{"gene":"ACTR3","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2021,"finding":"Conditional knockout of murine Actr3 (encoding Arp3) causes near-complete loss of functional Arp2/3 complex expression, abolished lamellipodia formation and membrane ruffling, reduced actin turnover rates at the cell periphery, compromised directionality of migration and collective migration, and paradoxically enhanced cell spreading via induction of filopodia. Induced Arp3 depletion also reproducibly increased FMNL2/3 formin expression, correlating with explosive filopodia induction, revealing a compensatory relationship between Arp2/3 and formin-based actin networks.","method":"Conditional (tamoxifen-inducible) Actr3 knockout mouse fibroblast cell lines; immunofluorescence; FRAP; live-cell migration assays; chemotaxis assays","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal phenotypic readouts (lamellipodia, ruffling, actin turnover by FRAP, migration directionality, formin expression), replicated across multiple assays in a single rigorous study","pmids":["33598464"],"is_preprint":false},{"year":2022,"finding":"Nuclear BRAFV600E physically interacts with Arp2/3 complex members ACTR2 (ARP2) and ACTR3 (ARP3) in thyroid cancer cells; proteomic analysis identified ACTR3 as the most enriched nuclear BRAFV600E partner. ACTR3 expression was correlated with lymph node stage and extrathyroidal extension, and was validated with functional assays demonstrating a role in aggressive behavior and vemurafenib resistance.","method":"Nuclear/cytosolic fractionation; proteomic analysis of BRAFV600E immunoprecipitates; functional assays in PTC cells and xenograft mouse model; IHC on 100 PTC specimens","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic IP identification of ACTR3 as nuclear BRAFV600E partner with functional validation assays, single lab","pmids":["35968344"],"is_preprint":false},{"year":2016,"finding":"PKD2 (protein kinase D2) physically interacts with the entire seven-subunit Arp2/3 complex, including ACTR3, in both cytosolic and Golgi-enriched subcellular fractions, as demonstrated by affinity enrichment combined with chemical cross-linking/mass spectrometry, providing evidence of a direct PKD2–Arp2/3 protein-protein interaction.","method":"Affinity enrichment; chemical cross-linking/mass spectrometry (XL-MS); subcellular fractionation into cytosolic and Golgi fractions","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical cross-linking MS provides evidence for direct interaction, complemented by subcellular fractionation, single lab","pmids":["27559607"],"is_preprint":false},{"year":2021,"finding":"Knockdown of ACTR3 in pancreatic ductal adenocarcinoma (PDAC) cells significantly inhibited invasive and migratory capacity, altered F-actin distribution, and changed the expression of EMT markers (e.g., E-cadherin, vimentin), indicating that ACTR3 promotes cell migration and invasion by inducing epithelial-mesenchymal transition in PDAC.","method":"siRNA knockdown of ACTR3 in PDAC cell lines; transwell migration/invasion assays; Western blotting for EMT markers; phalloidin staining of F-actin","journal":"Journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clean KD with defined cellular phenotype and EMT marker changes, multiple assays, single lab","pmids":["34790395"],"is_preprint":false},{"year":2021,"finding":"LUZP1 loss in mouse fibroblasts (CRISPR/Cas9 knockout) induces changes in ACTR3 (ARP3) protein levels and phospho-cofilin ratios, suggesting that LUZP1 regulates actin polymerization through the Arp2/3 pathway beyond its role in filament bundling.","method":"CRISPR/Cas9 Luzp1 knockout in mouse fibroblasts; Western blotting for ACTR3 and phospho-cofilin; cell migration and invasion assays","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect measure (ACTR3 protein level changes upon Luzp1 KO), no direct functional manipulation of ACTR3 itself","pmids":["33869174"],"is_preprint":false},{"year":2026,"finding":"Lysine 2-hydroxyisobutyrylation (Khib) at the K42 site of ACTR3 is reduced in psoriatic lesional skin. Decreased K42-Khib modification (modeled by K42A mutation) exacerbates psoriatic inflammation and keratinocyte proliferation. The deacetylases SIRT1 and HDAC1 reduce ACTR3 Khib modification levels. Reduced K42-Khib of ACTR3 promotes keratinocyte proliferation by activating the TAK1-MK2-HSP27 signaling pathway; TAK1 antagonists reversed this effect.","method":"Khib-modified protein profiling by mass spectrometry on human