{"gene":"APC2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1999,"finding":"Drosophila APC2 (dAPC2) binds Armadillo (β-catenin homolog) and acts as a negative regulator of Wingless (Wnt) signaling in the embryonic epidermis. Genetic epistasis places dAPC2 downstream of wg and upstream of arm, dTCF, and dishevelled. dAPC2 colocalizes with actin filaments and shows asymmetric localization in neuroblasts, suggesting cytoskeletal association.","method":"Genetic epistasis (loss-of-function allele), direct binding assay, immunolocalization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple markers, direct binding shown, replicated across multiple cellular contexts in a focused mechanistic study","pmids":["10491393"],"is_preprint":false},{"year":1998,"finding":"Human APCL/APC2 protein contains five copies of the 20-amino-acid APC-repeat motif; this domain binds β-catenin and depletes the intracellular β-catenin pool. APC2 also regulates the interaction of β-catenin with TCF transcription factors, as shown by reporter-gene assay in APC-null colon carcinoma cells.","method":"Direct binding assay (20-aa repeat domain), reporter-gene (TOP-flash) transcriptional assay in APC-/- cells","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and functional transcriptional assay, single lab, two orthogonal methods","pmids":["9823329"],"is_preprint":false},{"year":1999,"finding":"Mammalian APC2 contains two SAMP domains, both required for binding to conductin (Axin2). APC2 downregulates active β-catenin–TCF complex formation, as demonstrated by transient transcriptional activation assays in APC-null colon carcinoma cells.","method":"Domain-deletion binding analysis, transient transcriptional assay (TOP/FOP) in APC-/- cells","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping and functional reporter assay, single lab, two orthogonal methods","pmids":["10021369"],"is_preprint":false},{"year":2001,"finding":"APC2 and its binding partner Armadillo (β-catenin) localize to sites of cortical spindle attachment during syncytial mitoses in early Drosophila embryos. APC2–Armadillo complexes tether mitotic spindles to cortical actin. Zeste-white 3 kinase (GSK-3β homolog) phosphorylates APC and Armadillo and regulates the localization of APC2–Armadillo complexes, which is required for proper spindle positioning.","method":"Immunolocalization, live imaging, genetic loss-of-function (zw3/GSK-3 mutants), co-localization with actin/microtubule markers","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization tied to functional spindle-anchoring phenotype, genetic epistasis with kinase, multiple orthogonal approaches","pmids":["11584277"],"is_preprint":false},{"year":2001,"finding":"APC2 (the cullin subunit) and APC11 (the RING subunit) form a heterodimeric complex that constitutes the minimal ubiquitin ligase module of the human APC/C. This minimal module, together with Ubc4 or UbcH10, catalyzes ubiquitination of securin and cyclin B1 but lacks substrate specificity. APC11 and UbcH10 both bind the C-terminal cullin homology domain of APC2; Ubc4 interacts with APC11 directly.","method":"Baculoviral reconstitution of ubiquitin ligase activity in vitro, binding domain mapping, mutagenesis of APC11 Zn2+-binding residues","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — full reconstitution in vitro, mutagenesis, domain-binding mapping; rigorous single-lab study with multiple orthogonal methods","pmids":["11739784"],"is_preprint":false},{"year":1998,"finding":"Budding yeast RSI1/APC2 is a subunit of the APC (anaphase-promoting complex). Temperature-sensitive rsi1/apc2 mutants arrest in metaphase, fail to degrade Clb2p, and cannot degrade securin (Pds1p); the anaphase block is suppressed by deletion of PDS1. Rsi1p/Apc2p co-immunoprecipitates with Cdc23p (another APC subunit).","method":"Temperature-sensitive genetic screen, epistasis (PDS1 deletion rescue), co-immunoprecipitation with Cdc23p","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, co-IP, and clear cell-cycle arrest phenotype; consistent with broader APC/C literature","pmids":["9430641"],"is_preprint":false},{"year":2002,"finding":"Simultaneous loss of both Drosophila Apc1 and Apc2 causes global nuclear accumulation of Armadillo/β-catenin and constitutive activation of Wingless/Wnt transduction throughout development, demonstrating that the two proteins have redundant, global roles in restricting β-catenin-mediated transcription, even in tissues previously thought to rely only on one paralog.","method":"Genetic double-mutant epistasis, immunostaining for nuclear Armadillo, reporter assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — classical genetic epistasis with double-mutant analysis, multiple tissue readouts, well-controlled","pmids":["11923210"],"is_preprint":false},{"year":2002,"finding":"Drosophila APC2 and APC1 have overlapping roles in regulating Wingless signaling in the embryonic epidermis and imaginal discs, despite striking differences in their intracellular localizations. Single mutants are often normal, but simultaneous elimination reveals functional redundancy.","method":"Genetic double-mutant analysis, immunostaining, transgenic rescue","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic double-mutant genetic analysis with multiple tissue readouts, two companion papers","pmids":["12297097","12297098"],"is_preprint":false},{"year":2002,"finding":"In Drosophila larval neuroblasts, APC2 shows a highly dynamic, asymmetric cortical localization through the cell cycle, whereas APC1 localizes to centrosomes and microtubules. Despite different localizations, both play redundant roles in maintaining neuroblast numbers; the double mutant has severely reduced larval neuroblasts through a mechanism that does not involve Wg signaling misregulation, implicating cytoskeletal/adhesive APC functions.","method":"Immunolocalization, genetic double-mutant analysis, epistasis ruling out Wg pathway","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-mutant phenotype with localization data; pathway placement by epistasis is partial (Wg ruled out)","pmids":["12297097"],"is_preprint":false},{"year":2002,"finding":"Inversin interacts with the APC/C subunit APC2 via D-box motifs; site-directed mutagenesis of the conserved D-box residues in inversin abrogates this interaction, suggesting inversin is an APC2 target subject to APC/C-mediated degradation.","method":"Co-immunoprecipitation, site-directed mutagenesis of D-box motifs","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding + mutagenesis confirmation, single lab, focused on APC/C-subunit APC2","pmids":["12471060"],"is_preprint":false},{"year":2000,"finding":"APCL/APC2 binds p53-binding protein 2 (53BP2) via an interaction requiring both the SH3 domain and ankyrin-repeat domain of 53BP2 with the C-terminus of APCL. This binding translocates 53BP2 to the perinuclear region of mammalian cells; truncated APCL abrogates this co-localization, suggesting APC2 regulates the subcellular location of 53BP2.","method":"Yeast two-hybrid screen, in vitro binding assay, domain-mapping, confocal co-localization","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and confocal co-localization with truncation controls, single lab","pmids":["10646860"],"is_preprint":false},{"year":2001,"finding":"Human APC2 localizes to the Golgi apparatus and actin-containing structures (and occasionally microtubules) when overexpressed in SKOV3 cells; endogenous APC2 is diffusely cytoplasmic and colocalizes with Golgi and actin filaments. APC2 remains associated with actin filaments after cytochalasin D treatment, indicating it associates with actin through a direct or stable mechanism.","method":"Fluorescence microscopy, immunofluorescence, cytochalasin D treatment, FISH allelic imbalance analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with pharmacological perturbation; single lab but multiple approaches","pmids":["11691822"],"is_preprint":false},{"year":2005,"finding":"Cryo-EM 3D reconstruction of human and Xenopus APC/C mapped Cdh1 (coactivator) and Apc2 (cullin subunit) to the same side of the asymmetric complex, establishing that substrate ubiquitination occurs on this face. Cdh1 binding induces a conformational change in a large flexible APC/C domain, suggesting Cdh1 activates APC/C both by recruiting substrates and by conformational rearrangement.","method":"Cryo-EM angular reconstitution, random conical tilt (RCT), STEM mass measurement, antibody labeling for subunit mapping","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural mapping with STEM validation; single lab but structural evidence is direct","pmids":["16364912"],"is_preprint":false},{"year":2009,"finding":"APC2 is distributed along microtubules in growth cones and axon shafts of retinal axons. Overexpression of APC2 stabilizes microtubules; shRNA knockdown of APC2 in chick retinas reduces microtubule stability. APC2-knockdown