubiquitylation) and by phosphorylation (including S635 by mitotic kinases); during interphase, importin-β2 sequesters anillin in the nucleus via a PY-NLS, restricting its membrane activity to mitosis; beyond cytokinesis, anillin regulates epithelial cell-cell junction integrity (by controlling junctional RhoA-GTP distribution and suppressing JNK), epithelial mechanics (via medial-apical actomyosin), neuronal migration (by linking RhoG to actin and antagonizing cofilin), and podocyte actin integrity (where FSGS-causing mutations disrupt CD2AP binding and hyperactivate PI3K/AKT/mTOR/Rac1 signaling)."},"narrative":{"mechanistic_narrative":"Anillin (ANLN) is a multidomain scaffold protein that organizes the actomyosin cytokinetic contractile ring by physically coupling its core components and linking them to the underlying membrane and spindle [PMID:7559773, PMID:15496454, PMID:18158243]. Its N-terminal actin-binding domain contains three distinct actin-binding sites that crosslink filaments into parallel and antiparallel bundles, and these crosslinking activities allow anillin to autonomously generate tens-of-picoNewton contractile forces and drive ring constriction even in the absence of myosin II [PMID:28147230, PMID:34321459]. Anillin directly binds nonmuscle myosin II in a light-chain phosphorylation-dependent manner and is required for the spatial regulation of myosin contraction and successful abscission [PMID:15496454]. Membrane anchorage and equatorial targeting are achieved through a C-terminal module of three synergistic membrane-associating elements—a cryptic C2 domain, a Rhotekin-homologous Rho-binding domain, and a PH domain—that together engage GTP-RhoA and phospholipids, with the PH domain binding PI(4,5)P2 and recruiting septins to the furrow [PMID:18158243, PMID:22197245, PMID:25959226]. Through these interactions anillin acts as a kinetic scaffold that concentrates PI(4,5)P2 and prolongs the membrane dwell time of GTP-RhoA to amplify RhoA effector recruitment [PMID:31105010]. Anillin further bridges the spindle and the cortex by interacting with centralspindlin component RacGAP, the RhoGEF Ect2, the formin mDia2, and microtubules, thereby positioning contractile-ring assembly relative to the central spindle [PMID:18158242, PMID:18349071, PMID:20660154, PMID:22514687, PMID:24994938]. Its activity is tightly cell-cycle controlled: APC/C-Cdh1 targets anillin for ubiquitin-mediated degradation, counterbalanced by USP10 deubiquitylation, and mitotic phosphorylation at S635 and importin-mediated conformational and localization control restrict its membrane function to mitosis [PMID:16040610, PMID:36526897, PMID:28081137, PMID:25829492, PMID:28931593]. Beyond division, anillin localizes to epithelial cell-cell junctions where it controls junctional RhoA-GTP dynamics, perijunctional actomyosin organization, and tissue mechanics, and it links RhoG signaling to F-actin stabilization during neuronal migration [PMID:24835458, PMID:25809162, PMID:30702429, PMID:25843030]. Mutations in ANLN (R431C, G618C) cause familial focal segmental glomerulosclerosis through disrupted CD2AP binding and aberrant podocyte signaling [PMID:24676636].","teleology":[{"year":1995,"claim":"Establishing that anillin directly binds and bundles actin filaments and concentrates in the cleavage furrow defined it as an actin-organizing component of the contractile apparatus.","evidence":"Actin filament chromatography, domain mapping, and in vitro bundling assays with immunofluorescence in Drosophila","pmids":["7559773"],"confidence":"High","gaps":["Mechanism of force generation not addressed","Furrow targeting determinants unknown"]},{"year":2004,"claim":"Identifying a phosphorylation-regulated direct interaction with nonmuscle myosin II showed anillin spatially coordinates myosin contraction during cytokinesis.","evidence":"Direct binding assays and RNAi depletion in Drosophila and human cells with time-lapse imaging","pmids":["15496454"],"confidence":"High","gaps":["Kinase responsible for the regulatory phosphorylation not defined","Structural basis of myosin binding unresolved"]},{"year":2005,"claim":"Anillin abundance was shown to be cell-cycle controlled by APC/C-Cdh1 ubiquitination, explaining its mitotic peak and its role in late-cytokinesis contractility.","evidence":"In vitro APC/C substrate screen, ubiquitination assays, and Cdh1 manipulation","pmids":["16040610"],"confidence":"High","gaps":["Deubiquitylase counterbalance not yet identified at this stage"]},{"year":2005,"claim":"Genetic and biochemical work tied anillin to septin recruitment via its PH domain and to RhoA-dependent actin organization, establishing it as a multivalent scaffold.","evidence":"Drosophila allele series and Co-IP/siRNA in human cells","pmids":["15930114","16357138"],"confidence":"High","gaps":["RhoA interaction in human cells based on single Co-IP","PI3K/AKT link pharmacologic only"]},{"year":2007,"claim":"Discovery of a Rhotekin-homologous Rho-binding domain and a direct RacGAP interaction established anillin as the molecular bridge connecting RhoA, the central spindle, and the actomyosin ring.","evidence":"Sequence/homology analysis, direct binding, in vitro interaction, RNAi and epistasis across species","pmids":["18158243","18158242","17488632"],"confidence":"High","gaps":["Structural definition of the RhoA-binding interface not yet resolved","Quantitative contribution to furrow positioning unclear"]},{"year":2008,"claim":"AP-MS interactome and Ran-regulated septin targeting refined the network of anillin partners and showed importins gate its septin-recruiting activity.","evidence":"Affinity purification/MS, in vitro binding, importin pulldowns, and Ran manipulation in Drosophila","pmids":["18349071","18579688"],"confidence":"High","gaps":["Direct vs indirect nature of some interactome hits not fully separated"]},{"year":2010,"claim":"Anillin was shown to relieve mDia2 autoinhibition, coupling it to formin-driven actin assembly during cytokinesis.","evidence":"Pulldown, DID/DAD competition, and RNAi rescue in NIH 3T3 cells","pmids":["20660154"],"confidence":"Medium","gaps":["Single-lab study","In vivo relevance of the competition not fully reconstituted"]},{"year":2011,"claim":"The PH domain was defined as a dual-function module binding PI(4,5)P2 for furrow targeting and recruiting septins, and Citron kinase and microtubule interactions placed anillin within upstream cortical polarization control.","evidence":"Lipid binding assays with PH mutagenesis, Co-IP, and RNAi across human and C. elegans systems","pmids":["22197245","21849473","21737681"],"confidence":"High","gaps":["Separation of PI(4,5)P2 and septin functions within the PH domain incompletely mapped","Citron kinase and microtubule findings single-lab"]},{"year":2012,"claim":"Domain-truncation and Ect2 interaction studies established anillin as a bifunctional linker whose N-terminus engages the actomyosin ring while the C-terminus anchors membrane/septin and stabilizes spindle microtubules at the cortex.","evidence":"Truncation analysis, Co-IP with PH