psoriatic and healthy skin biopsies; ACTR3 K42A mutation experiments in IMQ-induced psoriatic mouse model; Western blotting; TAK1 antagonist treatment; SIRT1/HDAC1 knockdown/overexpression experiments","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identified by MS, functionally validated by point mutation in vivo, pathway placed by TAK1 antagonist rescue, single lab with multiple orthogonal approaches","pmids":["42089462"],"is_preprint":false},{"year":2019,"finding":"ACTR3 was identified as a host factor required for Salmonella uptake in human macrophages; CRISPR knockout of ACTR3 in THP-1 macrophages conferred resistance to Salmonella infection, placing ACTR3 in the actin dynamics pathway necessary for bacterial phagocytosis.","method":"Genome-wide CRISPR knockout screen in THP-1 macrophages; validation of individual gene knockouts for Salmonella uptake resistance","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional screen with ACTR3 identified and listed among validated hits in actin dynamics group, loss-of-function phenotype demonstrated","pmids":["31594818"],"is_preprint":false},{"year":2026,"finding":"CORO1C interacts with the ACTR2/ARP2-ACTR3/ARP3 complex; this interaction is essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity during macroautophagy.","method":"Genome-wide loss-of-function screen in mouse haploid ESCs; CORO1C-ACTR2/ACTR3 interaction studies; coro1c-/- mouse model with autophagy phenotype analysis by TEM and immunofluorescence","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo phenotype, interaction validated; ACTR3's specific role is inferred from CORO1C-Arp2/3 interaction studies rather than direct ACTR3 manipulation","pmids":["41968673"],"is_preprint":false},{"year":2021,"finding":"miR-486-5p downregulates ACTR3 expression (along with SMAD2 and CDK4) in gastric cancer-associated peritoneal mesothelial cells (HMrSV5); decreased exosomal delivery of miR-486-5p from peritoneal metastasis gastric cancer cells leads to increased ACTR3 expression and promotes EMT progression in recipient cells.","method":"miRNA array; qRT-PCR; Western blotting for ACTR3, SMAD2, CDK4; miR-486-5p transfection; laser confocal microscopy for exosomal delivery tracking","journal":"World journal of surgical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ACTR3 identified as miR-486-5p target by Western blot with no direct functional validation of ACTR3's role in EMT independently","pmids":["34686196"],"is_preprint":false}],"current_model":"ACTR3 (ARP3) is a core subunit of the Arp2/3 complex that nucleates branched actin filament networks; its loss abolishes lamellipodia, reduces actin turnover, impairs directional migration, and triggers compensatory formin (FMNL2/3) upregulation and filopodia formation; it promotes cell invasion and EMT in cancer cells, participates in Salmonella phagocytosis via actin dynamics, interacts with PKD2 at the Golgi and with nuclear BRAFV600E in thyroid cancer, supports autophagosome formation through CORO1C-dependent branched actin assembly, and its activity is regulated post-translationally by lysine 2-hydroxyisobutyrylation at K42 (written/erased by SIRT1/HDAC1), with reduced K42-Khib activating the TAK1-MK2-HSP27 pathway to drive keratinocyte hyperproliferation in psoriasis."},"narrative":{"mechanistic_narrative":"ACTR3 (ARP3) is a core subunit of the Arp2/3 complex that nucleates branched actin filament networks underlying cell-edge protrusion and motility [PMID:33598464]. Conditional loss of Actr3 abolishes functional Arp2/3 expression, eliminates lamellipodia and membrane ruffling, slows peripheral actin turnover, and degrades directional and collective migration; cells compensate by upregulating FMNL2/3 formins and switching to filopodia-based protrusion, revealing antagonistic balance between Arp2/3- and formin-based actin networks [PMID:33598464]. This branched-actin function is co-opted in several cellular contexts: ACTR3 is required for Salmonella phagocytosis in macrophages [PMID:31594818], and the Arp2/3 complex partners with CORO1C to assemble branched actin needed for p62/SQSTM1 body formation and autophagosome integrity during macroautophagy [PMID:41968673]. In cancer, ACTR3 promotes migration, invasion, and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma [PMID:34790395], physically associates with nuclear BRAFV600E in thyroid cancer where it correlates with aggressive disease and vemurafenib resistance [PMID:35968344], and is engaged by PKD2 at the Golgi and