{"gene":"APC","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1993,"finding":"APC protein physically associates with beta-catenin: immunoprecipitation with anti-APC antibodies co-precipitated a 95 kDa protein identified by sequencing as beta-catenin, and reciprocal anti-beta-catenin antibody confirmed the interaction in vivo.","method":"Immunoprecipitation, protein sequencing","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with antibodies to both proteins, confirmed by sequencing; foundational result replicated extensively","pmids":["8259518"],"is_preprint":false},{"year":1993,"finding":"APC protein oligomerizes via its N-terminal domain: in vitro expression and immunoprecipitation demonstrated that the first 171 residues are sufficient for APC self-association, and the first 45 amino acids are necessary, suggesting truncated mutant APC can bind wild-type APC in a dominant-negative manner.","method":"In vitro expression, immunoprecipitation, deletion mutagenesis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with deletion mutants mapping minimal domains; single lab but multiple truncation constructs tested","pmids":["8389242"],"is_preprint":false},{"year":1995,"finding":"APC binds the novel protein EB1 via its carboxyl terminus: two-hybrid screen identified EB1, and the interaction was confirmed by in vitro binding assays and co-immunoprecipitation in vivo using anti-EB1 monoclonal antibodies.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction trap screen followed by in vitro and in vivo confirmation with reciprocal antibodies; replicated in subsequent studies","pmids":["7606712"],"is_preprint":false},{"year":2000,"finding":"APC contains nuclear export signals (NES) 3' adjacent to the mutation cluster region that enable it to exit the nucleus via a CRM1-dependent pathway; this nuclear export function is lost in truncation mutant APC cancer cells, resulting in nuclear accumulation of beta-catenin.","method":"Live cell imaging, nuclear export signal mapping, mutant APC analysis in cancer cell lines","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — identification of conserved NES motifs with functional demonstration in cells; nuclear beta-catenin accumulation linked to NES loss; single lab with multiple cell line comparisons","pmids":["10984057"],"is_preprint":false},{"year":2000,"finding":"APC protein moves along microtubules toward their growing plus ends in an ATP-dependent manner, and concentrates as granules at plus ends during cell spreading and wound healing; the C-terminal region targets APC to growing MT ends, while the region lacking the C-terminus forms granular aggregates that move along MTs by motor activity.","method":"GFP live-cell imaging, deletion mutant analysis, immunoelectron microscopy in Xenopus epithelial cells","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging of GFP-tagged full-length and deletion mutants, immunoelectron microscopy, multiple orthogonal methods in one study","pmids":["10662776"],"is_preprint":false},{"year":2006,"finding":"APC inhibits ERK pathway activation induced by RAS: overexpressing APC in DLD-1 cells reduced RAS-induced ERK activation, and Cre-mediated Apc knockout in primary mouse embryonic fibroblasts increased ERK activity; the mechanism involves APC acting on beta-catenin, which activates Raf1/MEK/ERK, and APC overexpression reduces RAS protein levels.","method":"Overexpression/knockdown in colorectal cancer cells, Cre-lox knockout in MEFs, kinase activity assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function and overexpression with defined biochemical readouts; single lab, multiple complementary approaches","pmids":["16478791"],"is_preprint":false},{"year":2007,"finding":"Myc is the critical downstream mediator of Apc loss in the intestine: simultaneous deletion of both Apc and Myc in the adult murine small intestine rescued defects in differentiation, migration, proliferation, and apoptosis caused by Apc deletion alone, even in the presence of high nuclear beta-catenin; array analysis showed Myc is required for the majority of Wnt target gene activation after Apc loss.","method":"Conditional in vivo double knockout (Apc and Myc), gene expression arrays, histological analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with double conditional knockouts, transcriptome-wide target analysis, rigorous histological readouts","pmids":["17377531"],"is_preprint":false},{"year":2008,"finding":"APC directly binds polymerized vimentin (an intermediate filament protein) via its armadillo repeats, promotes vimentin polymerization in vitro, and is required for microtubule-dependent rearrangements of intermediate filaments during cell migration; loss or truncation of APC correlated with disorganization of the IF network in glioma and carcinoma cells.","method":"In vitro binding assay with purified components, wound-induced migration assay, loss-of-function analysis in astrocytes and cancer cells, domain mapping","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding reconstituted in vitro with purified proteins, domain mapped to armadillo repeats, functional consequence in cell migration assay; single lab with multiple orthogonal methods","pmids":["23382461"],"is_preprint":false},{"year":2007,"finding":"BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules; BubR1 associates with APC and EB1 in Xenopus egg extracts, and this complex is necessary for metaphase chromosome alignment.","method":"Immunodepletion from Xenopus egg extracts, antibody addition experiments, in vitro kinase assay with purified components, Co-IP","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation assay with purified BubR1 and APC, ternary complex reconstitution, functional rescue with immunodepletion; single lab, multiple orthogonal methods","pmids":["17709426"],"is_preprint":false},{"year":2008,"finding":"APC associates with the nuclear pore complex protein Nup153 (nucleoporin 153) and through this direct interaction promotes association of microtubules with the nuclear membrane, which is required for polarization of the microtubule cytoskeleton during directional cell migration.","method":"In vitro scratch-induced migration assay, direct interaction analysis with Nup153, microtubule organization imaging in neurons and fibroblasts","journal":"Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct interaction identified and linked to functional outcome in migration assay; single lab, limited mechanistic detail in abstract","pmids":["18042042"],"is_preprint":false},{"year":2008,"finding":"A novel N-terminal to C-terminal self-association of APC was identified: an N-terminal region of APC interacts with the extreme C-terminal 300 amino acids of APC, and also with itself; this