retinal axons show reduced response to ephrin-A2 guidance cues and drastic alterations in retinotectal topographic projections in vivo.","method":"Immunohistochemistry, overexpression assay (microtubule stabilization), shRNA knockdown in chick retina, in vitro guidance assay, in vivo retinotectal projection analysis","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss- and gain-of-function with direct cellular phenotypes (microtubule stability, axon guidance), both in vitro and in vivo, multiple orthogonal readouts","pmids":["19759310"],"is_preprint":false},{"year":2011,"finding":"Cortical localization of Drosophila APC2 requires both the Armadillo repeats and a novel C-terminal domain (neither alone is sufficient). The Armadillo repeats also mediate APC2 self-association. Cortical localization is required for APC2's role in organizing actin but is dispensable for its role in Wnt/Wingless signaling, as shown by rescue experiments with a C-terminal-deletion APC2.","method":"Domain-deletion analysis, S2 cell transfection, rescue assays in APC mutant embryos (actin and Wnt phenotypes), co-immunoprecipitation for self-association","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain dissection with functional rescue in two separate biological readouts, self-association confirmed by co-IP","pmids":["21486956"],"is_preprint":false},{"year":2013,"finding":"Loss of APC2 in Drosophila embryos leads to increased chromosome segregation errors through a cascade: incomplete centrosome separation → failure to inhibit ectopic cleavage furrows → mitotic defects and DNA damage. APC2 functions at the embryonic cortex together with Axin to promote mitotic fidelity through cytoskeletal regulation.","method":"Genetic loss-of-function, live imaging of chromosome segregation, epistasis with Axin, immunostaining for centrosome and furrow markers","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-imaging of segregation errors + mechanistic pathway dissection with multiple genetic tests and cytoskeletal readouts","pmids":["24026117"],"is_preprint":false},{"year":2014,"finding":"The spliceosome subunit SNW1 is required for correct splicing of APC2 pre-mRNA; SNW1 depletion reduces APC2 protein levels, decreases APC/C ubiquitin ligase activity, delays mitosis, and contributes to sister chromatid cohesion defects ('cohesion fatigue'). Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1-depleted cells.","method":"siRNA knockdown, transcriptome-wide splicing analysis, intron-less cDNA rescue experiment, cohesion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic rescue with intron-less cDNA, genome-wide splicing mapping, direct functional readout of APC/C activity","pmids":["25257309"],"is_preprint":false},{"year":2015,"finding":"Loss-of-function mutation in APC2 causes Sotos syndrome-like features including impaired learning/memory and abnormal head shape in Apc2-/- mice, through loss of cytoskeletal regulation in neurons. APC2 is a downstream effector of NSD1: NSD1 knockdown downregulates Apc2 expression, and the neuronal migration/laminar positioning defect caused by Nsd1 knockdown is rescued by forced Apc2 expression.","method":"Mouse knockout, whole-exome sequencing (patient), Nsd1 knockdown in embryonic mouse brains, forced expression rescue, behavioral assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse phenotype + epistasis rescue with re-expression, multiple orthogonal readouts including behavioral and cellular","pmids":["25753423"],"is_preprint":false},{"year":2016,"finding":"Tankyrase (TNKS) poly(ADP-ribose) polymerase binds a C-terminal RPQPSG motif in Drosophila APC2 (conserved in human APC2 but absent in human APC1). APC2 recruits TNKS into the β-catenin destruction complex. TNKS directly PARylates both Drosophila Axin and APC2, but PARylation does not globally regulate APC2 protein levels as it does for Axin. TNKS inhibition reduces β-catenin signaling through effects at both Axin and APC2.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro PARylation assay, motif-mapping, cell-based Wnt reporter assays with TNKS inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Y2H + Co-IP + in vitro PARylation assay + functional cell-based readout; multiple orthogonal methods in a single focused study","pmids":["27068743"],"is_preprint":false},{"year":2018,"finding":"APC2 promotes dynamics (plus-end growth) of minus-end-out microtubules in vertebrate dendrites and thereby regulates dendritic morphology. APC2 localizes as distinct clusters along microtubule bundles in dendrites; localization is driven by LC8-binding and two separate microtubule-interacting domains. APC2 depletion reduces plus-end dynamics of minus-end-out microtubules, increases microtubule sliding, and causes dendritic morphology defects.","method":"shRNA knockdown, live microtubule dynamics imaging (EB3 tracking), domain-deletion localization analysis, morphology quantification in neurons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-imaging of microtubule dynamics combined with domain dissection and KD phenotypic readout in neurons; multiple orthogonal methods","pmids":["30018294"],"is_preprint":false},{"year":2018,"finding":"APC2 associates with the actin cortex through a multipart mechanism in Drosophila: cortical localization requires an N-terminal APC Self-Association Domain (ASAD) that mediates self-association, and a conserved coiled-coil within the C-terminal 30 amino acid (C30) domain. APC2 regulates cortical actin dynamics and distribution in Drosophila follicular epithelium and nurse cells.","method":"Domain-deletion and mutagenesis in S2 cells, immunofluorescence in Drosophila ovary, actin dynamics analysis","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion with functional cellular readout; single lab, extends prior localization work","pmids":["30019417"],"is_preprint":false},{"year":2018,"finding":"Drosophila Brain Tumor (Brat) acts cell-autonomously through its B-Box domains to regulate the expression and localization of Apc2 at the plus ends of microtubules in commissural axons. Brat and Apc2 promote axon growth across the midline independently of canonical Wnt/β-catenin transcriptional signaling, implicating Apc2 microtubule-stabilizing function in axon guidance.","method":"Genetic epistasis (Brat and Apc2 mutants), immunolocalization in commissural axons, genetic interaction analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with localization data; pathway independence from Wnt shown genetically; single lab","pmids":["29617376"],"is_preprint":false},{"year":2018,"finding":"In Drosophila neurons, Apc2 localizes to dendrite branch points where it recruits Apc and thereby steers growing microtubule plus ends to maintain minus-end-out polarity. Apc2-GFP positioning at branch points requires energy production by mitochondria (spastin acts upstream of mitochondria), Nrg/Ank2, Arp2/3-mediated branched actin (downstream of Rac1), and a Fz/G-protein/Axin module.","method":"Candidate RNAi screen, secondary genetic screens, live imaging of Apc2-GFP at branch points, epistasis analysis","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNAi screen with mechanistic pathway dissection; live imaging; single lab","pmids":["29602811"],"is_preprint":false},{"year":2012,"finding":"Drosophila Apc11 (lemmingA/LmgA) interacts with Morula/Apc2 and together they form a ternary complex with Vihar (the E2-C type ubiquitin-conjugating enzyme), establishing that the Apc11–Apc2 module recruits the E2 enzyme to the APC/C.","method":"Genetic complementation, immunoprecipitation/pull-down, yeast complementation assay","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction mapping by Co-IP/pull-down plus genetic complementation; single lab","pmids":["22417125"],"is_preprint":false},{"year":2010,"finding":"FBG1 (an SCF F-box protein) binds APC2 directly via a D-Box within the FBG1 F-box domain, as shown by immunoprecipitation and mutagenesis. Co-expression of FBG1 increases total APC2 protein levels but sequesters free APC2, inhibiting cell proliferation and inducing S-phase arrest.","method":"Co-immunoprecipitation, mutagenesis of D-box, flow cytometry (FACS) cell cycle analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + mutagenesis + functional cell-cycle readout; single lab, single study","pmids":["21135578"],"is_preprint":false},{"year":2020,"finding":"APC2 (as APC/C subunit) is enriched at the postsynapse of neuromuscular junctions in postmitotic myotubes. In response to agrin stimulation, APC2 promotes ubiquitination of DOK7 at lysine 243, leading to its proteolytic degradation; this requires MuSK kinase activity and phosphorylation of tyrosine 106 in DOK7. This negatively regulates acetylcholine receptor clustering as part of NMJ homeostasis.","method":"Immunofluorescence at NMJ, ubiquitination assay, site-directed mutagenesis (K243, Y106), co-immunoprecipitation, AChR clustering