in the cytosol [PMID:27559607]. ACTR3 activity is tuned post-translationally: lysine 2-hydroxyisobutyrylation at K42, controlled by SIRT1 and HDAC1, is reduced in psoriatic skin, and loss of this modification activates the TAK1-MK2-HSP27 pathway to drive keratinocyte hyperproliferation [PMID:42089462].","teleology":[{"year":2016,"claim":"Whether ACTR3, as part of the intact Arp2/3 complex, engages specific upstream regulators at defined organelles was unresolved; this work placed the complex in direct contact with a signaling kinase at the Golgi.","evidence":"Affinity enrichment with chemical cross-linking/mass spectrometry and subcellular fractionation showing PKD2 binding to the seven-subunit Arp2/3 complex including ACTR3","pmids":["27559607"],"confidence":"Medium","gaps":["Functional consequence of the PKD2-Arp2/3 interaction not established","Whether ACTR3 is a direct contact point versus a complex-level interaction unresolved"]},{"year":2019,"claim":"It was unclear which actin machinery components are essential for bacterial internalization in macrophages; an unbiased screen placed ACTR3 in the actin dynamics pathway required for phagocytosis.","evidence":"Genome-wide CRISPR knockout screen in THP-1 macrophages with validation that ACTR3 loss confers Salmonella uptake resistance","pmids":["31594818"],"confidence":"Medium","gaps":["Mechanistic step of phagocytic actin remodeling that requires ACTR3 not dissected","Upstream nucleation-promoting factors not identified"]},{"year":2021,"claim":"The cell-biological consequences of removing ACTR3 had not been cleanly defined genetically; conditional knockout established its non-redundant role in lamellipodial actin and revealed compensatory formin upregulation.","evidence":"Tamoxifen-inducible Actr3 knockout mouse fibroblasts with immunofluorescence, FRAP, and live-cell migration/chemotaxis assays","pmids":["33598464"],"confidence":"High","gaps":["Molecular trigger for FMNL2/3 induction upon Arp2/3 loss not defined","Phenotypes characterized in fibroblasts; cell-type generality not tested"]},{"year":2021,"claim":"Whether ACTR3 contributes to cancer cell aggressiveness was open; knockdown in PDAC linked it to invasion and EMT.","evidence":"siRNA knockdown in PDAC cell lines with transwell invasion assays, EMT marker Western blots, and F-actin staining","pmids":["34790395"],"confidence":"Medium","gaps":["Whether EMT changes are a direct consequence of actin nucleation or downstream signaling unresolved","In vivo validation absent"]},{"year":2021,"claim":"Upstream regulators of ACTR3 abundance were poorly mapped; LUZP1 loss and miR-486-5p were reported to alter ACTR3 levels.","evidence":"CRISPR Luzp1 knockout in fibroblasts with Western blotting for ACTR3 and phospho-cofilin; separately, miR-486-5p transfection and exosomal tracking in gastric cancer-associated mesothelial cells","pmids":["33869174","34686196"],"confidence":"Low","gaps":["ACTR3 changes are indirect readouts with no direct functional manipulation of ACTR3","Direct versus indirect regulation not distinguished"]},{"year":2022,"claim":"A non-cytoskeletal, nuclear association for ACTR3 was unknown; proteomics identified it as the top nuclear BRAFV600E partner in thyroid cancer with links to aggressiveness and drug resistance.","evidence":"Nuclear/cytosolic fractionation, proteomic analysis of BRAFV600E immunoprecipitates, functional assays, xenografts, and IHC on 100 PTC specimens","pmids":["35968344"],"confidence":"Medium","gaps":["Mechanism by which nuclear ACTR3-BRAFV600E drives resistance unresolved","Whether the canonical Arp2/3 complex is involved in the nucleus not addressed"]},{"year":2026,"claim":"How ACTR3 activity is tuned post-translationally and links to inflammatory disease was unknown; a site-specific Khib modification at K42 was shown to gate keratinocyte proliferation via a defined kinase pathway.","evidence":"Khib profiling by mass spectrometry of human skin, K42A mutation in an IMQ-induced psoriatic mouse model, SIRT1/HDAC1 manipulation, and TAK1 antagonist rescue","pmids":["42089462"],"confidence":"Medium","gaps":["How K42-Khib alters actin nucleation biochemically not resolved","Link between K42 modification status and TAK1-MK2-HSP27 activation mechanistically incomplete"]},{"year":2026,"claim":"Whether branched actin contributes to autophagosome biogenesis was unclear; CORO1C was shown to bridge the ARP2-ARP3 complex to branched actin assembly required for p62 body formation and autophagosome integrity.","evidence":"Genome-wide