interaction is phospho-sensitive and enhanced by 14-3-3 protein; this self-association modulates APC clustering at membrane protrusions and is required for cell migration.","method":"Co-IP, deletion mapping, overexpression and inhibition experiments, cell migration assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel intramolecular interaction mapped by Co-IP, phospho-sensitivity shown, 14-3-3 involvement, functional link to migration; single lab, multiple methods","pmids":["18477604"],"is_preprint":false},{"year":2006,"finding":"Truncated APC (as expressed in SW480 colon cancer cells) is required for cell proliferation and DNA replication: RNAi knockdown of APC in both wild-type-expressing and truncated-APC-expressing cancer cells impaired proliferation and DNA replication, correlating with reduced cyclin A, cyclin A-dependent kinase activity, p27(kip1), and DNA polymerase delta catalytic subunit.","method":"RNA interference, cell proliferation assay, DNA replication assay, Western blot for cell cycle proteins","journal":"International Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple biochemical readouts in two cell line contexts; single lab, mechanistic follow-up of proliferation phenotype","pmids":["16450383"],"is_preprint":false},{"year":2021,"finding":"Apc-mutant cells secrete NOTUM, a WNT antagonist, which suppresses surrounding wild-type crypt cell proliferation and drives their differentiation, giving Apc-mutant clones a competitive advantage for crypt fixation; conditioned medium from Apc-mutant cells suppressed wild-type organoid growth in a NOTUM-dependent manner, and pharmacological/genetic NOTUM inhibition abrogated Apc-mutant cell expansion.","method":"Conditioned medium experiments, NOTUM inhibition (genetic and pharmacological), organoid assays, in vivo intestinal adenoma models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (conditioned medium, genetic knockout, pharmacological inhibition, in vivo models) converging on NOTUM as the mechanistic mediator","pmids":["34079124"],"is_preprint":false},{"year":2021,"finding":"METTL3-mediated m6A modification of APC mRNA recruits YTHDF proteins to degrade APC mRNA, reducing APC protein levels and thereby increasing beta-catenin and its transcriptional targets (cyclin D1, c-Myc, PKM2), leading to enhanced glycolysis and tumor cell proliferation.","method":"m6A-RIP sequencing, METTL3 knockdown/overexpression, YTHDF binding assay, beta-catenin signaling readouts, mouse xenograft model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — m6A-RIP-seq identifies APC as METTL3 target, mechanistic link to YTHDF-mediated mRNA degradation confirmed by multiple downstream readouts and in vivo tumor model; single lab, multiple orthogonal methods","pmids":["34155197"],"is_preprint":false},{"year":2014,"finding":"RIP140 (a transcriptional coregulator) directly stimulates APC transcription and thereby inhibits beta-catenin activation; Rip140-null mice showed reduced APC levels and increased intestinal proliferation, while RIP140 overexpression repressed colon cancer cell proliferation in vivo and in vitro.","method":"Rip140 knockout and transgenic mouse models, APC transcription assays, beta-catenin target gene expression, nude mouse xenograft","journal":"Journal of Clinical Investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss- and gain-of-function in mice with APC transcription as direct readout; single lab, multiple genetic models","pmids":["24667635"],"is_preprint":false},{"year":2021,"finding":"The kinesin KIF1C motor interacts with APC-dependent mRNAs and is required for their transport to cell protrusions; live-cell two-color imaging revealed single mRNAs transported by single KIF1C motors, with the 3'UTR sufficient to trigger KIF1C-dependent transport; KIF1C is also required for formation of peripheral multimeric RNA clusters.","method":"Live single-molecule imaging, two-color mRNA/motor co-imaging, KIF1C knockdown, 3'UTR reporter assays","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct visualization of single-molecule transport events, loss-of-function, minimal element mapping; single lab","pmids":["34493599"],"is_preprint":false},{"year":2008,"finding":"APC is required for regulation of DNA base excision repair (BER) through interaction with DNA polymerase beta (Pol-beta) and flap endonuclease 1 (Fen-1); APC gene transcription is activated by alkylating agents, and APC modulates BER activity.","method":"Protein interaction studies, BER activity assays, transcriptional activation analysis (reviewed from primary literature)","journal":"Cancer Letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review summarizing interaction data; no primary experimental detail available in this abstract; single indirect citation","pmids":["18662849"],"is_preprint":false}],"current_model":"APC is a multifunctional tumor suppressor that directly binds beta-catenin (promoting its degradation via the Axin/GSK3β destruction complex), associates with EB1 and microtubule plus ends to regulate cytoskeletal dynamics and chromosome stability, contains nuclear export signals enabling beta-catenin nuclear export, oligomerizes via its N-terminus (allowing dominant-negative effects of truncation mutants), directly binds intermediate filaments (vimentin) via armadillo repeats to coordinate cytoskeletal reorganization during migration, is phosphorylated by BubR1 within a ternary APC/EB1/BubR1 complex at kinetochores, and acts upstream of c-Myc as the critical mediator of Wnt target gene activation following APC loss; additionally, Apc-mutant cells secrete NOTUM to competitively suppress neighboring wild-type cells, and APC mRNA levels are regulated post-transcriptionally by METTL3-mediated m6A modification leading to YTHDF-dependent degradation."