assay","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-directed mutagenesis identifying specific ubiquitination site, functional AChR-clustering readout, mechanistic requirement for upstream kinase; multiple orthogonal methods","pmids":["32687671"],"is_preprint":false},{"year":2031,"finding":"FOXO4 binds the APC2 gene promoter (shown by chromatin immunoprecipitation) to transcriptionally upregulate APC2 expression, which in turn increases phosphorylation and degradation of β-catenin, suppressing CRC cell migration and metastasis. APC2 knockdown reverses the anti-metastatic effects of FOXO4 overexpression.","method":"Chromatin immunoprecipitation (ChIP), APC2 knockdown rescue, cell migration/invasion assays, xenograft metastasis model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional rescue validates pathway placement; single lab","pmids":["34631691"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of S. cerevisiae APC/C complexes show that the catalytic module (Apc2:Apc11) is already positioned to bind E2 enzyme in the apo-state (without coactivator), in contrast to human APC/C where coactivator binding induces a conformational change of Apc2:Apc11 to allow E2 binding. This identifies a species-specific regulatory mechanism for the Apc2-containing catalytic module.","method":"Cryo-EM structure determination (apo and CDH1-bound, phosphorylated and unphosphorylated S. cerevisiae APC/C)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality structural data but preprint, single study; mechanism is comparative between species","pmids":["bio_10.1101_2024.06.19.599685"],"is_preprint":true},{"year":2025,"finding":"The BubR1 TPR domain interacts with Apc2 (as well as Mad2 and Cdc20-APC/C). This interaction, identified by cryo-EM structure of the MCC-APC/C complex, contributes to MCC assembly and MCC-APC/C binding to enable rapid spindle assembly checkpoint signaling.","method":"Cryo-EM structure of MCC-APC/C complex, functional and biochemical analyses of BubR1 TPR domain mutations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural identification plus biochemical validation; preprint, single lab","pmids":["bio_10.1101_2025.10.13.682252"],"is_preprint":true}],"current_model":"APC2 (APCL) is a multifunctional scaffold protein that acts as the cullin subunit of the APC/C E3 ubiquitin ligase (where it forms a minimal catalytic module with APC11 to ubiquitinate mitotic substrates such as securin and cyclin B1), and independently functions as a Wnt pathway negative regulator by binding β-catenin/Armadillo through 20-aa repeat motifs and binding Axin/conductin through SAMP domains to promote β-catenin destruction; in neurons and other polarized cells APC2 also directly stabilizes and regulates the dynamics of microtubules (particularly minus-end-out microtubules in dendrites and growth cones), associates with cortical actin through self-association and coiled-coil domains, tethers mitotic spindles to the actin cortex (regulated by GSK-3/Zeste-white 3 kinase phosphorylation of APC2–Armadillo complexes), and is subject to PARylation by Tankyrase and transcriptional regulation by NSD1/FOXO4, with loss-of-function causing lissencephaly, neuronal migration defects, and chromosomal instability."},"narrative":{"mechanistic_narrative":"APC2 is a multifunctional scaffold that operates in two largely separable domains of cell biology: as the cullin subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase, and as a negative regulator of Wnt/Wingless signaling [PMID:9430641, PMID:9823329]. Within the APC/C, APC2 dimerizes with the RING subunit APC11 to form the minimal catalytic ubiquitin-ligase module that, with E2 enzymes (Ubc4/UbcH10), ubiquitinates mitotic substrates such as securin and cyclin B1 [PMID:11739784, PMID:22417125]; cryo-EM maps APC2 and the Cdh1 coactivator to the substrate-ubiquitination face of the asymmetric complex, where coactivator binding repositions the catalytic module to license E2 engagement [PMID:16364912, PMID:bio_10.1101_2024.06.19.599685]. Loss of APC/C function via APC2 produces metaphase arrest and failed degradation of mitotic regulators, and reduced APC2 contributes to chromosome segregation and sister-chromatid cohesion defects [PMID:9430641, PMID:25257309]. Independently of mitosis, APC2 restrains Wnt signaling: its 20-amino-acid APC-repeat motifs bind β-catenin/Armadillo and its SAMP domains bind Axin/conductin, assembling a destruction complex that depletes β-catenin and downregulates β-catenin–TCF transcription [PMID:9823329, PMID:10021369], and it recruits Tankyrase into this complex through a conserved C-terminal motif [PMID:27068743]. APC2 also stabilizes and regulates microtubules: it promotes plus-end dynamics of minus-end-out microtubules in dendrites and stabilizes microtubules in growth cones to direct axon guidance and dendritic morphology [PMID:30018294, PMID:19759310], and it associates with cortical actin through self-association and coiled-coil domains to tether mitotic spindles and organize the actin cortex [PMID:11584277, PMID:30019417, PMID:21486956]. APC2 is a downstream effector of NSD1 in neuronal migration, and its loss causes Sotos-syndrome-like learning and morphological defects in mice [PMID:25753423].","teleology":[{"year":1998,"claim":"Established that APC2 is a functional subunit of the anaphase-promoting complex, answering whether the cullin-like protein has a direct cell-cycle role.","evidence":"Temperature-sensitive yeast rsi1/apc2 mutants, PDS1-deletion epistasis, co-IP with Cdc23p","pmids":["9430641"],"confidence":"High","gaps":["Did not define the catalytic mechanism or direct E2 partner of APC2 within the complex"]},{"year":1998,"claim":"Defined APC2 as a Wnt-pathway negative regulator by showing its 20-aa repeats bind and deplete β-catenin and modulate β-catenin–TCF transcription.","evidence":"Domain binding assay plus TOP-flash reporter in APC-null colon carcinoma cells","pmids":["9823329"],"confidence":"Medium","gaps":["Single lab; did not establish the Axin-binding requirement or in vivo significance"]},{"year":1999,"claim":"Connected APC2 to the destruction-complex scaffold by mapping the two SAMP domains required for Axin/conductin binding.","evidence":"Domain-deletion binding and transient TOP/FOP transcriptional assays in APC-null cells","pmids":["10021369"],"confidence":"Medium","gaps":["Did not show stoichiometry or assembly of the full destruction complex"]},{"year":1999,"claim":"Validated APC2 as a genetically defined Wnt antagonist in vivo and hinted at a cytoskeletal association, broadening its role beyond a biochemical interactor.","evidence":"Drosophila genetic epistasis, direct Armadillo binding, immunolocalization with actin","pmids":["10491393"],"confidence":"High","gaps":["Cytoskeletal association was correlative; functional consequence not yet tested"]},{"year":2001,"claim":"Defined the minimal catalytic module of the APC/C, showing the APC2–APC11 heterodimer with an E2 suffices for substrate ubiquitination but lacks specificity.","evidence":"Baculoviral in vitro reconstitution, binding-domain mapping, APC11 Zn-residue mutagenesis","pmids":["11739784"],"confidence":"High","gaps":["Substrate specificity determinants reside elsewhere; structural basis of E2 positioning unresolved"]},{"year":2001,"claim":"Revealed a non-degradative, cytoskeletal function: APC2–Armadillo complexes tether mitotic spindles to cortical actin under GSK-3/Zw3 control.","evidence":"Drosophila immunolocalization, live imaging, zw3 loss-of-function epistasis","pmids":["11584277"],"confidence":"High","gaps":["Molecular link between APC2 and the actin cortex not yet defined at the domain level"]},{"year":2002,"claim":"Demonstrated global functional redundancy between APC2 and APC1 in restricting β-catenin–driven transcription throughout development.","evidence":"Drosophila double-mutant epistasis, nuclear Armadillo staining, reporter assays","pmids":["11923210","12297097","12297098"],"confidence":"High","gaps":["Did not explain why two paralogs with distinct localizations are both required"]},{"year":2002,"claim":"Separated a Wnt-independent APC2 role, showing neuroblast maintenance defects in APC2/APC1 double mutants without Wg misregulation.","evidence":"Drosophila genetic double-mutant analysis with Wg-pathway epistasis ruled out","pmids":["12297097"],"confidence":"Medium","gaps":["The implicated cytoskeletal/adhesive mechanism was inferred, not directly demonstrated"]},{"year":2000,"claim":"Identified APC2 as a regulator of partner subcellular localization, redirecting 53BP2 to the perinuclear region via its C-terminus.","evidence":"Yeast two-hybrid, in vitro binding, domain mapping, confocal co-localization","pmids":["10646860"],"confidence":"Medium","gaps":["Functional consequence of 53BP2 relocalization unknown; single lab"]},{"year":2001,"claim":"Characterized endogenous APC2 localization to Golgi and actin filaments, with actin association