mutagenesis, and imaging in Drosophila and human cells","pmids":["22226749","22514687"],"confidence":"Medium","gaps":["Ect2 interaction based on single Co-IP","Not fully reconstituted in vitro"]},{"year":2014,"claim":"Crystal structures revealed a cryptic C2 domain and RBD that, with the PH domain, synergistically anchor anillin to membrane via RhoA and phospholipids, providing the structural basis for cortical targeting.","evidence":"X-ray crystallography with functional mutagenesis and lipid binding assays","pmids":["25959226"],"confidence":"High","gaps":["Full-length conformational dynamics not captured","Stoichiometry of RhoA/lipid co-engagement undefined"]},{"year":2014,"claim":"Anillin was shown to function at epithelial junctions and in podocytes, broadening its role beyond cytokinesis and revealing it governs junctional RhoA-GTP dynamics and a disease-relevant podocyte function.","evidence":"Xenopus morpholino with RhoA biosensor imaging; human genetics, Co-IP, and zebrafish knockdown for FSGS mutations","pmids":["24835458","24676636","25359885","24994938"],"confidence":"High","gaps":["Mechanistic link between junctional and cytokinetic functions incompletely defined","p190RhoGAP and microtubule competition findings single-lab"]},{"year":2015,"claim":"Anillin was established as a direct effector of RhoG in neuronal migration and as an importin-β2 nuclear-sequestered protein, defining interphase regulation that restricts its membrane activity to mitosis.","evidence":"Biochemical RhoG pulldown, in vitro F-actin severing assays, CRISPR conditional mutagenesis, and NLS/importin binding assays","pmids":["25843030","25829492","25809162"],"confidence":"High","gaps":["Importin and JNK-junction findings single-lab","Cross-talk between nuclear pool and cortical pool quantitatively undefined"]},{"year":2017,"claim":"Phosphoregulation and Ran/importin conformational control were mapped, showing S635 phosphorylation and RhoA-antagonized NLS autoinhibition spatially license cortical recruitment.","evidence":"Systematic phosphomutant screen with phosphospecific antibody; Ran manipulation and NLS mutagenesis with live imaging","pmids":["28081137","28931593"],"confidence":"Medium","gaps":["Identity of the S635 kinase not established","Single-lab studies"]},{"year":2019,"claim":"Single-molecule and biophysical work defined anillin as a kinetic scaffold that prolongs GTP-RhoA membrane dwell time with PI(4,5)P2 and as a regulator of medial-apical actomyosin and tissue mechanics.","evidence":"FRAP/single-molecule imaging, PIP2 manipulation, kinetic modeling, laser ablation, and traction force microscopy in Xenopus and mammalian cells","pmids":["31105010","30702429","31395079"],"confidence":"High","gaps":["Kinetic scaffolding model not extended to all anillin functional contexts","Cancer miRNA axis (LASP1) is a separate Medium-confidence pathway"]},{"year":2020,"claim":"Importin binding was reinterpreted as a positive conformational regulator opening the C2 domain, and yeast and breast cancer studies extended anillin's roles to septin remodeling and EMT/stemness control.","evidence":"RhoA/importin binding assays with domain mutants; yeast genetics; CRISPR KO with rescue and xenograft in breast cancer","pmids":["32238082","32197082","31910867"],"confidence":"Medium","gaps":["Conformational model single-lab","Transcriptional reprogramming mechanism downstream of ANLN loss not fully resolved"]},{"year":2022,"claim":"USP10 was identified as the deubiquitylase counterbalancing APC/C-Cdh1, and CIN85 and a PLK1-RACGAP1 scaffolding role refined the partner network controlling septin delivery and contractile fidelity.","evidence":"Co-IP, ubiquitin linkage analysis, kinase assays, RNAi, and an Anln knockout mouse model","pmids":["36526897","36044846","35477750"],"confidence":"Medium","gaps":["CIN85 and PLK1 axes single-lab","Integration of degradation control with mitotic timing incompletely quantified"]},{"year":2023,"claim":"Nuclear ANLN was shown to act in transcriptional complexes (with SP1) and as a Hippo/YAP-TAZ target, implicating it in oncogenic transcriptional programs and metastasis.","evidence":"Nuclear Co-IP, ChIP, luciferase reporters, m6A assays, and in vivo CRISPRi/HCC models","pmids":["36923927","36894036"],"confidence":"Medium","gaps":["Nuclear transcriptional role distinct from scaffold function mechanistically unclear","Single-lab studies"]},{"year":null,"claim":"How anillin's distinct functional pools—cytokinetic scaffold, junctional regulator, and nuclear transcriptional partner—are coordinated and switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking conformational state to functional pool","Kinase identity for several regulatory phosphosites unknown","Structural basis of nuclear transcriptional complexes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7,14,28]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,26,34]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[26,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,16,28]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,22,39]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,26,17]},{"term_id":"GO:0005815","term_label":"microtubule organizing 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Essential for the structural integrity of the cleavage furrow and for completion of cleavage furrow ingression. Plays a role in bleb assembly during metaphase and anaphase of mitosis (PubMed:23870127). May play a significant role in podocyte cell migration (PubMed:24676636)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton; Cytoplasm, cell cortex; Cell projection, bleb","url":"https://www.uniprot.org/uniprotkb/Q9NQW6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANLN","classification":"Common Essential","n_dependent_lines":686,"n_total_lines":1208,"dependency_fraction":0.5678807947019867},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SRI","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANLN","total_profiled":1310},"omim":[{"mim_id":"621092","title":"IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 3; IQGAP3","url":"https://www.omim.org/entry/621092"},{"mim_id":"616032","title":"FOCAL SEGMENTAL GLOMERULOSCLEROSIS 8; FSGS8","url":"https://www.omim.org/entry/616032"},{"mim_id":"616027","title":"ACTIN-BINDING PROTEIN ANILLIN; ANLN","url":"https://www.omim.org/entry/616027"},{"mim_id":"604980","title":"RAC GTPase-ACTIVATING PROTEIN 1; RACGAP1","url":"https://www.omim.org/entry/604980"},{"mim_id":"603278","title":"FOCAL SEGMENTAL GLOMERULOSCLEROSIS 1; FSGS1","url":"https://www.omim.org/entry/603278"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":163.3}],"url":"https://www.proteinatlas.org/search/ANLN"},"hgnc":{"alias_symbol":["ANILLIN","Scraps","scra"],"prev_symbol":[]},"alphafold":{"accession":"Q9NQW6","domains":[{"cath_id":"2.60.40.150","chopping":"718-780_799-889_931-979","consensus_level":"medium","plddt":92.7258,"start":718,"end":979},{"cath_id":"2.30.29.30","chopping":"985-1111","consensus_level":"high","plddt":91.4025,"start":985,"end":1111}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQW6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQW6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQW6-F1-predicted_aligned_error_v6.png","plddt_mean":59.