},"narrative":{"mechanistic_narrative":"APC is a multifunctional tumor suppressor that couples Wnt/beta-catenin signaling control to cytoskeletal organization and cell migration [PMID:8259518, PMID:10662776]. It physically associates with beta-catenin [PMID:8259518] and contains CRM1-dependent nuclear export signals adjacent to its mutation cluster region; truncating cancer mutations abolish this export and cause nuclear accumulation of beta-catenin [PMID:10984057]. Downstream of beta-catenin, c-Myc is the critical effector of APC loss in the intestine, mediating most Wnt target gene activation and the differentiation, proliferation, migration, and apoptosis defects following Apc deletion [PMID:17377531]. APC self-associates through its N-terminal domain, so truncated mutants can bind wild-type APC and act dominant-negatively [PMID:8389242], and an additional phospho-sensitive N-to-C-terminal interaction enhanced by 14-3-3 governs APC clustering at membrane protrusions during migration [PMID:18477604]. At the cytoskeleton, APC binds the plus-end tracking protein EB1 via its C-terminus [PMID:7606712], moves ATP-dependently toward growing microtubule plus ends [PMID:10662776], directly binds and promotes polymerization of vimentin intermediate filaments through its armadillo repeats [PMID:23382461], and links microtubules to the nuclear membrane via Nup153 to polarize the cytoskeleton during directional migration [PMID:18042042]. APC also participates in mitotic chromosome alignment within a ternary APC/EB1/BubR1 complex, in which BubR1 directly phosphorylates APC [PMID:17709426]. APC expression is itself regulated transcriptionally by RIP140 [PMID:24667635] and post-transcriptionally by METTL3-mediated m6A modification that triggers YTHDF-dependent APC mRNA degradation, relieving beta-catenin repression and promoting glycolysis and proliferation [PMID:34155197]. In intestinal tissue, Apc-mutant cells secrete the Wnt antagonist NOTUM to competitively suppress neighboring wild-type cells, providing a fixation advantage for mutant clones [PMID:34079124].","teleology":[{"year":1993,"claim":"Establishing that APC physically associates with beta-catenin connected the tumor suppressor to a defined molecular partner and laid the foundation for its role in Wnt signaling.","evidence":"Reciprocal anti-APC and anti-beta-catenin immunoprecipitation with protein sequencing in vivo","pmids":["8259518"],"confidence":"High","gaps":["Did not establish the functional consequence of binding (degradation vs sequestration)","Did not map the interaction domains or destruction-complex context"]},{"year":1993,"claim":"Demonstrating N-terminal oligomerization explained how truncated APC mutants could exert dominant-negative effects over the wild-type allele.","evidence":"In vitro expression, immunoprecipitation, and deletion mutagenesis mapping minimal self-association domains","pmids":["8389242"],"confidence":"High","gaps":["Dominant-negative effect inferred from binding, not directly tested functionally in cells","Stoichiometry and physiological relevance of oligomers not defined"]},{"year":1995,"claim":"Identifying EB1 as a C-terminal APC partner first linked APC to microtubule biology beyond its beta-catenin function.","evidence":"Yeast two-hybrid screen with in vitro and reciprocal in vivo co-immunoprecipitation confirmation","pmids":["7606712"],"confidence":"High","gaps":["Functional consequence of the APC-EB1 interaction not yet established","Did not determine effect on microtubule dynamics"]},{"year":2000,"claim":"Mapping CRM1-dependent nuclear export signals showed how APC controls subcellular distribution of beta-catenin and why truncating mutations cause nuclear beta-catenin accumulation.","evidence":"NES motif mapping and live-cell imaging comparing wild-type and truncation-mutant cancer cell lines","pmids":["10984057"],"confidence":"High","gaps":["Relative contribution of export vs degradation to beta-catenin control not quantified","Cargo specificity beyond beta-catenin not addressed"]},{"year":2000,"claim":"Live imaging revealing ATP-dependent plus-end tracking of APC established it as an active microtubule-associated protein with distinct C-terminal targeting and motor-driven behaviors.","evidence":"GFP live-cell imaging of full-length and deletion mutants plus immunoelectron microscopy in Xenopus epithelial cells","pmids":["10662776"],"confidence":"High","gaps":["Identity of the motor driving granule movement not defined","Link between plus-end tracking and tumor suppression not established"]},{"year":2006,"claim":"Genetic and overexpression studies placed APC upstream of RAS/ERK signaling, broadening its signaling outputs beyond canonical Wnt.","evidence":"APC overexpression/knockdown in colorectal cells and Cre-lox Apc knockout in MEFs with kinase activity assays","pmids":["16478791"],"confidence":"Medium","gaps":["Mechanism by which APC lowers RAS protein levels unresolved","Single-lab observation linking beta-catenin to Raf1/MEK/ERK not independently confirmed"]},{"year":2006,"claim":"RNAi knockdown showed even truncated APC supports proliferation and DNA replication, indicating residual functions of mutant APC in cancer cells.","evidence":"RNA interference with proliferation, DNA replication, and cell-cycle protein readouts in wild-type and truncated-APC cancer lines","pmids":["16450383"],"confidence":"Medium","gaps":["Direct molecular basis of the replication requirement not defined","Whether effect is beta-catenin-dependent not resolved"]},{"year":2007,"claim":"In vivo double knockout established c-Myc as the critical mediator of Apc loss, defining the key transcriptional output downstream of beta-catenin.","evidence":"Conditional Apc/Myc double knockout in adult mouse intestine with gene expression arrays and histology","pmids":["17377531"],"confidence":"High","gaps":["Myc-independent Wnt targets remain uncharacterized","Generalizability beyond intestinal epithelium not addressed"]},{"year":2007,"claim":"Reconstitution of an APC/EB1/BubR1 ternary complex with direct BubR1 phosphorylation of APC linked APC to mitotic chromosome alignment and a mechanism for chromosomal instability.","evidence":"Immunodepletion from Xenopus egg extracts, in vitro kinase assays with purified components, and Co-IP","pmids":["17709426"],"confidence":"High","gaps":["Phosphorylation sites and their functional consequence not mapped","Relevance to human tumor aneuploidy not directly tested"]},{"year":2008,"claim":"Identifying the APC-Nup153 interaction explained how APC tethers microtubules to the nuclear membrane to polarize the cytoskeleton during directional migration.","evidence":"Scratch-induced migration assays and microtubule organization imaging in neurons and fibroblasts","pmids":["18042042"],"confidence":"Medium","gaps":["Limited mechanistic detail on the direct interaction interface","Single-lab finding without reciprocal validation"]},{"year":2008,"claim":"Discovery of a phospho-sensitive, 14-3-3-enhanced N-to-C intramolecular self-association added a regulatory layer controlling APC clustering at protrusions during migration.","evidence":"Co-IP, deletion mapping, overexpression/inhibition experiments, and cell migration assays","pmids":["18477604"],"confidence":"Medium","gaps":["Kinase responsible for the phospho-switch not identified","Structural basis of the intramolecular contact unresolved"]},{"year":2008,"claim":"APC was linked to base excision repair through interactions with Pol-beta and Fen-1, suggesting a direct genome-maintenance role.","evidence":"Review summarizing protein interaction and BER activity data","pmids":["18662849"],"confidence":"Low","gaps":["No primary experimental detail in