screen in mouse haploid ESCs, CORO1C-ACTR2/ACTR3 interaction studies, and coro1c-/- mouse autophagy phenotyping by TEM and immunofluorescence","pmids":["41968673"],"confidence":"Medium","gaps":["ACTR3's specific role inferred from CORO1C-Arp2/3 interaction rather than direct ACTR3 manipulation","Site of branched actin assembly relative to the autophagosome not pinpointed"]},{"year":null,"claim":"How ACTR3's single actin-nucleation activity is differentially deployed and regulated across migration, phagocytosis, autophagy, nuclear signaling, and disease contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking K42-Khib to nucleation activity","Context-specific nucleation-promoting factors not systematically mapped","Non-canonical nuclear function not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":["Arp2/3 complex"],"partners":["ACTR2","CORO1C","PKD2","BRAF","LUZP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61158","full_name":"Actin-related protein 3","aliases":["Actin-like protein 3"],"length_aa":418,"mass_kda":47.4,"function":"ATP-binding component of the Arp2/3 complex, a multiprotein complex that mediates actin polymerization upon stimulation by nucleation-promoting factor (NPF) (PubMed:9000076). The Arp2/3 complex mediates the formation of branched actin networks in the cytoplasm, providing the force for cell motility (PubMed:9000076). Seems to contact the pointed end of the daughter actin filament (PubMed:9000076). In podocytes, required for the formation of lamellipodia downstream of AVIL and PLCE1 regulation (PubMed:29058690). In addition to its role in the cytoplasmic cytoskeleton, the Arp2/3 complex also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA (PubMed:17220302, PubMed:29925947). The Arp2/3 complex promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs) (PubMed:29925947). Plays a role in ciliogenesis (PubMed:20393563)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection; Nucleus","url":"https://www.uniprot.org/uniprotkb/P61158/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTR3","classification":"Common Essential","n_dependent_lines":591,"n_total_lines":1208,"dependency_fraction":0.48923841059602646},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":10.0},{"gene":"ARPC2","stoichiometry":10.0},{"gene":"ARPC3","stoichiometry":10.0},{"gene":"USP22","stoichiometry":10.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ARL3","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ACTR3","total_profiled":1310},"omim":[{"mim_id":"619590","title":"PHOSPHOLIPID PHOSPHATASE-RELATED PROTEIN 1; PLPPR1","url":"https://www.omim.org/entry/619590"},{"mim_id":"613397","title":"ADVILLIN; AVIL","url":"https://www.omim.org/entry/613397"},{"mim_id":"605952","title":"SORTING NEXIN 9; SNX9","url":"https://www.omim.org/entry/605952"},{"mim_id":"604227","title":"ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 5; ARPC5","url":"https://www.omim.org/entry/604227"},{"mim_id":"604226","title":"ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 4; ARPC4","url":"https://www.omim.org/entry/604226"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACTR3"},"hgnc":{"alias_symbol":["ARP3"],"prev_symbol":[]},"alphafold":{"accession":"P61158","domains":[{"cath_id":"3.30.420.40","chopping":"7-33_76-144_373-407","consensus_level":"high","plddt":95.6872,"start":7,"end":407},{"cath_id":"3.30.420.40","chopping":"155-194_294-367","consensus_level":"high","plddt":94.6586,"start":155,"end":367},{"cath_id":"3.90.640.10","chopping":"196-281","consensus_level":"high","plddt":94.3458,"start":196,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61158","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61158-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61158-F1-predicted_aligned_error_v6.png","plddt_mean":91.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTR3","jax_strain_url":"https://www.jax.org/strain/search?query=ACTR3"},"sequence":{"accession":"P61158","fasta_url":"https://rest.uniprot.org/uniprotkb/P61158.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61158/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61158"}},"corpus_meta":[{"pmid":"22370639","id":"PMC_22370639","title":"Zinc-finger 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Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30779416","citation_count":2,"is_preprint":false},{"pmid":"41495793","id":"PMC_41495793","title":"Single-cell RNA sequencing reveals the therapeutic mechanism of Calvatia lilacina in promoting wound healing of anal fistula.","date":"2026","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41495793","citation_count":1,"is_preprint":false},{"pmid":"35968344","id":"PMC_35968344","title":"Nuclear interaction of Arp2/3 complex and BRAFV600E promotes aggressive behavior and vemurafenib resistance of thyroid cancer.