resistant to cytochalasin D.","evidence":"Immunofluorescence, cytochalasin D perturbation, FISH allelic imbalance","pmids":["11691822"],"confidence":"Medium","gaps":["Overexpression artifacts possible; direct versus indirect actin binding not resolved"]},{"year":2002,"claim":"Extended APC/C substrate recognition by showing inversin binds APC2 through D-box motifs, marking it as a candidate degradation target.","evidence":"Co-IP and site-directed D-box mutagenesis","pmids":["12471060"],"confidence":"Medium","gaps":["Did not demonstrate APC/C-dependent inversin turnover directly"]},{"year":2005,"claim":"Placed APC2 structurally on the ubiquitination face of the APC/C and showed Cdh1 activates by conformational rearrangement, not only substrate recruitment.","evidence":"Cryo-EM 3D reconstruction with STEM mass measurement and antibody subunit labeling","pmids":["16364912"],"confidence":"High","gaps":["Low-resolution; atomic basis of the conformational change not resolved"]},{"year":2009,"claim":"Established APC2 as a microtubule stabilizer required for axon guidance, defining a discrete cytoskeletal function in neurons.","evidence":"Overexpression/shRNA in chick retina, in vitro guidance assay, in vivo retinotectal mapping","pmids":["19759310"],"confidence":"High","gaps":["Direct microtubule-binding mode not mapped at the domain level here"]},{"year":2010,"claim":"Revealed regulation of free APC2 levels and the cell cycle by the F-box protein FBG1, which binds APC2 via a D-box and sequesters it.","evidence":"Co-IP, D-box mutagenesis, FACS cell-cycle analysis","pmids":["21135578"],"confidence":"Medium","gaps":["Whether sequestration acts on the APC/C or Wnt pool of APC2 unclear"]},{"year":2011,"claim":"Dissected APC2 cortical targeting, showing Armadillo repeats plus a novel C-terminal domain drive localization and self-association, separable from Wnt function.","evidence":"Domain-deletion in S2 cells, rescue of actin and Wnt phenotypes, co-IP for self-association","pmids":["21486956"],"confidence":"High","gaps":["The cortical receptor/anchor that recruits APC2 not identified"]},{"year":2012,"claim":"Showed the APC2–APC11 module recruits the E2-C enzyme Vihar, confirming the E2-loading role of the catalytic module in vivo.","evidence":"Drosophila genetic complementation, IP/pull-down, yeast complementation","pmids":["22417125"],"confidence":"Medium","gaps":["Did not resolve conformational requirements for E2 engagement"]},{"year":2013,"claim":"Linked APC2 cortical/cytoskeletal function to genome stability via a centrosome-separation→ectopic-furrow cascade promoting mitotic fidelity.","evidence":"Drosophila loss-of-function, live imaging of segregation errors, Axin epistasis","pmids":["24026117"],"confidence":"High","gaps":["Mechanistic link between cortical APC2 and centrosome separation not molecularly defined"]},{"year":2014,"claim":"Connected APC2 levels to cohesion by showing SNW1-dependent APC2 splicing maintains APC/C activity and prevents cohesion fatigue.","evidence":"siRNA, transcriptome splicing analysis, intron-less cDNA rescue, cohesion assays","pmids":["25257309"],"confidence":"High","gaps":["A regulatory rather than direct APC2 mechanism; APC2-specific splicing dependence not generalized"]},{"year":2015,"claim":"Defined APC2 as a downstream effector of NSD1 in neuronal migration and tied its loss to Sotos-syndrome-like neurological phenotypes.","evidence":"Apc2-/- mice, patient exome, Nsd1 knockdown with forced Apc2 rescue, behavioral assays","pmids":["25753423"],"confidence":"High","gaps":["The cytoskeletal step downstream of NSD1→APC2 not fully resolved"]},{"year":2016,"claim":"Identified Tankyrase as a destruction-complex component recruited by an APC2 C-terminal motif and a PARylation target distinct from Axin in its regulation.","evidence":"Y2H, co-IP, in vitro PARylation, motif mapping, Wnt reporter with TNKS inhibitors","pmids":["27068743"],"confidence":"High","gaps":["Functional consequence of APC2 PARylation (vs Axin) not defined since it does not control APC2 levels"]},{"year":2018,"claim":"Established APC2 control of minus-end-out microtubule dynamics in dendrites, mapping its localization to LC8-binding and microtubule-interacting domains.","evidence":"shRNA, EB3 live imaging, domain-deletion localization, neuronal morphology quantification","pmids":["30018294"],"confidence":"High","gaps":["Mechanism by which APC2 biases polarity at the molecular level not fully resolved"]},{"year":2018,"claim":"Defined the cortical actin association mechanism, requiring the N-terminal ASAD self-association domain and a C30 coiled-coil.","evidence":"Domain-deletion/mutagenesis in S2 cells, Drosophila ovary immunofluorescence, actin dynamics","pmids":["30019417"],"confidence":"Medium","gaps":["Direct actin-binding partner versus indirect tethering not distinguished"]},{"year":2018,"claim":"Placed APC2 microtubule function downstream of regulatory inputs (Brat; 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mechanism of FOXO4-driven APC2 induction in normal tissue untested"]},{"year":2024,"claim":"Resolved a species-specific regulatory difference: yeast Apc2:Apc11 is pre-positioned for E2 binding in the apo state, unlike human APC/C requiring coactivator-induced rearrangement.","evidence":"Cryo-EM of apo and CDH1-bound yeast APC/C (preprint)","pmids":["bio_10.1101_2024.06.19.599685"],"confidence":"Medium","gaps":["Preprint; functional consequence of the species difference not validated biochemically"]},{"year":2025,"claim":"Implicated Apc2 in spindle-assembly-checkpoint signaling through a BubR1 TPR-domain interaction within the MCC-APC/C complex.","evidence":"Cryo-EM of MCC-APC/C, BubR1 TPR mutational analysis (preprint)","pmids":["bio_10.1101_2025.10.13.682252"],"confidence":"Medium","gaps":["Preprint; the specific contribution of the Apc2 contact to checkpoint kinetics not isolated"]},{"year":null,"claim":"How APC2's distinct functional pools — APC/C catalytic subunit, destruction-complex scaffold, and microtubule/actin regulator — are partitioned and co-regulated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative partitioning of APC2 between mitotic, Wnt, and cytoskeletal complexes","Post-translational control directing APC2 to each pool undefined","Structural basis of microtubule and actin binding not determined at atomic resolution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,25]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[4,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[13,19,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[11,13,19,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,20]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,6,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,25]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,17,19]}],"complexes":["APC/C (anaphase-promoting complex/cyclosome)","β-catenin destruction complex"],"partners":["APC11","CTNNB1","AXIN2","TNKS","TP53BP2","DOK7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02655","full_name":"Apolipoprotein C-II","aliases":["Apolipoprotein C2"],"length_aa":101,"mass_kda":11.3,"function":"Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. 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organoid","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.19.633822","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.19.599685","title":"A comparative study of the cryo-EM structures of  <i>S. cerevisiae</i>  and human anaphase-promoting complex/cyclosome (APC/C)","date":"2024-06-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.19.599685","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28762,"output_tokens":7496,"usd":0.099363,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16649,"output_tokens":6659,"usd":0.12486,"stage2_stop_reason":"end_turn"},"total_usd":0.224223,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Drosophila APC2 (dAPC2) binds Armadillo (β-catenin homolog) and acts as a negative regulator of Wingless (Wnt) signaling in the embryonic epidermis. Genetic epistasis places dAPC2 downstream of wg and upstream of arm, dTCF, and dishevelled. dAPC2 colocalizes with actin filaments and shows asymmetric localization in neuroblasts, suggesting cytoskeletal association.\",\n      \"method\": \"Genetic epistasis (loss-of-function allele), direct binding assay, immunolocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple markers, direct binding shown, replicated across multiple cellular contexts in a focused mechanistic study\",\n      \"pmids\": [\"10491393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human APCL/APC2 protein contains five copies of the 20-amino-acid APC-repeat motif; this domain binds β-catenin and depletes the intracellular β-catenin pool. APC2 also regulates the interaction of β-catenin with TCF transcription factors, as shown by reporter-gene assay in APC-null colon carcinoma cells.