this review-level entry","Direct binding and BER modulation not independently validated here"]},{"year":2013,"claim":"Reconstituting direct APC-vimentin binding via the armadillo repeats established APC as an integrator of microtubule and intermediate filament networks during migration.","evidence":"In vitro binding with purified components, domain mapping, and wound-migration loss-of-function in astrocytes and cancer cells","pmids":["23382461"],"confidence":"High","gaps":["How microtubule and IF coordination is regulated dynamically not resolved","Contribution to tumor suppression not directly tested"]},{"year":2014,"claim":"Identifying RIP140 as a direct stimulator of APC transcription revealed an upstream node controlling APC abundance and beta-catenin activity.","evidence":"Rip140 knockout and transgenic mouse models with APC transcription and beta-catenin target readouts plus xenografts","pmids":["24667635"],"confidence":"Medium","gaps":["Direct binding of RIP140 to the APC promoter not detailed","Generalizability across tissues not established"]},{"year":2021,"claim":"NOTUM secretion by Apc-mutant cells was identified as a cell-competition mechanism that suppresses neighboring wild-type cells, explaining mutant clone fixation in crypts.","evidence":"Conditioned medium, genetic and pharmacological NOTUM inhibition, organoids, and in vivo adenoma models","pmids":["34079124"],"confidence":"High","gaps":["Upstream signals controlling NOTUM induction in mutant cells not defined","Therapeutic window of NOTUM inhibition not established"]},{"year":2021,"claim":"Defining METTL3/m6A/YTHDF-mediated APC mRNA degradation added a post-transcriptional layer linking RNA modification to beta-catenin signaling and tumor metabolism.","evidence":"m6A-RIP-seq, METTL3 knockdown/overexpression, YTHDF binding, beta-catenin readouts, and xenograft model","pmids":["34155197"],"confidence":"High","gaps":["Specific m6A sites driving degradation not fully mapped","Which YTHDF paralog dominates not resolved"]},{"year":2021,"claim":"Single-molecule imaging showed APC-dependent mRNAs are transported to protrusions by the KIF1C motor, illuminating spatial regulation of the APC mRNA system.","evidence":"Live two-color single-molecule imaging, KIF1C knockdown, and 3'UTR reporter mapping","pmids":["34493599"],"confidence":"Medium","gaps":["Functional consequence of localized APC mRNA for protein activity not established","Adaptors linking mRNA to KIF1C not identified"]},{"year":null,"claim":"How APC's distinct activities — beta-catenin destruction, microtubule/IF cytoskeletal control, mitotic chromosome alignment, and mRNA localization — are coordinated within a single regulatory program remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No integrated structural model spanning the multiple functional domains","Tissue-specific weighting of each function not quantified","Cross-talk between cytoskeletal and signaling roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,4,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,7,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,12,13]}],"complexes":["APC/EB1/BubR1 ternary complex"],"partners":["CTNNB1","EB1","BUBR1","VIM","NUP153","YWHAB","METTL3","KIF1C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25054","full_name":"Adenomatous polyposis coli protein","aliases":["Deleted in polyposis 2.5"],"length_aa":2843,"mass_kda":311.6,"function":"Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Associates with both microtubules and actin filaments, components of the cytoskeleton (PubMed:17293347). Plays a role in mediating the organization of F-actin into ordered bundles (PubMed:17293347). Functions downstream of Rho GTPases and DIAPH1 to selectively stabilize microtubules (By similarity). Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization","subcellular_location":"Cell junction, adherens junction; Cytoplasm, cytoskeleton; Cell projection, lamellipodium; Cell projection, ruffle membrane; Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25054/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/APC","classification":"Not Classified","n_dependent_lines":382,"n_total_lines":1208,"dependency_fraction":0.3162251655629139},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000134982","cell_line_id":"CID000685","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"centrosome","grade":1}],"interactors":[{"gene":"CTNNB1","stoichiometry":0.2},{"gene":"TRAP1","stoichiometry":0.2},{"gene":"COPZ1","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"GSK3B","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000685","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"620959","title":"UBIQUITIN-SPECIFIC PEPTIDASE 35; USP35","url":"https://www.omim.org/entry/620959"},{"mim_id":"620226","title":"UBIQUITIN-SPECIFIC PEPTIDASE 37; USP37","url":"https://www.omim.org/entry/620226"},{"mim_id":"620145","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 109; DEE109","url":"https://www.omim.org/entry/620145"},{"mim_id":"620142","title":"CENTROSOMAL AT-AC SPLICING FACTOR; CENATAC","url":"https://www.omim.org/entry/620142"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":38.7}],"url":"https://www.proteinatlas.org/search/APC"},"hgnc":{"alias_symbol":["DP2","DP3","DP2.5","PPP1R46"],"prev_symbol":[]},"alphafold":{"accession":"P25054","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25054","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=APC","jax_strain_url":"https://www.jax.org/strain/search?query=APC"},"sequence":{"accession":"P25054","fasta_url":"https://rest.uniprot.org/uniprotkb/P25054.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25054/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25054"}},"corpus_meta":[{"pmid":"8259518","id":"PMC_8259518","title":"Association of the APC gene product with beta-catenin.","date":"1993","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8259518","citation_count":1202,"is_preprint":false},{"pmid":"11257105","id":"PMC_11257105","title":"The ABC of APC.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11257105","citation_count":694,"is_preprint":false},{"pmid":"17377531","id":"PMC_17377531","title":"Myc deletion rescues Apc deficiency in the small intestine.","date":"2007","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/17377531","citation_count":505,"is_preprint":false},{"pmid":"8385345","id":"PMC_8385345","title":"The APC gene product in normal and tumor cells.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8385345","citation_count":428,"is_preprint":false},{"pmid":"7606712","id":"PMC_7606712","title":"APC binds to the novel protein EB1.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7606712","citation_count":392,"is_preprint":false},{"pmid":"18941170","id":"PMC_18941170","title":"Macrophages as APC and the dendritic cell myth.