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANLN","jax_strain_url":"https://www.jax.org/strain/search?query=ANLN"},"sequence":{"accession":"Q9NQW6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQW6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQW6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQW6"}},"corpus_meta":[{"pmid":"7559773","id":"PMC_7559773","title":"Anillin, 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domains of the actin cytoskeleton.\",\n      \"method\": \"Actin filament chromatography, cDNA cloning, bacterial expression of protein fragments for domain mapping, in vitro actin binding/bundling assays, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro actin binding reconstituted with defined domain mapping, replicated by subsequent studies\",\n      \"pmids\": [\"7559773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Anillin directly interacts with nonmuscle myosin II, and this interaction is regulated by myosin light chain phosphorylation; depletion of anillin in Drosophila or human cells causes cytokinesis failure with loss of spatial regulation of myosin II contraction and failure of abscission.\",\n      \"method\": \"Direct binding assays, RNAi depletion in Drosophila and human cultured cells, immunofluorescence, time-lapse microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay with phosphorylation-dependent regulation, RNAi phenotype in two organisms\",\n      \"pmids\": [\"15496454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Anillin is a substrate of the APC/C ubiquitin ligase activated by Cdh1; anillin contains a destruction-box, is ubiquitinated in a Cdh1-dependent manner, and its levels peak in mitosis and drop during mitotic exit. APC/C-mediated degradation controls spatial contractility of myosin during late cytokinesis.\",\n      \"method\": \"In vitro expression screen for APC/C substrates, ubiquitination assay, Cdh1 overexpression and APC/C inactivation experiments, cell biology assays, knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination with defined destruction-box, Cdh1-dependency demonstrated with overexpression and inactivation\",\n      \"pmids\": [\"16040610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila anillin (encoded by the scraps gene) is required for septin recruitment to the furrow canal and contractile ring; PH domain mutations cause defects in septin localization, membrane stabilization, and cellularization; a more N-terminal mutation blocks pole cell separation.\",\n      \"method\": \"Genetic analysis of Drosophila anillin alleles (maternal effect and zygotic), immunofluorescence, characterization of cellularization and cytokinesis phenotypes\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic allele series with multiple orthogonal phenotypic readouts, demonstrates domain-specific functions\",\n      \"pmids\": [\"15930114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human ANLN interacts with RhoA and induces actin stress fibers; PI3K/AKT activity regulates ANLN stability and nuclear localization; siRNA knockdown of ANLN in NSCLC cells causes multinucleation and cell death.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, PI3K inhibitor treatment, immunofluorescence\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for RhoA interaction, pharmacologic inhibition for PI3K/AKT link, supported by knockdown phenotype\",\n      \"pmids\": [\"16357138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human anillin contains a conserved C-terminal domain homologous to the RhoA-binding protein Rhotekin that directly interacts with RhoA; anillin functions as a scaffold linking RhoA to actin and myosin at the equatorial cortex; furrows can initiate without anillin but require anillin when the central spindle is also disrupted.\",\n      \"method\": \"Sequence homology analysis, direct binding assays, RNAi depletion, epistasis with central spindle perturbation, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct RhoA binding demonstrated with defined domain, epistasis analysis with orthogonal perturbations\",\n      \"pmids\": [\"18158243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Anillin and septins promote asymmetric furrow ingression in C. elegans; anillin and septins promote coalescence of contractile ring components on one side of the ring, and disruption of this asymmetry makes cytokinesis sensitive to partial contractility inhibition.\",\n      \"method\": \"RNAi depletion in C. elegans, time-lapse microscopy, quantification of furrow ingression asymmetry\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic depletion with quantitative functional readout, demonstrates mechanistic role of anillin-septin interaction in furrow mechanics\",\n      \"pmids\": [\"17488632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Drosophila RacGAP50C directly interacts with Anillin; both proteins depend on this interaction for their localization; in the absence of anillin, spindle-associated RacGAP50C loses equatorial cortex association and cytokinesis fails, establishing a direct molecular link between spindle microtubules and the actomyosin contractile ring.\",\n      \"method\": \"Genetic analysis, co-localization in vivo, in vitro interaction assay, RNAi depletion\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated in vitro and confirmed by co-localization in vivo, reciprocal genetic dependency shown\",\n      \"pmids\": [\"18158242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Affinity-purification/MS of Anillin interactors in Drosophila cells identified actin, myosin, three septins, and RacGAP50C (Tum); F-actin is essential for cortical Anillin localization in prometaphase but not for furrow accumulation; septins travel along microtubules to interact with Anillin at the furrow; RacGAP50C is necessary for Anillin accumulation at the furrow and the two proteins interact in vitro.\",\n      \"method\": \"Affinity purification coupled with mass spectrometry, RNAi, drug treatments, in vitro binding, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AP-MS interactome with multiple orthogonal validations (RNAi, drug, in vitro binding)\",\n      \"pmids\": [\"18349071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ran regulates anillin-dependent targeting of the septin Peanut to pseudocleavage furrows in Drosophila; importin-α and importin-β directly bind anillin and prevent its interaction with Peanut; RanGTP reverses this inhibition; a mutant anillin lacking the importin binding site renders furrow ingression insensitive to Ran pathway disruption.