\",\n      \"method\": \"Direct binding assay (20-aa repeat domain), reporter-gene (TOP-flash) transcriptional assay in APC-/- cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and functional transcriptional assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"9823329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mammalian APC2 contains two SAMP domains, both required for binding to conductin (Axin2). APC2 downregulates active β-catenin–TCF complex formation, as demonstrated by transient transcriptional activation assays in APC-null colon carcinoma cells.\",\n      \"method\": \"Domain-deletion binding analysis, transient transcriptional assay (TOP/FOP) in APC-/- cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping and functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"10021369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"APC2 and its binding partner Armadillo (β-catenin) localize to sites of cortical spindle attachment during syncytial mitoses in early Drosophila embryos. APC2–Armadillo complexes tether mitotic spindles to cortical actin. Zeste-white 3 kinase (GSK-3β homolog) phosphorylates APC and Armadillo and regulates the localization of APC2–Armadillo complexes, which is required for proper spindle positioning.\",\n      \"method\": \"Immunolocalization, live imaging, genetic loss-of-function (zw3/GSK-3 mutants), co-localization with actin/microtubule markers\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization tied to functional spindle-anchoring phenotype, genetic epistasis with kinase, multiple orthogonal approaches\",\n      \"pmids\": [\"11584277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"APC2 (the cullin subunit) and APC11 (the RING subunit) form a heterodimeric complex that constitutes the minimal ubiquitin ligase module of the human APC/C. This minimal module, together with Ubc4 or UbcH10, catalyzes ubiquitination of securin and cyclin B1 but lacks substrate specificity. APC11 and UbcH10 both bind the C-terminal cullin homology domain of APC2; Ubc4 interacts with APC11 directly.\",\n      \"method\": \"Baculoviral reconstitution of ubiquitin ligase activity in vitro, binding domain mapping, mutagenesis of APC11 Zn2+-binding residues\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full reconstitution in vitro, mutagenesis, domain-binding mapping; rigorous single-lab study with multiple orthogonal methods\",\n      \"pmids\": [\"11739784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Budding yeast RSI1/APC2 is a subunit of the APC (anaphase-promoting complex). Temperature-sensitive rsi1/apc2 mutants arrest in metaphase, fail to degrade Clb2p, and cannot degrade securin (Pds1p); the anaphase block is suppressed by deletion of PDS1. Rsi1p/Apc2p co-immunoprecipitates with Cdc23p (another APC subunit).\",\n      \"method\": \"Temperature-sensitive genetic screen, epistasis (PDS1 deletion rescue), co-immunoprecipitation with Cdc23p\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, co-IP, and clear cell-cycle arrest phenotype; consistent with broader APC/C literature\",\n      \"pmids\": [\"9430641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Simultaneous loss of both Drosophila Apc1 and Apc2 causes global nuclear accumulation of Armadillo/β-catenin and constitutive activation of Wingless/Wnt transduction throughout development, demonstrating that the two proteins have redundant, global roles in restricting β-catenin-mediated transcription, even in tissues previously thought to rely only on one paralog.\",\n      \"method\": \"Genetic double-mutant epistasis, immunostaining for nuclear Armadillo, reporter assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — classical genetic epistasis with double-mutant analysis, multiple tissue readouts, well-controlled\",\n      \"pmids\": [\"11923210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Drosophila APC2 and APC1 have overlapping roles in regulating Wingless signaling in the embryonic epidermis and imaginal discs, despite striking differences in their intracellular localizations. Single mutants are often normal, but simultaneous elimination reveals functional redundancy.\",\n      \"method\": \"Genetic double-mutant analysis, immunostaining, transgenic rescue\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic double-mutant genetic analysis with multiple tissue readouts, two companion papers\",\n      \"pmids\": [\"12297097\", \"12297098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Drosophila larval neuroblasts, APC2 shows a highly dynamic, asymmetric cortical localization through the cell cycle, whereas APC1 localizes to centrosomes and microtubules. Despite different localizations, both play redundant roles in maintaining neuroblast numbers; the double mutant has severely reduced larval neuroblasts through a mechanism that does not involve Wg signaling misregulation, implicating cytoskeletal/adhesive APC functions.\",\n      \"method\": \"Immunolocalization, genetic double-mutant analysis, epistasis ruling out Wg pathway\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-mutant phenotype with localization data; pathway placement by epistasis is partial (Wg ruled out)\",\n      \"pmids\": [\"12297097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Inversin interacts with the APC/C subunit APC2 via D-box motifs; site-directed mutagenesis of the conserved D-box residues in inversin abrogates this interaction, suggesting inversin is an APC2 target subject to APC/C-mediated degradation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of D-box motifs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding + mutagenesis confirmation, single lab, focused on APC/C-subunit APC2\",\n      \"pmids\": [\"12471060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"APCL/APC2 binds p53-binding protein 2 (53BP2) via an interaction requiring both the SH3 domain and ankyrin-repeat domain of 53BP2 with the C-terminus of APCL. This binding translocates 53BP2 to the perinuclear region of mammalian cells; truncated APCL abrogates this co-localization, suggesting APC2 regulates the subcellular location of 53BP2.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, domain-mapping, confocal co-localization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro binding and confocal co-localization with truncation controls, single lab\",\n      \"pmids\": [\"10646860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human APC2 localizes to the Golgi apparatus and actin-containing structures (and occasionally microtubules) when overexpressed in SKOV3 cells; endogenous APC2 is diffusely cytoplasmic and colocalizes with Golgi and actin filaments. APC2 remains associated with actin filaments after cytochalasin D treatment, indicating it associates with actin through a direct or stable mechanism.\",\n      \"method\": \"Fluorescence microscopy, immunofluorescence, cytochalasin D treatment, FISH allelic imbalance analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with pharmacological perturbation; single lab but multiple approaches\",\n      \"pmids\": [\"11691822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Cryo-EM 3D reconstruction of human and Xenopus APC/C mapped Cdh1 (coactivator) and Apc2 (cullin subunit) to the same side of the asymmetric complex, establishing that substrate ubiquitination occurs on this face. Cdh1 binding induces a conformational change in a large flexible APC/C domain, suggesting Cdh1 activates APC/C both by recruiting substrates and by conformational rearrangement.\",\n      \"method\": \"Cryo-EM angular reconstitution, random conical tilt (RCT), STEM mass measurement, antibody labeling for subunit mapping\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural mapping with STEM validation; single lab but structural evidence is direct\",\n      \"pmids\": [\"16364912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"APC2 is distributed along microtubules in growth cones and axon shafts of retinal axons. Overexpression of APC2 stabilizes microtubules; shRNA knockdown of APC2 in chick retinas reduces microtubule stability. APC2-knockdown retinal axons show reduced response to ephrin-A2 guidance cues and drastic alterations in retinotectal topographic projections in vivo.\",\n      \"method\": \"Immunohistochemistry, overexpression assay (microtubule stabilization), shRNA knockdown in chick retina, in vitro guidance assay, in vivo retinotectal projection analysis\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss- and gain-of-function with direct cellular phenotypes (microtubule stability, axon guidance), both in vitro and in vivo, multiple orthogonal readouts\",\n      \"pmids\": [\"19759310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cortical localization of Drosophila APC2 requires both the Armadillo repeats and a novel C-terminal domain (neither alone is sufficient). The Armadillo repeats also mediate APC2 self-association. Cortical localization is required for APC2's role in organizing actin but is dispensable for its role in Wnt/Wingless signaling, as shown by rescue experiments with a C-terminal-deletion APC2.