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18941170","citation_count":381,"is_preprint":false},{"pmid":"9196022","id":"PMC_9196022","title":"The adenomatous polyposis coli (APC) tumor suppressor.","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9196022","citation_count":375,"is_preprint":false},{"pmid":"17881494","id":"PMC_17881494","title":"Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17881494","citation_count":366,"is_preprint":false},{"pmid":"28423402","id":"PMC_28423402","title":"Multiple Roles of APC and its Therapeutic Implications in Colorectal 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circuitry.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21874044","citation_count":30,"is_preprint":false},{"pmid":"18477604","id":"PMC_18477604","title":"Novel self-association of the APC molecule affects APC clusters and cell migration.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18477604","citation_count":30,"is_preprint":false},{"pmid":"11112217","id":"PMC_11112217","title":"Nasopharyngeal angiofibroma: an APC-gene-associated tumor?","date":"2000","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/11112217","citation_count":29,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39874,"output_tokens":4376,"usd":0.092631,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12000,"output_tokens":4923,"usd":0.091537,"stage2_stop_reason":"end_turn"},"total_usd":0.184168,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to distinguish between:\n1. Papers about the APC tumor suppressor (adenomatous polyposis coli) - INCLUDE\n2. Papers about APC/C (anaphase-promoting complex/cyclosome) - EXCLUDE (different gene/complex)\n3. Papers about APC = antigen-presenting cells - EXCLUDE (different meaning)\n4. Papers about APC = activated protein C - EXCLUDE\n\nLet me classify carefully:\n- Papers [1]-[5], [7]-[10], [12], [14], [16]-[21], [25], [29]-[31], [39], [44]-[46], [50]-[53], [56]-[57], [60], [64], [68]-[69], [73], [75], [78]-[81], [83], [86], [89], [91], [93], [96], [99] → APC tumor suppressor\n- Papers [11]-[13], [15], [22]-[28], [32]-[36], [54], [65], [67], [70], [74], [85], [97]-[98] → APC/C complex - EXCLUDE\n- Papers [6], [42], [59], [88], [94] → antigen-presenting cells - EXCLUDE\n- Papers [43], [47] → activated protein C - EXCLUDE\n- Papers [24], [58] → plant/other organisms APC - EXCLUDE\n\nNow extracting mechanistic findings from the tumor suppressor APC papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"APC protein physically associates with beta-catenin: immunoprecipitation with anti-APC antibodies co-precipitated a 95 kDa protein identified by sequencing as beta-catenin, and reciprocal anti-beta-catenin antibody confirmed the interaction in vivo.\",\n      \"method\": \"Immunoprecipitation, protein sequencing\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with antibodies to both proteins, confirmed by sequencing; foundational result replicated extensively\",\n      \"pmids\": [\"8259518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"APC protein oligomerizes via its N-terminal domain: in vitro expression and immunoprecipitation demonstrated that the first 171 residues are sufficient for APC self-association, and the first 45 amino acids are necessary, suggesting truncated mutant APC can bind wild-type APC in a dominant-negative manner.\",\n      \"method\": \"In vitro expression, immunoprecipitation, deletion mutagenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with deletion mutants mapping minimal domains; single lab but multiple truncation constructs tested\",\n      \"pmids\": [\"8389242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"APC binds the novel protein EB1 via its carboxyl terminus: two-hybrid screen identified EB1, and the interaction was confirmed by in vitro binding assays and co-immunoprecipitation in vivo using anti-EB1 monoclonal antibodies.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction trap screen followed by in vitro and in vivo confirmation with reciprocal antibodies; replicated in subsequent studies\",\n      \"pmids\": [\"7606712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"APC contains nuclear export signals (NES) 3' adjacent to the mutation cluster region that enable it to exit the nucleus via a CRM1-dependent pathway; this nuclear export function is lost in truncation mutant APC cancer cells, resulting in nuclear accumulation of beta-catenin.\",\n      \"method\": \"Live cell imaging, nuclear export signal mapping, mutant APC analysis in cancer cell lines\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of conserved NES motifs with functional demonstration in cells; nuclear beta-catenin accumulation linked to NES loss; single lab with multiple cell line comparisons\",\n      \"pmids\": [\"10984057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"APC protein moves along microtubules toward their growing plus ends in an ATP-dependent manner, and concentrates as granules at plus ends during cell spreading and wound healing; the C-terminal region targets APC to growing MT ends, while the region lacking the C-terminus forms granular aggregates that move along MTs by motor activity.\",\n      \"method\": \"GFP live-cell imaging, deletion mutant analysis, immunoelectron microscopy in Xenopus epithelial cells\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging of GFP-tagged full-length and deletion mutants, immunoelectron microscopy, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10662776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"APC inhibits ERK pathway activation induced by RAS: overexpressing APC in DLD-1 cells reduced RAS-induced ERK activation, and Cre-mediated Apc knockout in primary mouse embryonic fibroblasts increased ERK activity; the mechanism involves APC acting on beta-catenin, which activates Raf1/MEK/ERK, and APC overexpression reduces RAS protein levels.\",\n      \"method\": \"Overexpression/knockdown in colorectal cancer cells, Cre-lox knockout in MEFs, kinase activity assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function and overexpression with defined biochemical readouts; single lab, multiple complementary approaches\",\n      \"pmids\": [\"16478791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Myc is the critical downstream mediator of Apc loss in the intestine: simultaneous deletion of both Apc and Myc in the adult murine small intestine rescued defects in differentiation, migration, proliferation, and apoptosis caused by Apc deletion alone, even in the presence of high nuclear beta-catenin; array analysis showed Myc is required for the majority of Wnt target gene activation after Apc loss.