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35968344","citation_count":1,"is_preprint":false},{"pmid":"37610317","id":"PMC_37610317","title":"Genome-wide association analysis of neck ring traits in NongHua ma male ducks.","date":"2023","source":"British poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/37610317","citation_count":1,"is_preprint":false},{"pmid":"42089462","id":"PMC_42089462","title":"ACTR3 enhances the hyperproliferation of psoriatic keratinocytes by activating the TAK1-MK2-HSP27 pathway.","date":"2026","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/42089462","citation_count":0,"is_preprint":false},{"pmid":"35804609","id":"PMC_35804609","title":"Dietary Inclusion of Dried Chicory Root Affects Cecal Mucosa Proteome of Nursery Pigs.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/35804609","citation_count":0,"is_preprint":false},{"pmid":"41968673","id":"PMC_41968673","title":"CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41968673","citation_count":0,"is_preprint":false},{"pmid":"39394955","id":"PMC_39394955","title":"Should it stay or should it go: gap junction protein GJA1/Cx43 conveys damaged lysosomes to the cell periphery to potentiate exocytosis.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39394955","citation_count":0,"is_preprint":false},{"pmid":"42020408","id":"PMC_42020408","title":"Genetic determinants of fatigue up to 2 years after radiotherapy in prostate cancer patients.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42020408","citation_count":0,"is_preprint":false},{"pmid":"41669692","id":"PMC_41669692","title":"A plasma proteomic signature of the actin-coagulation axis accurately predicts progression to active tuberculosis.","date":"2026","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41669692","citation_count":0,"is_preprint":false},{"pmid":"41922977","id":"PMC_41922977","title":"Identification of discriminative plasma protein biomarkers for recent Mycobacterium tuberculosis infection: a pilot data‑independent acquisition mass spectrometry‑based proteomics study.","date":"2026","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41922977","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.19.624405","title":"An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer","date":"2024-11-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.624405","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24755,"output_tokens":2757,"usd":0.05781,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9948,"output_tokens":3172,"usd":0.06452,"stage2_stop_reason":"end_turn"},"total_usd":0.12233,"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\": 2021,\n      \"finding\": \"Conditional knockout of murine Actr3 (encoding Arp3) causes near-complete loss of functional Arp2/3 complex expression, abolished lamellipodia formation and membrane ruffling, reduced actin turnover rates at the cell periphery, compromised directionality of migration and collective migration, and paradoxically enhanced cell spreading via induction of filopodia. Induced Arp3 depletion also reproducibly increased FMNL2/3 formin expression, correlating with explosive filopodia induction, revealing a compensatory relationship between Arp2/3 and formin-based actin networks.\",\n      \"method\": \"Conditional (tamoxifen-inducible) Actr3 knockout mouse fibroblast cell lines; immunofluorescence; FRAP; live-cell migration assays; chemotaxis assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal phenotypic readouts (lamellipodia, ruffling, actin turnover by FRAP, migration directionality, formin expression), replicated across multiple assays in a single rigorous study\",\n      \"pmids\": [\"33598464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear BRAFV600E physically interacts with Arp2/3 complex members ACTR2 (ARP2) and ACTR3 (ARP3) in thyroid cancer cells; proteomic analysis identified ACTR3 as the most enriched nuclear BRAFV600E partner. ACTR3 expression was correlated with lymph node stage and extrathyroidal extension, and was validated with functional assays demonstrating a role in aggressive behavior and vemurafenib resistance.