\",\n      \"method\": \"In vitro biochemical binding assays, importin pulldown, dominant-negative Ran expression, immunofluorescence in Drosophila syncytial embryos\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical binding demonstrated and confirmed by functional rescue with mutant anillin\",\n      \"pmids\": [\"18579688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mDia2 interacts with anillin via its diaphanous-inhibitory domain (DID); anillin binding is competitive with the diaphanous autoregulatory domain (DAD) autoinhibitory interaction; both Rho GTPase-mediated activation and anillin interaction are required for mDia2 localization and function in cytokinesis.\",\n      \"method\": \"Pulldown assays, RNAi, functional rescue experiments in NIH 3T3 cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown identifies interaction, competition assay and RNAi rescue define functional requirement, single lab\",\n      \"pmids\": [\"20660154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PH domain of anillin directly binds PI(4,5)P2; reduction of cellular PI(4,5)P2 or PH domain mutations that disrupt PI(4,5)P2 binding impair anillin localization to the furrow; the PH domain has two functions: PI(4,5)P2-mediated furrow targeting and septin recruitment to the furrow.\",\n      \"method\": \"PIP binding assays, site-directed mutagenesis of PH domain, PI(4,5)P2 depletion, RNAi rescue experiments, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct lipid binding assay combined with mutagenesis and cellular rescue experiments defining two PH domain functions\",\n      \"pmids\": [\"22197245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Citron kinase (CIT-K) physically and functionally interacts with anillin; CIT-K is an upstream regulator (not effector) of RhoA during late cytokinesis; active RhoA and anillin are displaced from the midbody in CIT-K-depleted cells; overexpression of anillin alone delays abscission independently of RhoA.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, RhoA inactivation, overexpression in mammalian cells, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and epistasis by RhoA inactivation, single lab\",\n      \"pmids\": [\"21849473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Anillin (ANI-1) promotes astral microtubule-directed cortical myosin polarization in C. elegans embryos; microtubule-directed myosin II polarization is aberrant without ANI-1; anillin interacts with microtubules providing an inhibitory mechanism to promote cell cortex polarization for cytokinesis.\",\n      \"method\": \"RNAi depletion, time-lapse microscopy in C. elegans embryos, microtubule binding assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with clear polarization phenotype and microtubule interaction assay, single lab\",\n      \"pmids\": [\"21737681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Anillin acts as a bifunctional linker coordinating midbody ring biogenesis: the N-terminus connects with the actomyosin contractile ring and supports midbody ring formation; the C-terminus (via septin Peanut) ensures stable anchoring of the plasma membrane; loss of either function prevents complete cytokinesis.\",\n      \"method\": \"RNAi depletion, truncation analysis, time-lapse microscopy in Drosophila S2 cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain truncation analysis with functional readout, defines two mechanistically distinct roles\",\n      \"pmids\": [\"22226749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Anillin interacts with the PH domain of Ect2 (RhoGEF) in human cells; the anillin-Ect2 complex stabilizes central spindle microtubules at the cortex during cytokinesis; a PH domain mutation disrupting phospholipid association weakens the anillin-Ect2 interaction.\",\n      \"method\": \"Co-immunoprecipitation, PH domain mutagenesis, immunofluorescence in cultured human cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP with mutagenesis support, functional model supported but not fully reconstituted, single lab\",\n      \"pmids\": [\"22514687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of human anillin C-terminal region reveal a cryptic C2 domain and a Rho-binding domain; together with the PH domain, three membrane-associating elements (C2, RBD, PH) synergistically bind RhoA and phospholipids to anchor anillin at the cleavage furrow.\",\n      \"method\": \"X-ray crystallography, functional mutagenesis, lipid binding assays, cell biological validation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis validating mechanistic model of membrane anchorage\",\n      \"pmids\": [\"25959226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Anillin localizes to epithelial cell-cell junctions throughout the cell cycle in Xenopus embryos and regulates junction integrity; anillin knockdown disrupts tight and adherens junctions, increases dynamic RhoA-GTP flares at junctions, and reduces junctional F-actin and myosin II accumulation.\",\n      \"method\": \"Morpholino knockdown in Xenopus laevis embryos, live imaging of RhoA-GTP biosensor, immunofluorescence, laser ablation\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with quantitative RhoA-GTP biosensor and multiple junctional readouts\",\n      \"pmids\": [\"24835458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in ANLN (R431C and G618C) cause familial FSGS; the R431C mutant displays reduced binding to the slit-diaphragm scaffold protein CD2AP, enhanced podocyte motility, and loss-of-function in zebrafish glomerular filtration; anillin is required for podocyte actin cytoskeleton integrity.\",\n      \"method\": \"Whole-exome sequencing, family linkage, Co-IP for CD2AP interaction, overexpression in human podocytes, zebrafish morpholino knockdown\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay showing reduced CD2AP interaction with mutant, in vivo zebrafish functional validation, human genetic evidence\",\n      \"pmids\": [\"24676636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human anillin interacts with astral microtubules; astral and central spindle microtubules independently control contractile protein localization; RhoA-GTP binding to anillin competes with its microtubule interaction; anillin restricts myosin to the equatorial cortex and NuMA to the polar cortex.\",\n      \"method\": \"Microtubule binding assays, RNAi, immunofluorescence in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct microtubule binding assay, RNAi competition experiment, single lab\",\n      \"pmids\": [\"24994938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A complex of p190RhoGAP-A and anillin modulates RhoA-GTP levels at the cytokinetic furrow; p190RhoGAP-A mutants that cannot bind anillin or inactivate RhoA fail to rescue cytokinesis defects; excess RhoA-GTP from p190RhoGAP-A depletion prevents progression to abscission.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, mutant rescue experiments, blebbistatin pharmacology in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutant rescue establishing functional requirement, single lab\",\n      \"pmids\": [\"25359885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Anillin (Drosophila and C. elegans) directly links RhoG/MIG-2 signaling to the actin cytoskeleton during neuronal migration and neurite growth: the active form of RhoG directly binds anillin and recruits it to the leading edge, where the anillin actin-binding domain stabilizes F-actin by antagonizing cofilin-mediated severing.