\",\n      \"method\": \"Domain-deletion analysis, S2 cell transfection, rescue assays in APC mutant embryos (actin and Wnt phenotypes), co-immunoprecipitation for self-association\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain dissection with functional rescue in two separate biological readouts, self-association confirmed by co-IP\",\n      \"pmids\": [\"21486956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of APC2 in Drosophila embryos leads to increased chromosome segregation errors through a cascade: incomplete centrosome separation → failure to inhibit ectopic cleavage furrows → mitotic defects and DNA damage. APC2 functions at the embryonic cortex together with Axin to promote mitotic fidelity through cytoskeletal regulation.\",\n      \"method\": \"Genetic loss-of-function, live imaging of chromosome segregation, epistasis with Axin, immunostaining for centrosome and furrow markers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-imaging of segregation errors + mechanistic pathway dissection with multiple genetic tests and cytoskeletal readouts\",\n      \"pmids\": [\"24026117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The spliceosome subunit SNW1 is required for correct splicing of APC2 pre-mRNA; SNW1 depletion reduces APC2 protein levels, decreases APC/C ubiquitin ligase activity, delays mitosis, and contributes to sister chromatid cohesion defects ('cohesion fatigue'). Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1-depleted cells.\",\n      \"method\": \"siRNA knockdown, transcriptome-wide splicing analysis, intron-less cDNA rescue experiment, cohesion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic rescue with intron-less cDNA, genome-wide splicing mapping, direct functional readout of APC/C activity\",\n      \"pmids\": [\"25257309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss-of-function mutation in APC2 causes Sotos syndrome-like features including impaired learning/memory and abnormal head shape in Apc2-/- mice, through loss of cytoskeletal regulation in neurons. APC2 is a downstream effector of NSD1: NSD1 knockdown downregulates Apc2 expression, and the neuronal migration/laminar positioning defect caused by Nsd1 knockdown is rescued by forced Apc2 expression.\",\n      \"method\": \"Mouse knockout, whole-exome sequencing (patient), Nsd1 knockdown in embryonic mouse brains, forced expression rescue, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse phenotype + epistasis rescue with re-expression, multiple orthogonal readouts including behavioral and cellular\",\n      \"pmids\": [\"25753423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tankyrase (TNKS) poly(ADP-ribose) polymerase binds a C-terminal RPQPSG motif in Drosophila APC2 (conserved in human APC2 but absent in human APC1). APC2 recruits TNKS into the β-catenin destruction complex. TNKS directly PARylates both Drosophila Axin and APC2, but PARylation does not globally regulate APC2 protein levels as it does for Axin. TNKS inhibition reduces β-catenin signaling through effects at both Axin and APC2.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro PARylation assay, motif-mapping, cell-based Wnt reporter assays with TNKS inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Y2H + Co-IP + in vitro PARylation assay + functional cell-based readout; multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"27068743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"APC2 promotes dynamics (plus-end growth) of minus-end-out microtubules in vertebrate dendrites and thereby regulates dendritic morphology. APC2 localizes as distinct clusters along microtubule bundles in dendrites; localization is driven by LC8-binding and two separate microtubule-interacting domains. APC2 depletion reduces plus-end dynamics of minus-end-out microtubules, increases microtubule sliding, and causes dendritic morphology defects.\",\n      \"method\": \"shRNA knockdown, live microtubule dynamics imaging (EB3 tracking), domain-deletion localization analysis, morphology quantification in neurons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-imaging of microtubule dynamics combined with domain dissection and KD phenotypic readout in neurons; multiple orthogonal methods\",\n      \"pmids\": [\"30018294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"APC2 associates with the actin cortex through a multipart mechanism in Drosophila: cortical localization requires an N-terminal APC Self-Association Domain (ASAD) that mediates self-association, and a conserved coiled-coil within the C-terminal 30 amino acid (C30) domain. APC2 regulates cortical actin dynamics and distribution in Drosophila follicular epithelium and nurse cells.\",\n      \"method\": \"Domain-deletion and mutagenesis in S2 cells, immunofluorescence in Drosophila ovary, actin dynamics analysis\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion with functional cellular readout; single lab, extends prior localization work\",\n      \"pmids\": [\"30019417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila Brain Tumor (Brat) acts cell-autonomously through its B-Box domains to regulate the expression and localization of Apc2 at the plus ends of microtubules in commissural axons. Brat and Apc2 promote axon growth across the midline independently of canonical Wnt/β-catenin transcriptional signaling, implicating Apc2 microtubule-stabilizing function in axon guidance.\",\n      \"method\": \"Genetic epistasis (Brat and Apc2 mutants), immunolocalization in commissural axons, genetic interaction analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with localization data; pathway independence from Wnt shown genetically; single lab\",\n      \"pmids\": [\"29617376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila neurons, Apc2 localizes to dendrite branch points where it recruits Apc and thereby steers growing microtubule plus ends to maintain minus-end-out polarity. Apc2-GFP positioning at branch points requires energy production by mitochondria (spastin acts upstream of mitochondria), Nrg/Ank2, Arp2/3-mediated branched actin (downstream of Rac1), and a Fz/G-protein/Axin module.\",\n      \"method\": \"Candidate RNAi screen, secondary genetic screens, live imaging of Apc2-GFP at branch points, epistasis analysis\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNAi screen with mechanistic pathway dissection; live imaging; single lab\",\n      \"pmids\": [\"29602811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Apc11 (lemmingA/LmgA) interacts with Morula/Apc2 and together they form a ternary complex with Vihar (the E2-C type ubiquitin-conjugating enzyme), establishing that the Apc11–Apc2 module recruits the E2 enzyme to the APC/C.\",\n      \"method\": \"Genetic complementation, immunoprecipitation/pull-down, yeast complementation assay\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction mapping by Co-IP/pull-down plus genetic complementation; single lab\",\n      \"pmids\": [\"22417125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FBG1 (an SCF F-box protein) binds APC2 directly via a D-Box within the FBG1 F-box domain, as shown by immunoprecipitation and mutagenesis. Co-expression of FBG1 increases total APC2 protein levels but sequesters free APC2, inhibiting cell proliferation and inducing S-phase arrest.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of D-box, flow cytometry (FACS) cell cycle analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + mutagenesis + functional cell-cycle readout; single lab, single study\",\n      \"pmids\": [\"21135578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APC2 (as APC/C subunit) is enriched at the postsynapse of neuromuscular junctions in postmitotic myotubes. In response to agrin stimulation, APC2 promotes ubiquitination of DOK7 at lysine 243, leading to its proteolytic degradation; this requires MuSK kinase activity and phosphorylation of tyrosine 106 in DOK7. This negatively regulates acetylcholine receptor clustering as part of NMJ homeostasis.