\",\n      \"method\": \"Nuclear/cytosolic fractionation; proteomic analysis of BRAFV600E immunoprecipitates; functional assays in PTC cells and xenograft mouse model; IHC on 100 PTC specimens\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic IP identification of ACTR3 as nuclear BRAFV600E partner with functional validation assays, single lab\",\n      \"pmids\": [\"35968344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKD2 (protein kinase D2) physically interacts with the entire seven-subunit Arp2/3 complex, including ACTR3, in both cytosolic and Golgi-enriched subcellular fractions, as demonstrated by affinity enrichment combined with chemical cross-linking/mass spectrometry, providing evidence of a direct PKD2–Arp2/3 protein-protein interaction.\",\n      \"method\": \"Affinity enrichment; chemical cross-linking/mass spectrometry (XL-MS); subcellular fractionation into cytosolic and Golgi fractions\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical cross-linking MS provides evidence for direct interaction, complemented by subcellular fractionation, single lab\",\n      \"pmids\": [\"27559607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knockdown of ACTR3 in pancreatic ductal adenocarcinoma (PDAC) cells significantly inhibited invasive and migratory capacity, altered F-actin distribution, and changed the expression of EMT markers (e.g., E-cadherin, vimentin), indicating that ACTR3 promotes cell migration and invasion by inducing epithelial-mesenchymal transition in PDAC.\",\n      \"method\": \"siRNA knockdown of ACTR3 in PDAC cell lines; transwell migration/invasion assays; Western blotting for EMT markers; phalloidin staining of F-actin\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clean KD with defined cellular phenotype and EMT marker changes, multiple assays, single lab\",\n      \"pmids\": [\"34790395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LUZP1 loss in mouse fibroblasts (CRISPR/Cas9 knockout) induces changes in ACTR3 (ARP3) protein levels and phospho-cofilin ratios, suggesting that LUZP1 regulates actin polymerization through the Arp2/3 pathway beyond its role in filament bundling.\",\n      \"method\": \"CRISPR/Cas9 Luzp1 knockout in mouse fibroblasts; Western blotting for ACTR3 and phospho-cofilin; cell migration and invasion assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect measure (ACTR3 protein level changes upon Luzp1 KO), no direct functional manipulation of ACTR3 itself\",\n      \"pmids\": [\"33869174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Lysine 2-hydroxyisobutyrylation (Khib) at the K42 site of ACTR3 is reduced in psoriatic lesional skin. Decreased K42-Khib modification (modeled by K42A mutation) exacerbates psoriatic inflammation and keratinocyte proliferation. The deacetylases SIRT1 and HDAC1 reduce ACTR3 Khib modification levels. Reduced K42-Khib of ACTR3 promotes keratinocyte proliferation by activating the TAK1-MK2-HSP27 signaling pathway; TAK1 antagonists reversed this effect.\",\n      \"method\": \"Khib-modified protein profiling by mass spectrometry on human psoriatic and healthy skin biopsies; ACTR3 K42A mutation experiments in IMQ-induced psoriatic mouse model; Western blotting; TAK1 antagonist treatment; SIRT1/HDAC1 knockdown/overexpression experiments\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identified by MS, functionally validated by point mutation in vivo, pathway placed by TAK1 antagonist rescue, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"42089462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ACTR3 was identified as a host factor required for Salmonella uptake in human macrophages; CRISPR knockout of ACTR3 in THP-1 macrophages conferred resistance to Salmonella infection, placing ACTR3 in the actin dynamics pathway necessary for bacterial phagocytosis.\",\n      \"method\": \"Genome-wide CRISPR knockout screen in THP-1 macrophages; validation of individual gene knockouts for Salmonella uptake resistance\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional screen with ACTR3 identified and listed among validated hits in actin dynamics group, loss-of-function phenotype demonstrated\",\n      \"pmids\": [\"31594818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CORO1C interacts with the ACTR2/ARP2-ACTR3/ARP3 complex; this interaction is essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity during macroautophagy.