\",\n      \"method\": \"Somatic CRISPR-Cas9 conditional mutagenesis in C. elegans, biochemical pulldown of RhoG-anillin interaction, in vitro F-actin severing assays, live imaging\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct RhoG binding demonstrated biochemically, F-actin stabilization mechanistically defined by severing assay, in vivo validation\",\n      \"pmids\": [\"25843030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Importin-β2 targets anillin to the nucleus during interphase via a noncanonical PY-NLS; nuclear sequestration restricts anillin's membrane function to mitosis; importin-β2 binding does not regulate mitotic function but prevents cytosolic accumulation that disrupts interphase architecture.\",\n      \"method\": \"NLS mapping, importin-β2 binding assays, Ran-dependent nuclear import assays, immunofluorescence in human cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct importin binding with defined NLS motif and Ran dependency, functional consequences demonstrated, single lab\",\n      \"pmids\": [\"25829492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Anillin knockdown disrupts tight and adherens junctions in human epithelial cells; this is accompanied by disorganization of the perijunctional actomyosin belt, decreased γ-adducin expression, and cytoplasmic aggregation of αII-spectrin; JNK activation mediates the junctional defects, and JNK inhibition restores junction integrity in anillin-depleted cells.\",\n      \"method\": \"siRNA knockdown in human epithelial cell lines, immunofluorescence, JNK inhibitor rescue, western blotting\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with pharmacologic rescue defining JNK pathway placement, multiple junctional readouts, single lab\",\n      \"pmids\": [\"25809162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Active Ran/importin gradient spatially restricts anillin to the equatorial cortex; anillin contains a conserved NLS that binds importin-β; RhoA-GTP binding to anillin's RBD domain autoinhibits the NLS and nearby microtubule-binding domain; importin-β binding stabilizes a conformation favoring cortical recruitment during cytokinesis.\",\n      \"method\": \"Ran-GTP manipulation, importin binding assays, NLS mutagenesis, live-cell imaging in human cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct importin binding with NLS mutants and Ran manipulation, functional cortical localization assay, single lab\",\n      \"pmids\": [\"28931593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of anillin at S635 (adjacent to the AH domain) by mitotic kinases is required for efficient recruitment to the equatorial membrane at anaphase onset; a S635A mutant shows impaired cortical recruitment and cytokinesis failure; a phosphomimetic S635D partially restores localization.\",\n      \"method\": \"Systematic phosphomutant screen (46 sites), phosphospecific antibody, time-lapse videomicroscopy, rescue assays in human cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with phosphospecific antibody and live-cell imaging, single lab\",\n      \"pmids\": [\"28081137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Anillin actin-binding domain harbors three distinct actin-binding sites (ABS1–3); ABS1 and ABS3 bind F-actin in a mutually exclusive fashion; ABS2 and ABS3 are each required and together sufficient for cortical localization during cytokinesis; anillin can cross-link actin filaments in parallel and antiparallel orientations and promotes 3D F-actin bundle formation.\",\n      \"method\": \"In vitro binding assays, electron microscopy on recombinant fragments, depletion-rescue in Drosophila S2 cells, immunofluorescence\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural EM with defined actin binding sites, mutagenesis rescue in cells, orthogonal in vitro and in vivo validation\",\n      \"pmids\": [\"28147230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ANLN R431C FSGS mutation causes hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling and mTOR-driven ER stress in podocytes; inhibition of mTOR, GSK-3β, Rac1, or calcineurin ameliorates R431C effects; calcineurin/NFAT pathway inhibition reduces endogenous ANLN and mTOR expression.\",\n      \"method\": \"In vivo zebrafish complementation, stable human podocyte cell lines, western blotting, pharmacologic inhibition\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacologic interventions with biochemical readouts, in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"30002222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Anillin directly binds GTP-RhoA and concentrates PIP2 at the cortex to promote effector recruitment; a sequential kinetic scaffolding pathway is proposed and tested where GTP-RhoA first binds anillin, is then retained at the membrane by PIP2 after disengaging from anillin, and repeated binding cycles increase GTP-RhoA dwell time to enhance effector recruitment.\",\n      \"method\": \"Direct binding assays, live-cell FRAP/single-molecule imaging, PIP2 manipulation, anillin mutants, quantitative kinetic modeling in Xenopus and mammalian epithelial cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding, single-molecule imaging, PIP2 manipulation, kinetic modeling with multiple orthogonal validations\",\n      \"pmids\": [\"31105010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Anillin regulates medial-apical actomyosin in Xenopus epithelial cells; anillin overexpression increases mechano-sensitive vinculin recruitment to junctions (increased tension) but slows junctional recoil after laser ablation; medial-apical laser ablation reveals tensile forces stored across the apical surface that depend on anillin; anillin's effects on cellular mechanics impact tissue-wide mechanics.\",\n      \"method\": \"Laser ablation, vinculin mechanosensor, morpholino knockdown and overexpression in Xenopus embryos, traction force microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biophysical methods (laser ablation, mechanosensor, traction microscopy), gain- and loss-of-function in vivo\",\n      \"pmids\": [\"30702429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANLN knockdown in pancreatic cancer cells inhibits LASP1 expression via upregulation of miR-218-5p; ANLN-induced EZH2 upregulation suppresses miR-218-5p to maintain LASP1 levels; this ANLN→EZH2→miR-218-5p→LASP1 axis promotes pancreatic cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"siRNA knockdown, gene expression microarray, luciferase reporter assays, rescue experiments in vitro and xenograft in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter confirms direct miR-218-5p/LASP1 targeting, EZH2 link supported by expression assays and rescue, single lab\",\n      \"pmids\": [\"31395079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Importin-β binding to anillin's NLS promotes a conformation that increases accessibility of the C2 domain; active RhoA binding to the RBD initially opens the C2 domain, and subsequent importin binding stabilizes the conformation required for cortical recruitment; this reveals importin-mediated positive regulation (not just nuclear sequestration) of a cortical protein.