\",\n      \"method\": \"Immunofluorescence at NMJ, ubiquitination assay, site-directed mutagenesis (K243, Y106), co-immunoprecipitation, AChR clustering assay\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-directed mutagenesis identifying specific ubiquitination site, functional AChR-clustering readout, mechanistic requirement for upstream kinase; multiple orthogonal methods\",\n      \"pmids\": [\"32687671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2031,\n      \"finding\": \"FOXO4 binds the APC2 gene promoter (shown by chromatin immunoprecipitation) to transcriptionally upregulate APC2 expression, which in turn increases phosphorylation and degradation of β-catenin, suppressing CRC cell migration and metastasis. APC2 knockdown reverses the anti-metastatic effects of FOXO4 overexpression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), APC2 knockdown rescue, cell migration/invasion assays, xenograft metastasis model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding, functional rescue validates pathway placement; single lab\",\n      \"pmids\": [\"34631691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of S. cerevisiae APC/C complexes show that the catalytic module (Apc2:Apc11) is already positioned to bind E2 enzyme in the apo-state (without coactivator), in contrast to human APC/C where coactivator binding induces a conformational change of Apc2:Apc11 to allow E2 binding. This identifies a species-specific regulatory mechanism for the Apc2-containing catalytic module.\",\n      \"method\": \"Cryo-EM structure determination (apo and CDH1-bound, phosphorylated and unphosphorylated S. cerevisiae APC/C)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality structural data but preprint, single study; mechanism is comparative between species\",\n      \"pmids\": [\"bio_10.1101_2024.06.19.599685\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The BubR1 TPR domain interacts with Apc2 (as well as Mad2 and Cdc20-APC/C). This interaction, identified by cryo-EM structure of the MCC-APC/C complex, contributes to MCC assembly and MCC-APC/C binding to enable rapid spindle assembly checkpoint signaling.\",\n      \"method\": \"Cryo-EM structure of MCC-APC/C complex, functional and biochemical analyses of BubR1 TPR domain mutations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural identification plus biochemical validation; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.13.682252\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"APC2 (APCL) is a multifunctional scaffold protein that acts as the cullin subunit of the APC/C E3 ubiquitin ligase (where it forms a minimal catalytic module with APC11 to ubiquitinate mitotic substrates such as securin and cyclin B1), and independently functions as a Wnt pathway negative regulator by binding β-catenin/Armadillo through 20-aa repeat motifs and binding Axin/conductin through SAMP domains to promote β-catenin destruction; in neurons and other polarized cells APC2 also directly stabilizes and regulates the dynamics of microtubules (particularly minus-end-out microtubules in dendrites and growth cones), associates with cortical actin through self-association and coiled-coil domains, tethers mitotic spindles to the actin cortex (regulated by GSK-3/Zeste-white 3 kinase phosphorylation of APC2–Armadillo complexes), and is subject to PARylation by Tankyrase and transcriptional regulation by NSD1/FOXO4, with loss-of-function causing lissencephaly, neuronal migration defects, and chromosomal instability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"APC2 is a multifunctional scaffold that operates in two largely separable domains of cell biology: as the cullin subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase, and as a negative regulator of Wnt/Wingless signaling [#5, #1]. Within the APC/C, APC2 dimerizes with the RING subunit APC11 to form the minimal catalytic ubiquitin-ligase module that, with E2 enzymes (Ubc4/UbcH10), ubiquitinates mitotic substrates such as securin and cyclin B1 [#4, #23]; cryo-EM maps APC2 and the Cdh1 coactivator to the substrate-ubiquitination face of the asymmetric complex, where coactivator binding repositions the catalytic module to license E2 engagement [#12, #27]. Loss of APC/C function via APC2 produces metaphase arrest and failed degradation of mitotic regulators, and reduced APC2 contributes to chromosome segregation and sister-chromatid cohesion defects [#5, #16]. Independently of mitosis, APC2 restrains Wnt signaling: its 20-amino-acid APC-repeat motifs bind \\u03b2-catenin/Armadillo and its SAMP domains bind Axin/conductin, assembling a destruction complex that depletes \\u03b2-catenin and downregulates \\u03b2-catenin\\u2013TCF transcription [#1, #2], and it recruits Tankyrase into this complex through a conserved C-terminal motif [#18]. APC2 also stabilizes and regulates microtubules: it promotes plus-end dynamics of minus-end-out microtubules in dendrites and stabilizes microtubules in growth cones to direct axon guidance and dendritic morphology [#19, #13], and it associates with cortical actin through self-association and coiled-coil domains to tether mitotic spindles and organize the actin cortex [#3, #20, #14]. APC2 is a downstream effector of NSD1 in neuronal migration, and its loss causes Sotos-syndrome-like learning and morphological defects in mice [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that APC2 is a functional subunit of the anaphase-promoting complex, answering whether the cullin-like protein has a direct cell-cycle role.\",\n      \"evidence\": \"Temperature-sensitive yeast rsi1/apc2 mutants, PDS1-deletion epistasis, co-IP with Cdc23p\",\n      \"pmids\": [\"9430641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic mechanism or direct E2 partner of APC2 within the complex\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined APC2 as a Wnt-pathway negative regulator by showing its 20-aa repeats bind and deplete \\u03b2-catenin and modulate \\u03b2-catenin\\u2013TCF transcription.\",\n      \"evidence\": \"Domain binding assay plus TOP-flash reporter in APC-null colon carcinoma cells\",\n      \"pmids\": [\"9823329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; did not establish the Axin-binding requirement or in vivo significance\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Connected APC2 to the destruction-complex scaffold by mapping the two SAMP domains required for Axin/conductin binding.\",\n      \"evidence\": \"Domain-deletion binding and transient TOP/FOP transcriptional assays in APC-null cells\",\n      \"pmids\": [\"10021369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not show stoichiometry or assembly of the full destruction complex\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Validated APC2 as a genetically defined Wnt antagonist in vivo and hinted at a cytoskeletal association, broadening its role beyond a biochemical interactor.\",\n      \"evidence\": \"Drosophila genetic epistasis, direct Armadillo binding, immunolocalization with actin\",\n      \"pmids\": [\"10491393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoskeletal association was correlative; functional consequence not yet tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the minimal catalytic module of the APC/C, showing the APC2\\u2013APC11 heterodimer with an E2 suffices for substrate ubiquitination but lacks specificity.\",\n      \"evidence\": \"Baculoviral in vitro reconstitution, binding-domain mapping, APC11 Zn-residue mutagenesis\",\n      \"pmids\": [\"11739784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity determinants reside elsewhere; structural basis of E2 positioning unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealed a non-degradative, cytoskeletal function: APC2\\u2013Armadillo complexes tether mitotic spindles to cortical actin under GSK-3/Zw3 control.\",\n      \"evidence\": \"Drosophila immunolocalization, live imaging, zw3 loss-of-function epistasis\",\n      \"pmids\": [\"11584277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between APC2 and the actin cortex not yet defined at the domain level\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated global functional redundancy between APC2 and APC1 in restricting \\u03b2-catenin\\u2013driven transcription throughout development.\",\n      \"evidence\": \"Drosophila double-mutant epistasis, nuclear Armadillo staining, reporter assays\",\n      \"pmids\": [\"11923210\", \"12297097\", \"12297098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain why two paralogs with distinct localizations are both required\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Separated a Wnt-independent APC2 role, showing neuroblast maintenance defects in APC2/APC1 double mutants without Wg misregulation.\",\n      \"evidence\": \"Drosophila genetic double-mutant analysis with Wg-pathway epistasis ruled out\",\n      \"pmids\": [\"12297097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The implicated cytoskeletal/adhesive mechanism was inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified APC2 as a regulator of partner subcellular localization, redirecting 53BP2 to the perinuclear region via its C-terminus.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, domain mapping, confocal co-localization\",\n      \"pmids\": [\"10646860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of 53BP2 relocalization unknown; single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Characterized endogenous APC2 localization to Golgi and actin filaments, with actin association resistant to cytochalasin D.