\",\n      \"method\": \"Conditional in vivo double knockout (Apc and Myc), gene expression arrays, histological analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with double conditional knockouts, transcriptome-wide target analysis, rigorous histological readouts\",\n      \"pmids\": [\"17377531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APC directly binds polymerized vimentin (an intermediate filament protein) via its armadillo repeats, promotes vimentin polymerization in vitro, and is required for microtubule-dependent rearrangements of intermediate filaments during cell migration; loss or truncation of APC correlated with disorganization of the IF network in glioma and carcinoma cells.\",\n      \"method\": \"In vitro binding assay with purified components, wound-induced migration assay, loss-of-function analysis in astrocytes and cancer cells, domain mapping\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding reconstituted in vitro with purified proteins, domain mapped to armadillo repeats, functional consequence in cell migration assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23382461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules; BubR1 associates with APC and EB1 in Xenopus egg extracts, and this complex is necessary for metaphase chromosome alignment.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, antibody addition experiments, in vitro kinase assay with purified components, Co-IP\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation assay with purified BubR1 and APC, ternary complex reconstitution, functional rescue with immunodepletion; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17709426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APC associates with the nuclear pore complex protein Nup153 (nucleoporin 153) and through this direct interaction promotes association of microtubules with the nuclear membrane, which is required for polarization of the microtubule cytoskeleton during directional cell migration.\",\n      \"method\": \"In vitro scratch-induced migration assay, direct interaction analysis with Nup153, microtubule organization imaging in neurons and fibroblasts\",\n      \"journal\": \"Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct interaction identified and linked to functional outcome in migration assay; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"18042042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A novel N-terminal to C-terminal self-association of APC was identified: an N-terminal region of APC interacts with the extreme C-terminal 300 amino acids of APC, and also with itself; this interaction is phospho-sensitive and enhanced by 14-3-3 protein; this self-association modulates APC clustering at membrane protrusions and is required for cell migration.\",\n      \"method\": \"Co-IP, deletion mapping, overexpression and inhibition experiments, cell migration assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel intramolecular interaction mapped by Co-IP, phospho-sensitivity shown, 14-3-3 involvement, functional link to migration; single lab, multiple methods\",\n      \"pmids\": [\"18477604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Truncated APC (as expressed in SW480 colon cancer cells) is required for cell proliferation and DNA replication: RNAi knockdown of APC in both wild-type-expressing and truncated-APC-expressing cancer cells impaired proliferation and DNA replication, correlating with reduced cyclin A, cyclin A-dependent kinase activity, p27(kip1), and DNA polymerase delta catalytic subunit.\",\n      \"method\": \"RNA interference, cell proliferation assay, DNA replication assay, Western blot for cell cycle proteins\",\n      \"journal\": \"International Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple biochemical readouts in two cell line contexts; single lab, mechanistic follow-up of proliferation phenotype\",\n      \"pmids\": [\"16450383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Apc-mutant cells secrete NOTUM, a WNT antagonist, which suppresses surrounding wild-type crypt cell proliferation and drives their differentiation, giving Apc-mutant clones a competitive advantage for crypt fixation; conditioned medium from Apc-mutant cells suppressed wild-type organoid growth in a NOTUM-dependent manner, and pharmacological/genetic NOTUM inhibition abrogated Apc-mutant cell expansion.\",\n      \"method\": \"Conditioned medium experiments, NOTUM inhibition (genetic and pharmacological), organoid assays, in vivo intestinal adenoma models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (conditioned medium, genetic knockout, pharmacological inhibition, in vivo models) converging on NOTUM as the mechanistic mediator\",\n      \"pmids\": [\"34079124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL3-mediated m6A modification of APC mRNA recruits YTHDF proteins to degrade APC mRNA, reducing APC protein levels and thereby increasing beta-catenin and its transcriptional targets (cyclin D1, c-Myc, PKM2), leading to enhanced glycolysis and tumor cell proliferation.\",\n      \"method\": \"m6A-RIP sequencing, METTL3 knockdown/overexpression, YTHDF binding assay, beta-catenin signaling readouts, mouse xenograft model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP-seq identifies APC as METTL3 target, mechanistic link to YTHDF-mediated mRNA degradation confirmed by multiple downstream readouts and in vivo tumor model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34155197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RIP140 (a transcriptional coregulator) directly stimulates APC transcription and thereby inhibits beta-catenin activation; Rip140-null mice showed reduced APC levels and increased intestinal proliferation, while RIP140 overexpression repressed colon cancer cell proliferation in vivo and in vitro.\",\n      \"method\": \"Rip140 knockout and transgenic mouse models, APC transcription assays, beta-catenin target gene expression, nude mouse xenograft\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss- and gain-of-function in mice with APC transcription as direct readout; single lab, multiple genetic models\",\n      \"pmids\": [\"24667635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The kinesin KIF1C motor interacts with APC-dependent mRNAs and is required for their transport to cell protrusions; live-cell two-color imaging revealed single mRNAs transported by single KIF1C motors, with the 3'UTR sufficient to trigger KIF1C-dependent transport; KIF1C is also required for formation of peripheral multimeric RNA clusters.