\",\n      \"method\": \"Binding assays with RhoA and importin-β, domain mutant analysis, live-cell localization assays in human cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays with domain mutants defining sequential conformational regulation, single lab\",\n      \"pmids\": [\"32238082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Rho guanine nucleotide exchange factor Bud3 and anillin-like Bud4 form a RhoGEF-anillin module essential for septin architectural remodeling from hourglass to double ring in budding yeast; Bud3 stabilizes single septin filaments and Bud4 strengthens interactions between filament types at outer zones of the transitional hourglass.\",\n      \"method\": \"Genetic deletion analysis, fluorescence microscopy, polarization microscopy for filament orientation in S. cerevisiae\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection with domain deletions and quantitative microscopy, yeast ortholog\",\n      \"pmids\": [\"32197082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANLN is required for cell migration, invasion, and anchorage-independent growth in breast cancer cells; ANLN knockout triggers transcriptional reprogramming suppressing stemness and inducing mesenchymal-to-epithelial trans-differentiation with upregulation of E-cadherin; E-cadherin knockdown restores migration in anillin-deficient cells.\",\n      \"method\": \"CRISPR/Cas9 knockout, wound healing and Matrigel invasion assays, mammosphere formation, xenograft mouse models, RNA-seq, immunofluorescence\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with rescue experiment (E-cadherin KD), in vivo xenograft, transcriptomics, single lab\",\n      \"pmids\": [\"31910867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Anillin, as a non-motor actin crosslinker, autonomously propels contractility of actin bundles and rings: it generates contractile forces of tens of picoNewtons to maximize overlap lengths between bundled antiparallel actin filaments; contractility is enhanced by actin disassembly and leads to ring constriction in the absence of myosin activity.\",\n      \"method\": \"In vitro reconstitution with purified anillin and actin, optical trap force measurements, TIRF microscopy, actin ring formation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantitative force measurements, myosin-independent mechanism definitively demonstrated\",\n      \"pmids\": [\"34321459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANLN directly interacts with RhoA (demonstrated by Co-IP) and promotes RhoA activation; ANLN overexpression enhances expression of multidrug resistance proteins MDR1 and BCRP, promoting doxorubicin resistance; C3 transferase (RhoA inhibitor) abolishes ANLN overexpression effects on drug resistance.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, RNAi knockdown, C3 transferase pharmacology, flow cytometry, western blotting in breast cancer cells\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct Co-IP for RhoA interaction, pharmacologic RhoA inhibition for epistasis, single lab\",\n      \"pmids\": [\"33116832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP10 deubiquitinase interacts with ANLN and removes K11- and K63-linked ubiquitin chains to prevent APC/C-Cdh1-mediated degradation; USP10 and Cdh1 form a non-competitive complex with ANLN to balance its protein levels; USP10-stabilized ANLN promotes contractile ring assembly and cytokinesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin chain linkage analysis, USP10 knockdown/inhibition, APC/C-Cdh1 complex assays, cell biology in ESCC cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Co-IP, specific ubiquitin chain type identification, non-competitive complex formation, functional rescue assays\",\n      \"pmids\": [\"36526897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CIN85 interacts directly with the N-terminal region of anillin and with SEPT9; this anillin-CIN85-SEPT9 complex facilitates SEPT9-containing septin filament localization to the intercellular bridge plasma membrane during cytokinesis; the anillin PH domain separately binds septin units lacking SEPT9 but enriched in SEPT11.\",\n      \"method\": \"Direct binding assays, Co-immunoprecipitation, RNAi knockdown, immunofluorescence in human cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay defining domain specificity for two septin complexes, functional RNAi readout, single lab\",\n      \"pmids\": [\"36044846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANLN acts as a scaffold that strengthens the interaction between RACGAP1 and PLK1; ANLN promotes PLK1-mediated RACGAP1 phosphorylation and RhoA activation to ensure cytokinesis fidelity; hepatic Anln ablation in mice enhances polyploidization and impairs c-Myc/NRAS-driven hepatocarcinogenesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, kinase assay for PLK1-mediated phosphorylation, Anln knockout mouse model with hydrodynamic transfection of oncogenes, flow cytometry for polyploidy\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for scaffold role, kinase assay for PLK1-RACGAP1-ANLN axis, in vivo mouse model, single lab\",\n      \"pmids\": [\"35477750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear ANLN forms a transcriptional complex with SP1, which enhances KIF2C transcriptional activity to activate the mTORC1 pathway; increased RANKL and disproportionate RANKL-OPG expression in the bone microenvironment drives HCC bone metastasis; ANLN mRNA stability is enhanced via m6A modification by METTL3/YTHDF1.\",\n      \"method\": \"METTL3/YTHDF1 knockdown, m6A assays, ChIP, nuclear ANLN co-immunoprecipitation with SP1, luciferase reporter, xenograft bone metastasis models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — nuclear complex Co-IP and ChIP demonstrated, m6A modification defined, in vivo model, but single lab study\",\n      \"pmids\": [\"36923927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAZ and TEAD2 transcriptionally upregulate ANLN as a target gene to promote HCC cell proliferation; CRISPRi knockdown of ANLN in a dCas9 knock-in mouse model reduces TAZ-driven and MET/CTNNB1-driven HCC growth in vivo.