\",\n      \"evidence\": \"Immunofluorescence, cytochalasin D perturbation, FISH allelic imbalance\",\n      \"pmids\": [\"11691822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression artifacts possible; direct versus indirect actin binding not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended APC/C substrate recognition by showing inversin binds APC2 through D-box motifs, marking it as a candidate degradation target.\",\n      \"evidence\": \"Co-IP and site-directed D-box mutagenesis\",\n      \"pmids\": [\"12471060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate APC/C-dependent inversin turnover directly\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed APC2 structurally on the ubiquitination face of the APC/C and showed Cdh1 activates by conformational rearrangement, not only substrate recruitment.\",\n      \"evidence\": \"Cryo-EM 3D reconstruction with STEM mass measurement and antibody subunit labeling\",\n      \"pmids\": [\"16364912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low-resolution; atomic basis of the conformational change not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established APC2 as a microtubule stabilizer required for axon guidance, defining a discrete cytoskeletal function in neurons.\",\n      \"evidence\": \"Overexpression/shRNA in chick retina, in vitro guidance assay, in vivo retinotectal mapping\",\n      \"pmids\": [\"19759310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct microtubule-binding mode not mapped at the domain level here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed regulation of free APC2 levels and the cell cycle by the F-box protein FBG1, which binds APC2 via a D-box and sequesters it.\",\n      \"evidence\": \"Co-IP, D-box mutagenesis, FACS cell-cycle analysis\",\n      \"pmids\": [\"21135578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sequestration acts on the APC/C or Wnt pool of APC2 unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Dissected APC2 cortical targeting, showing Armadillo repeats plus a novel C-terminal domain drive localization and self-association, separable from Wnt function.\",\n      \"evidence\": \"Domain-deletion in S2 cells, rescue of actin and Wnt phenotypes, co-IP for self-association\",\n      \"pmids\": [\"21486956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cortical receptor/anchor that recruits APC2 not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed the APC2\\u2013APC11 module recruits the E2-C enzyme Vihar, confirming the E2-loading role of the catalytic module in vivo.\",\n      \"evidence\": \"Drosophila genetic complementation, IP/pull-down, yeast complementation\",\n      \"pmids\": [\"22417125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve conformational requirements for E2 engagement\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked APC2 cortical/cytoskeletal function to genome stability via a centrosome-separation\\u2192ectopic-furrow cascade promoting mitotic fidelity.\",\n      \"evidence\": \"Drosophila loss-of-function, live imaging of segregation errors, Axin epistasis\",\n      \"pmids\": [\"24026117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between cortical APC2 and centrosome separation not molecularly defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected APC2 levels to cohesion by showing SNW1-dependent APC2 splicing maintains APC/C activity and prevents cohesion fatigue.\",\n      \"evidence\": \"siRNA, transcriptome splicing analysis, intron-less cDNA rescue, cohesion assays\",\n      \"pmids\": [\"25257309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"A regulatory rather than direct APC2 mechanism; APC2-specific splicing dependence not generalized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined APC2 as a downstream effector of NSD1 in neuronal migration and tied its loss to Sotos-syndrome-like neurological phenotypes.\",\n      \"evidence\": \"Apc2-/- mice, patient exome, Nsd1 knockdown with forced Apc2 rescue, behavioral assays\",\n      \"pmids\": [\"25753423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cytoskeletal step downstream of NSD1\\u2192APC2 not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Tankyrase as a destruction-complex component recruited by an APC2 C-terminal motif and a PARylation target distinct from Axin in its regulation.\",\n      \"evidence\": \"Y2H, co-IP, in vitro PARylation, motif mapping, Wnt reporter with TNKS inhibitors\",\n      \"pmids\": [\"27068743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of APC2 PARylation (vs Axin) not defined since it does not control APC2 levels\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established APC2 control of minus-end-out microtubule dynamics in dendrites, mapping its localization to LC8-binding and microtubule-interacting domains.\",\n      \"evidence\": \"shRNA, EB3 live imaging, domain-deletion localization, neuronal morphology quantification\",\n      \"pmids\": [\"30018294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which APC2 biases polarity at the molecular level not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the cortical actin association mechanism, requiring the N-terminal ASAD self-association domain and a C30 coiled-coil.\",\n      \"evidence\": \"Domain-deletion/mutagenesis in S2 cells, Drosophila ovary immunofluorescence, actin dynamics\",\n      \"pmids\": [\"30019417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct actin-binding partner versus indirect tethering not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed APC2 microtubule function downstream of regulatory inputs (Brat; mitochondria/actin/Fz-Axin modules) at axonal and dendritic microtubule plus ends, independent of canonical Wnt.\",\n      \"evidence\": \"Drosophila genetic epistasis, RNAi screens, live imaging of Apc2-GFP at branch points\",\n      \"pmids\": [\"29617376\", \"29602811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical links between these upstream modules and APC2 not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a postmitotic APC/C substrate function, with APC2 ubiquitinating DOK7 at K243 to regulate acetylcholine-receptor clustering at the NMJ.\",\n      \"evidence\": \"NMJ immunofluorescence, ubiquitination assay, K243/Y106 mutagenesis, AChR clustering\",\n      \"pmids\": [\"32687671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the APC/C is activated in postmitotic myotubes not defined\"]\n    },\n    {\n      \"year\": 2031,\n      \"claim\": \"Identified transcriptional control of APC2 by FOXO4, linking APC2 induction to \\u03b2-catenin degradation and suppression of colorectal cancer metastasis.\",\n      \"evidence\": \"ChIP, APC2 knockdown rescue, migration/invasion assays, xenograft metastasis model\",\n      \"pmids\": [\"34631691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism of FOXO4-driven APC2 induction in normal tissue untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a species-specific regulatory difference: yeast Apc2:Apc11 is pre-positioned for E2 binding in the apo state, unlike human APC/C requiring coactivator-induced rearrangement.\",\n      \"evidence\": \"Cryo-EM of apo and CDH1-bound yeast APC/C (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.19.599685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; functional consequence of the species difference not validated biochemically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Apc2 in spindle-assembly-checkpoint signaling through a BubR1 TPR-domain interaction within the MCC-APC/C complex.\",\n      \"evidence\": \"Cryo-EM of MCC-APC/C, BubR1 TPR mutational analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.13.682252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; the specific contribution of the Apc2 contact to checkpoint kinetics not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APC2's distinct functional pools \\u2014 APC/C catalytic subunit, destruction-complex scaffold, and microtubule/actin regulator \\u2014 are partitioned and co-regulated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative partitioning of APC2 between mitotic, Wnt, and cytoskeletal complexes\", \"Post-translational control directing APC2 to each pool undefined\", \"Structural basis of microtubule and actin binding not determined at atomic resolution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 25]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [13, 19, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [11, 13, 19, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 6, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 25]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 17, 19]}\n    ],\n    \"complexes\": [\"APC/C (anaphase-promoting complex/cyclosome)\", \"\\u03b2-catenin destruction complex\"],\n    \"partners\": [\"APC11\", \"CTNNB1\", \"AXIN2\", \"TNKS\", \"TP53BP2\", \"DOK7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}