\",\n      \"method\": \"Genome-wide loss-of-function screen in mouse haploid ESCs; CORO1C-ACTR2/ACTR3 interaction studies; coro1c-/- mouse model with autophagy phenotype analysis by TEM and immunofluorescence\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo phenotype, interaction validated; ACTR3's specific role is inferred from CORO1C-Arp2/3 interaction studies rather than direct ACTR3 manipulation\",\n      \"pmids\": [\"41968673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-486-5p downregulates ACTR3 expression (along with SMAD2 and CDK4) in gastric cancer-associated peritoneal mesothelial cells (HMrSV5); decreased exosomal delivery of miR-486-5p from peritoneal metastasis gastric cancer cells leads to increased ACTR3 expression and promotes EMT progression in recipient cells.\",\n      \"method\": \"miRNA array; qRT-PCR; Western blotting for ACTR3, SMAD2, CDK4; miR-486-5p transfection; laser confocal microscopy for exosomal delivery tracking\",\n      \"journal\": \"World journal of surgical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ACTR3 identified as miR-486-5p target by Western blot with no direct functional validation of ACTR3's role in EMT independently\",\n      \"pmids\": [\"34686196\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTR3 (ARP3) is a core subunit of the Arp2/3 complex that nucleates branched actin filament networks; its loss abolishes lamellipodia, reduces actin turnover, impairs directional migration, and triggers compensatory formin (FMNL2/3) upregulation and filopodia formation; it promotes cell invasion and EMT in cancer cells, participates in Salmonella phagocytosis via actin dynamics, interacts with PKD2 at the Golgi and with nuclear BRAFV600E in thyroid cancer, supports autophagosome formation through CORO1C-dependent branched actin assembly, and its activity is regulated post-translationally by lysine 2-hydroxyisobutyrylation at K42 (written/erased by SIRT1/HDAC1), with reduced K42-Khib activating the TAK1-MK2-HSP27 pathway to drive keratinocyte hyperproliferation in psoriasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTR3 (ARP3) is a core subunit of the Arp2/3 complex that nucleates branched actin filament networks underlying cell-edge protrusion and motility [#0]. Conditional loss of Actr3 abolishes functional Arp2/3 expression, eliminates lamellipodia and membrane ruffling, slows peripheral actin turnover, and degrades directional and collective migration; cells compensate by upregulating FMNL2/3 formins and switching to filopodia-based protrusion, revealing antagonistic balance between Arp2/3- and formin-based actin networks [#0]. This branched-actin function is co-opted in several cellular contexts: ACTR3 is required for Salmonella phagocytosis in macrophages [#6], and the Arp2/3 complex partners with CORO1C to assemble branched actin needed for p62/SQSTM1 body formation and autophagosome integrity during macroautophagy [#7]. In cancer, ACTR3 promotes migration, invasion, and epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma [#3], physically associates with nuclear BRAFV600E in thyroid cancer where it correlates with aggressive disease and vemurafenib resistance [#1], and is engaged by PKD2 at the Golgi and in the cytosol [#2]. ACTR3 activity is tuned post-translationally: lysine 2-hydroxyisobutyrylation at K42, controlled by SIRT1 and HDAC1, is reduced in psoriatic skin, and loss of this modification activates the TAK1-MK2-HSP27 pathway to drive keratinocyte hyperproliferation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether ACTR3, as part of the intact Arp2/3 complex, engages specific upstream regulators at defined organelles was unresolved; this work placed the complex in direct contact with a signaling kinase at the Golgi.\",\n      \"evidence\": \"Affinity enrichment with chemical cross-linking/mass spectrometry and subcellular fractionation showing PKD2 binding to the seven-subunit Arp2/3 complex including ACTR3\",\n      \"pmids\": [\"27559607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the PKD2-Arp2/3 interaction not established\", \"Whether ACTR3 is a direct contact point versus a complex-level interaction unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unclear which actin machinery components are essential for bacterial internalization in macrophages; an unbiased screen placed ACTR3 in the actin dynamics pathway required for phagocytosis.