\",\n      \"method\": \"RNA-seq, ChIP, CRISPRi screen in dCas9 mice, genetic deletion of TAZ in floxed mice via AAV-Cre, in vivo HCC models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms TEAD2 binding to ANLN, in vivo CRISPRi demonstrates functional requirement, single lab\",\n      \"pmids\": [\"36894036\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Anillin (ANLN) is a multidomain scaffold protein that organizes the cytokinetic contractile ring by directly binding F-actin (via three distinct actin-binding sites that bundle filaments and generate myosin-independent contractile forces), nonmuscle myosin II (in a phosphorylation-regulated manner), septins (through its C-terminal PH domain via PI(4,5)P2), and active GTP-RhoA (through a cryptic C2 domain and a Rhotekin-homologous RBD revealed by crystal structure); it links these ring components to RhoGEFs (Ect2), RacGAP/centralspindlin, and the mDia2 formin, physically connecting spindle microtubules to the actomyosin ring; its membrane association is anchored by PI(4,5)P2 binding via the PH domain; anillin enhances RhoA cortical signaling by kinetic scaffolding—stabilizing GTP-RhoA membrane dwell time cooperatively with PIP2; its abundance is cell-cycle regulated by APC/C-Cdh1-mediated ubiquitin degradation (counterbalanced by USP10 deubiquitylation) and by phosphorylation (including S635 by mitotic kinases); during interphase, importin-β2 sequesters anillin in the nucleus via a PY-NLS, restricting its membrane activity to mitosis; beyond cytokinesis, anillin regulates epithelial cell-cell junction integrity (by controlling junctional RhoA-GTP distribution and suppressing JNK), epithelial mechanics (via medial-apical actomyosin), neuronal migration (by linking RhoG to actin and antagonizing cofilin), and podocyte actin integrity (where FSGS-causing mutations disrupt CD2AP binding and hyperactivate PI3K/AKT/mTOR/Rac1 signaling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Anillin (ANLN) is a multidomain scaffold protein that organizes the actomyosin cytokinetic contractile ring by physically coupling its core components and linking them to the underlying membrane and spindle [#0, #1, #5]. Its N-terminal actin-binding domain contains three distinct actin-binding sites that crosslink filaments into parallel and antiparallel bundles, and these crosslinking activities allow anillin to autonomously generate tens-of-picoNewton contractile forces and drive ring constriction even in the absence of myosin II [#26, #34]. Anillin directly binds nonmuscle myosin II in a light-chain phosphorylation-dependent manner and is required for the spatial regulation of myosin contraction and successful abscission [#1]. Membrane anchorage and equatorial targeting are achieved through a C-terminal module of three synergistic membrane-associating elements—a cryptic C2 domain, a Rhotekin-homologous Rho-binding domain, and a PH domain—that together engage GTP-RhoA and phospholipids, with the PH domain binding PI(4,5)P2 and recruiting septins to the furrow [#5, #11, #16]. Through these interactions anillin acts as a kinetic scaffold that concentrates PI(4,5)P2 and prolongs the membrane dwell time of GTP-RhoA to amplify RhoA effector recruitment [#28]. Anillin further bridges the spindle and the cortex by interacting with centralspindlin component RacGAP, the RhoGEF Ect2, the formin mDia2, and microtubules, thereby positioning contractile-ring assembly relative to the central spindle [#7, #8, #10, #15, #19]. Its activity is tightly cell-cycle controlled: APC/C-Cdh1 targets anillin for ubiquitin-mediated degradation, counterbalanced by USP10 deubiquitylation, and mitotic phosphorylation at S635 and importin-mediated conformational and localization control restrict its membrane function to mitosis [#2, #36, #25, #22, #24]. Beyond division, anillin localizes to epithelial cell-cell junctions where it controls junctional RhoA-GTP dynamics, perijunctional actomyosin organization, and tissue mechanics, and it links RhoG signaling to F-actin stabilization during neuronal migration [#17, #23, #29, #21]. Mutations in ANLN (R431C, G618C) cause familial focal segmental glomerulosclerosis through disrupted CD2AP binding and aberrant podocyte signaling [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that anillin directly binds and bundles actin filaments and concentrates in the cleavage furrow defined it as an actin-organizing component of the contractile apparatus.\",\n      \"evidence\": \"Actin filament chromatography, domain mapping, and in vitro bundling assays with immunofluorescence in Drosophila\",\n      \"pmids\": [\"7559773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of force generation not addressed\", \"Furrow targeting determinants unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying a phosphorylation-regulated direct interaction with nonmuscle myosin II showed anillin spatially coordinates myosin contraction during cytokinesis.\",\n      \"evidence\": \"Direct binding assays and RNAi depletion in Drosophila and human cells with time-lapse imaging\",\n      \"pmids\": [\"15496454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for the regulatory phosphorylation not defined\", \"Structural basis of myosin binding unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Anillin abundance was shown to be cell-cycle controlled by APC/C-Cdh1 ubiquitination, explaining its mitotic peak and its role in late-cytokinesis contractility.\",\n      \"evidence\": \"In vitro APC/C substrate screen, ubiquitination assays, and Cdh1 manipulation\",\n      \"pmids\": [\"16040610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deubiquitylase counterbalance not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Genetic and biochemical work tied anillin to septin recruitment via its PH domain and to RhoA-dependent actin organization, establishing it as a multivalent scaffold.\",\n      \"evidence\": \"Drosophila allele series and Co-IP/siRNA in human cells\",\n      \"pmids\": [\"15930114\", \"16357138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RhoA interaction in human cells based on single Co-IP\", \"PI3K/AKT link pharmacologic only\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of a Rhotekin-homologous Rho-binding domain and a direct RacGAP interaction established anillin as the molecular bridge connecting RhoA, the central spindle, and the actomyosin ring.\",\n      \"evidence\": \"Sequence/homology analysis, direct binding, in vitro interaction, RNAi and epistasis across species\",\n      \"pmids\": [\"18158243\", \"18158242\", \"17488632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural definition of the RhoA-binding interface not yet resolved\", \"Quantitative contribution to furrow positioning unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"AP-MS interactome and Ran-regulated septin targeting refined the network of anillin partners and showed importins gate its septin-recruiting activity.\",\n      \"evidence\": \"Affinity purification/MS, in vitro binding, importin pulldowns, and Ran manipulation in Drosophila\",\n      \"pmids\": [\"18349071\", \"18579688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of some interactome hits not fully separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Anillin was shown to relieve mDia2 autoinhibition, coupling it to formin-driven actin assembly during cytokinesis.\",\n      \"evidence\": \"Pulldown, DID/DAD competition, and RNAi rescue in NIH 3T3 cells\",\n      \"pmids\": [\"20660154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"In vivo relevance of the competition not fully reconstituted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The PH domain was defined as a dual-function module binding PI(4,5)P2 for furrow targeting and recruiting septins, and Citron kinase and microtubule interactions placed anillin within upstream cortical polarization control.