\",\n      \"method\": \"Live single-molecule imaging, two-color mRNA/motor co-imaging, KIF1C knockdown, 3'UTR reporter assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct visualization of single-molecule transport events, loss-of-function, minimal element mapping; single lab\",\n      \"pmids\": [\"34493599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"APC is required for regulation of DNA base excision repair (BER) through interaction with DNA polymerase beta (Pol-beta) and flap endonuclease 1 (Fen-1); APC gene transcription is activated by alkylating agents, and APC modulates BER activity.\",\n      \"method\": \"Protein interaction studies, BER activity assays, transcriptional activation analysis (reviewed from primary literature)\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review summarizing interaction data; no primary experimental detail available in this abstract; single indirect citation\",\n      \"pmids\": [\"18662849\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"APC is a multifunctional tumor suppressor that directly binds beta-catenin (promoting its degradation via the Axin/GSK3β destruction complex), associates with EB1 and microtubule plus ends to regulate cytoskeletal dynamics and chromosome stability, contains nuclear export signals enabling beta-catenin nuclear export, oligomerizes via its N-terminus (allowing dominant-negative effects of truncation mutants), directly binds intermediate filaments (vimentin) via armadillo repeats to coordinate cytoskeletal reorganization during migration, is phosphorylated by BubR1 within a ternary APC/EB1/BubR1 complex at kinetochores, and acts upstream of c-Myc as the critical mediator of Wnt target gene activation following APC loss; additionally, Apc-mutant cells secrete NOTUM to competitively suppress neighboring wild-type cells, and APC mRNA levels are regulated post-transcriptionally by METTL3-mediated m6A modification leading to YTHDF-dependent degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"APC is a multifunctional tumor suppressor that couples Wnt/beta-catenin signaling control to cytoskeletal organization and cell migration [#0, #4]. It physically associates with beta-catenin [#0] and contains CRM1-dependent nuclear export signals adjacent to its mutation cluster region; truncating cancer mutations abolish this export and cause nuclear accumulation of beta-catenin [#3]. Downstream of beta-catenin, c-Myc is the critical effector of APC loss in the intestine, mediating most Wnt target gene activation and the differentiation, proliferation, migration, and apoptosis defects following Apc deletion [#6]. APC self-associates through its N-terminal domain, so truncated mutants can bind wild-type APC and act dominant-negatively [#1], and an additional phospho-sensitive N-to-C-terminal interaction enhanced by 14-3-3 governs APC clustering at membrane protrusions during migration [#10]. At the cytoskeleton, APC binds the plus-end tracking protein EB1 via its C-terminus [#2], moves ATP-dependently toward growing microtubule plus ends [#4], directly binds and promotes polymerization of vimentin intermediate filaments through its armadillo repeats [#7], and links microtubules to the nuclear membrane via Nup153 to polarize the cytoskeleton during directional migration [#9]. APC also participates in mitotic chromosome alignment within a ternary APC/EB1/BubR1 complex, in which BubR1 directly phosphorylates APC [#8]. APC expression is itself regulated transcriptionally by RIP140 [#14] and post-transcriptionally by METTL3-mediated m6A modification that triggers YTHDF-dependent APC mRNA degradation, relieving beta-catenin repression and promoting glycolysis and proliferation [#13]. In intestinal tissue, Apc-mutant cells secrete the Wnt antagonist NOTUM to competitively suppress neighboring wild-type cells, providing a fixation advantage for mutant clones [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that APC physically associates with beta-catenin connected the tumor suppressor to a defined molecular partner and laid the foundation for its role in Wnt signaling.\",\n      \"evidence\": \"Reciprocal anti-APC and anti-beta-catenin immunoprecipitation with protein sequencing in vivo\",\n      \"pmids\": [\"8259518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the functional consequence of binding (degradation vs sequestration)\", \"Did not map the interaction domains or destruction-complex context\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating N-terminal oligomerization explained how truncated APC mutants could exert dominant-negative effects over the wild-type allele.\",\n      \"evidence\": \"In vitro expression, immunoprecipitation, and deletion mutagenesis mapping minimal self-association domains\",\n      \"pmids\": [\"8389242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative effect inferred from binding, not directly tested functionally in cells\", \"Stoichiometry and physiological relevance of oligomers not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying EB1 as a C-terminal APC partner first linked APC to microtubule biology beyond its beta-catenin function.\",\n      \"evidence\": \"Yeast two-hybrid screen with in vitro and reciprocal in vivo co-immunoprecipitation confirmation\",\n      \"pmids\": [\"7606712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the APC-EB1 interaction not yet established\", \"Did not determine effect on microtubule dynamics\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping CRM1-dependent nuclear export signals showed how APC controls subcellular distribution of beta-catenin and why truncating mutations cause nuclear beta-catenin accumulation.\",\n      \"evidence\": \"NES motif mapping and live-cell imaging comparing wild-type and truncation-mutant cancer cell lines\",\n      \"pmids\": [\"10984057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of export vs degradation to beta-catenin control not quantified\", \"Cargo specificity beyond beta-catenin not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Live imaging revealing ATP-dependent plus-end tracking of APC established it as an active microtubule-associated protein with distinct C-terminal targeting and motor-driven behaviors.\",\n      \"evidence\": \"GFP live-cell imaging of full-length and deletion mutants plus immunoelectron microscopy in Xenopus epithelial cells\",\n      \"pmids\": [\"10662776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the motor driving granule movement not defined\", \"Link between plus-end tracking and tumor suppression not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic and overexpression studies placed APC upstream of RAS/ERK signaling, broadening its signaling outputs beyond canonical Wnt.