\",\n      \"evidence\": \"Genome-wide CRISPR knockout screen in THP-1 macrophages with validation that ACTR3 loss confers Salmonella uptake resistance\",\n      \"pmids\": [\"31594818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic step of phagocytic actin remodeling that requires ACTR3 not dissected\", \"Upstream nucleation-promoting factors not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The cell-biological consequences of removing ACTR3 had not been cleanly defined genetically; conditional knockout established its non-redundant role in lamellipodial actin and revealed compensatory formin upregulation.\",\n      \"evidence\": \"Tamoxifen-inducible Actr3 knockout mouse fibroblasts with immunofluorescence, FRAP, and live-cell migration/chemotaxis assays\",\n      \"pmids\": [\"33598464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for FMNL2/3 induction upon Arp2/3 loss not defined\", \"Phenotypes characterized in fibroblasts; cell-type generality not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether ACTR3 contributes to cancer cell aggressiveness was open; knockdown in PDAC linked it to invasion and EMT.\",\n      \"evidence\": \"siRNA knockdown in PDAC cell lines with transwell invasion assays, EMT marker Western blots, and F-actin staining\",\n      \"pmids\": [\"34790395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EMT changes are a direct consequence of actin nucleation or downstream signaling unresolved\", \"In vivo validation absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Upstream regulators of ACTR3 abundance were poorly mapped; LUZP1 loss and miR-486-5p were reported to alter ACTR3 levels.\",\n      \"evidence\": \"CRISPR Luzp1 knockout in fibroblasts with Western blotting for ACTR3 and phospho-cofilin; separately, miR-486-5p transfection and exosomal tracking in gastric cancer-associated mesothelial cells\",\n      \"pmids\": [\"33869174\", \"34686196\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ACTR3 changes are indirect readouts with no direct functional manipulation of ACTR3\", \"Direct versus indirect regulation not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-cytoskeletal, nuclear association for ACTR3 was unknown; proteomics identified it as the top nuclear BRAFV600E partner in thyroid cancer with links to aggressiveness and drug resistance.\",\n      \"evidence\": \"Nuclear/cytosolic fractionation, proteomic analysis of BRAFV600E immunoprecipitates, functional assays, xenografts, and IHC on 100 PTC specimens\",\n      \"pmids\": [\"35968344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which nuclear ACTR3-BRAFV600E drives resistance unresolved\", \"Whether the canonical Arp2/3 complex is involved in the nucleus not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"How ACTR3 activity is tuned post-translationally and links to inflammatory disease was unknown; a site-specific Khib modification at K42 was shown to gate keratinocyte proliferation via a defined kinase pathway.\",\n      \"evidence\": \"Khib profiling by mass spectrometry of human skin, K42A mutation in an IMQ-induced psoriatic mouse model, SIRT1/HDAC1 manipulation, and TAK1 antagonist rescue\",\n      \"pmids\": [\"42089462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K42-Khib alters actin nucleation biochemically not resolved\", \"Link between K42 modification status and TAK1-MK2-HSP27 activation mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether branched actin contributes to autophagosome biogenesis was unclear; CORO1C was shown to bridge the ARP2-ARP3 complex to branched actin assembly required for p62 body formation and autophagosome integrity.\",\n      \"evidence\": \"Genome-wide screen in mouse haploid ESCs, CORO1C-ACTR2/ACTR3 interaction studies, and coro1c-/- mouse autophagy phenotyping by TEM and immunofluorescence\",\n      \"pmids\": [\"41968673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ACTR3's specific role inferred from CORO1C-Arp2/3 interaction rather than direct ACTR3 manipulation\", \"Site of branched actin assembly relative to the autophagosome not pinpointed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACTR3's single actin-nucleation activity is differentially deployed and regulated across migration, phagocytosis, autophagy, nuclear signaling, and disease contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking K42-Khib to nucleation activity\", \"Context-specific nucleation-promoting factors not systematically mapped\", \"Non-canonical nuclear function not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"Arp2/3 complex\"],\n    \"partners\": [\"ACTR2\", \"CORO1C\", \"PKD2\", \"BRAF\", \"LUZP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}