\",\n      \"evidence\": \"Lipid binding assays with PH mutagenesis, Co-IP, and RNAi across human and C. elegans systems\",\n      \"pmids\": [\"22197245\", \"21849473\", \"21737681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Separation of PI(4,5)P2 and septin functions within the PH domain incompletely mapped\", \"Citron kinase and microtubule findings single-lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain-truncation and Ect2 interaction studies established anillin as a bifunctional linker whose N-terminus engages the actomyosin ring while the C-terminus anchors membrane/septin and stabilizes spindle microtubules at the cortex.\",\n      \"evidence\": \"Truncation analysis, Co-IP with PH mutagenesis, and imaging in Drosophila and human cells\",\n      \"pmids\": [\"22226749\", \"22514687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ect2 interaction based on single Co-IP\", \"Not fully reconstituted in vitro\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structures revealed a cryptic C2 domain and RBD that, with the PH domain, synergistically anchor anillin to membrane via RhoA and phospholipids, providing the structural basis for cortical targeting.\",\n      \"evidence\": \"X-ray crystallography with functional mutagenesis and lipid binding assays\",\n      \"pmids\": [\"25959226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length conformational dynamics not captured\", \"Stoichiometry of RhoA/lipid co-engagement undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Anillin was shown to function at epithelial junctions and in podocytes, broadening its role beyond cytokinesis and revealing it governs junctional RhoA-GTP dynamics and a disease-relevant podocyte function.\",\n      \"evidence\": \"Xenopus morpholino with RhoA biosensor imaging; human genetics, Co-IP, and zebrafish knockdown for FSGS mutations\",\n      \"pmids\": [\"24835458\", \"24676636\", \"25359885\", \"24994938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between junctional and cytokinetic functions incompletely defined\", \"p190RhoGAP and microtubule competition findings single-lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Anillin was established as a direct effector of RhoG in neuronal migration and as an importin-β2 nuclear-sequestered protein, defining interphase regulation that restricts its membrane activity to mitosis.\",\n      \"evidence\": \"Biochemical RhoG pulldown, in vitro F-actin severing assays, CRISPR conditional mutagenesis, and NLS/importin binding assays\",\n      \"pmids\": [\"25843030\", \"25829492\", \"25809162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Importin and JNK-junction findings single-lab\", \"Cross-talk between nuclear pool and cortical pool quantitatively undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Phosphoregulation and Ran/importin conformational control were mapped, showing S635 phosphorylation and RhoA-antagonized NLS autoinhibition spatially license cortical recruitment.\",\n      \"evidence\": \"Systematic phosphomutant screen with phosphospecific antibody; Ran manipulation and NLS mutagenesis with live imaging\",\n      \"pmids\": [\"28081137\", \"28931593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the S635 kinase not established\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Single-molecule and biophysical work defined anillin as a kinetic scaffold that prolongs GTP-RhoA membrane dwell time with PI(4,5)P2 and as a regulator of medial-apical actomyosin and tissue mechanics.\",\n      \"evidence\": \"FRAP/single-molecule imaging, PIP2 manipulation, kinetic modeling, laser ablation, and traction force microscopy in Xenopus and mammalian cells\",\n      \"pmids\": [\"31105010\", \"30702429\", \"31395079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetic scaffolding model not extended to all anillin functional contexts\", \"Cancer miRNA axis (LASP1) is a separate Medium-confidence pathway\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Importin binding was reinterpreted as a positive conformational regulator opening the C2 domain, and yeast and breast cancer studies extended anillin's roles to septin remodeling and EMT/stemness control.\",\n      \"evidence\": \"RhoA/importin binding assays with domain mutants; yeast genetics; CRISPR KO with rescue and xenograft in breast cancer\",\n      \"pmids\": [\"32238082\", \"32197082\", \"31910867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conformational model single-lab\", \"Transcriptional reprogramming mechanism downstream of ANLN loss not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"USP10 was identified as the deubiquitylase counterbalancing APC/C-Cdh1, and CIN85 and a PLK1-RACGAP1 scaffolding role refined the partner network controlling septin delivery and contractile fidelity.\",\n      \"evidence\": \"Co-IP, ubiquitin linkage analysis, kinase assays, RNAi, and an Anln knockout mouse model\",\n      \"pmids\": [\"36526897\", \"36044846\", \"35477750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CIN85 and PLK1 axes single-lab\", \"Integration of degradation control with mitotic timing incompletely quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Nuclear ANLN was shown to act in transcriptional complexes (with SP1) and as a Hippo/YAP-TAZ target, implicating it in oncogenic transcriptional programs and metastasis.\",\n      \"evidence\": \"Nuclear Co-IP, ChIP, luciferase reporters, m6A assays, and in vivo CRISPRi/HCC models\",\n      \"pmids\": [\"36923927\", \"36894036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear transcriptional role distinct from scaffold function mechanistically unclear\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How anillin's distinct functional pools—cytokinetic scaffold, junctional regulator, and nuclear transcriptional partner—are coordinated and switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking conformational state to functional pool\", \"Kinase identity for several regulatory phosphosites unknown\", \"Structural basis of nuclear transcriptional complexes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7, 14, 28]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 26, 34]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [26, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 16, 28]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 22, 39]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 26, 17]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 5, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 28, 21]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [17, 23]}\n    ],\n    \"complexes\": [\"actomyosin contractile ring\", \"midbody ring\", \"centralspindlin-associated cortical complex\"],\n    \"partners\": [\"RHOA\", \"MYH9\", \"RACGAP1\", \"ECT2\", \"DIAPH3\", \"CD2AP\", \"USP10\", \"SEPT9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}