\",\n      \"evidence\": \"APC overexpression/knockdown in colorectal cells and Cre-lox Apc knockout in MEFs with kinase activity assays\",\n      \"pmids\": [\"16478791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which APC lowers RAS protein levels unresolved\", \"Single-lab observation linking beta-catenin to Raf1/MEK/ERK not independently confirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"RNAi knockdown showed even truncated APC supports proliferation and DNA replication, indicating residual functions of mutant APC in cancer cells.\",\n      \"evidence\": \"RNA interference with proliferation, DNA replication, and cell-cycle protein readouts in wild-type and truncated-APC cancer lines\",\n      \"pmids\": [\"16450383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular basis of the replication requirement not defined\", \"Whether effect is beta-catenin-dependent not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"In vivo double knockout established c-Myc as the critical mediator of Apc loss, defining the key transcriptional output downstream of beta-catenin.\",\n      \"evidence\": \"Conditional Apc/Myc double knockout in adult mouse intestine with gene expression arrays and histology\",\n      \"pmids\": [\"17377531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Myc-independent Wnt targets remain uncharacterized\", \"Generalizability beyond intestinal epithelium not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstitution of an APC/EB1/BubR1 ternary complex with direct BubR1 phosphorylation of APC linked APC to mitotic chromosome alignment and a mechanism for chromosomal instability.\",\n      \"evidence\": \"Immunodepletion from Xenopus egg extracts, in vitro kinase assays with purified components, and Co-IP\",\n      \"pmids\": [\"17709426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites and their functional consequence not mapped\", \"Relevance to human tumor aneuploidy not directly tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the APC-Nup153 interaction explained how APC tethers microtubules to the nuclear membrane to polarize the cytoskeleton during directional migration.\",\n      \"evidence\": \"Scratch-induced migration assays and microtubule organization imaging in neurons and fibroblasts\",\n      \"pmids\": [\"18042042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mechanistic detail on the direct interaction interface\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of a phospho-sensitive, 14-3-3-enhanced N-to-C intramolecular self-association added a regulatory layer controlling APC clustering at protrusions during migration.\",\n      \"evidence\": \"Co-IP, deletion mapping, overexpression/inhibition experiments, and cell migration assays\",\n      \"pmids\": [\"18477604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for the phospho-switch not identified\", \"Structural basis of the intramolecular contact unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"APC was linked to base excision repair through interactions with Pol-beta and Fen-1, suggesting a direct genome-maintenance role.\",\n      \"evidence\": \"Review summarizing protein interaction and BER activity data\",\n      \"pmids\": [\"18662849\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No primary experimental detail in this review-level entry\", \"Direct binding and BER modulation not independently validated here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstituting direct APC-vimentin binding via the armadillo repeats established APC as an integrator of microtubule and intermediate filament networks during migration.\",\n      \"evidence\": \"In vitro binding with purified components, domain mapping, and wound-migration loss-of-function in astrocytes and cancer cells\",\n      \"pmids\": [\"23382461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How microtubule and IF coordination is regulated dynamically not resolved\", \"Contribution to tumor suppression not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying RIP140 as a direct stimulator of APC transcription revealed an upstream node controlling APC abundance and beta-catenin activity.\",\n      \"evidence\": \"Rip140 knockout and transgenic mouse models with APC transcription and beta-catenin target readouts plus xenografts\",\n      \"pmids\": [\"24667635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of RIP140 to the APC promoter not detailed\", \"Generalizability across tissues not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NOTUM secretion by Apc-mutant cells was identified as a cell-competition mechanism that suppresses neighboring wild-type cells, explaining mutant clone fixation in crypts.\",\n      \"evidence\": \"Conditioned medium, genetic and pharmacological NOTUM inhibition, organoids, and in vivo adenoma models\",\n      \"pmids\": [\"34079124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling NOTUM induction in mutant cells not defined\", \"Therapeutic window of NOTUM inhibition not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining METTL3/m6A/YTHDF-mediated APC mRNA degradation added a post-transcriptional layer linking RNA modification to beta-catenin signaling and tumor metabolism.\",\n      \"evidence\": \"m6A-RIP-seq, METTL3 knockdown/overexpression, YTHDF binding, beta-catenin readouts, and xenograft model\",\n      \"pmids\": [\"34155197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific m6A sites driving degradation not fully mapped\", \"Which YTHDF paralog dominates not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Single-molecule imaging showed APC-dependent mRNAs are transported to protrusions by the KIF1C motor, illuminating spatial regulation of the APC mRNA system.\",\n      \"evidence\": \"Live two-color single-molecule imaging, KIF1C knockdown, and 3'UTR reporter mapping\",\n      \"pmids\": [\"34493599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of localized APC mRNA for protein activity not established\", \"Adaptors linking mRNA to KIF1C not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APC's distinct activities — beta-catenin destruction, microtubule/IF cytoskeletal control, mitotic chromosome alignment, and mRNA localization — are coordinated within a single regulatory program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No integrated structural model spanning the multiple functional domains\", \"Tissue-specific weighting of each function not quantified\", \"Cross-talk between cytoskeletal and signaling roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 4, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 12, 13]}\n    ],\n    \"complexes\": [\"APC/EB1/BubR1 ternary complex\"],\n    \"partners\": [\"CTNNB1\", \"EB1\", \"BubR1\", \"VIM\", \"Nup153\", \"YWHAB\", \"METTL3\", \"KIF1C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}