{"gene":"ACTR2","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1994,"finding":"ACTR2 (type 2 activin receptor) forms a high-affinity heterotrimeric receptor complex on vascular endothelial cell surfaces with activin-binding proteins characteristic of type 1 and type 3 activin receptors. Complex formation does not require the kinase domain of ACTR2. Two classes of 125I-activin-A binding sites were identified: high affinity (Kd ~250 pM) and low affinity (Kd ~6.5–16 nM). Affinity labeling revealed labeled species of 55, 95, 100, and 160 kDa, all immunoprecipitated by anti-ACTR2 antibody.","method":"125I-activin-A affinity labeling, immunoprecipitation with anti-ACTR2 monoclonal antibody, transfection of full-length and kinase-dead truncated ACTR2 constructs in bovine aortic endothelial cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding assay with mutagenesis (kinase domain truncation), reciprocal immunoprecipitation, single lab but multiple orthogonal methods","pmids":["8307945"],"is_preprint":false},{"year":2021,"finding":"PTENε (PTEN5), a novel N-terminal-extended PTEN isoform, physically associates with and dephosphorylates ACTR2, governing filopodia formation and cell motility. Endogenous depletion of PTENε promotes filopodia formation and enhances metastasis of tumor cells.","method":"Co-immunoprecipitation, phosphatase assay (in vitro dephosphorylation of ACTR2), loss-of-function with filopodia and metastasis phenotypic readouts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP demonstrating physical association, in vitro dephosphorylation assay, loss-of-function with defined cellular phenotype, single lab but multiple orthogonal methods","pmids":["33755220"],"is_preprint":false},{"year":2020,"finding":"PLK4 drives recruitment of CEP85 and STIL to the leading edge of migrating cells, and downregulation of CEP85 and STIL leads to reduced ARP2 (ACTR2) phosphorylation and reorganization of the actin cytoskeleton, impairing directional cell migration.","method":"siRNA knockdown of CEP85/STIL, phosphorylation assay for ACTR2, live-cell migration assays, mutational analysis of CEP85-STIL-PLK4 interactions","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phosphorylation readout and migration phenotype, single lab, multiple methods","pmids":["32107292"],"is_preprint":false},{"year":2022,"finding":"YAP/TAZ mechanotransduction directly transcriptionally regulates ACTR2, which is involved in building the peri-nuclear actin cap; loss of YAP/TAZ reduces ACTR2 expression, compromises nuclear envelope integrity, and unleashes cGAS-STING signaling leading to tissue senescence.","method":"Genetic inactivation of YAP/TAZ in stromal cells, transcriptional reporter and ChIP assays for direct regulation of ACTR2, nuclear envelope integrity assays, STING inhibition rescue experiments","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular and cellular phenotypes, direct transcriptional regulation evidence, single lab but multiple orthogonal methods","pmids":["35768505"],"is_preprint":false},{"year":2017,"finding":"An Actr2 point mutation (p.R258G) identified in a sensitized ENU mutagenesis screen is associated with suppression of lethal thrombosis in Factor V Leiden/Tfpi haploinsufficient mice, suggesting ACTR2 plays a role in thrombosis regulation. Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism for the p.R258G variant.","method":"ENU mutagenesis screen, whole-exome sequencing, CRISPR/Cas9 knockin/knockout to generate independent Actr2 alleles, genetic epistasis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by mutagenesis screen, validated by independent CRISPR allele, single lab, two orthogonal genetic methods","pmids":["28827327"],"is_preprint":false},{"year":2016,"finding":"Loss of A-type lamins (LMNA knockdown) leads to reduced levels of ACTR2/3 (ARP2/3 complex subunits), reduced focal adhesion size, decreased early cell adhesion, and increased cell motility. Chemical inhibition of the ARP2/3 complex partly recapitulates the lamin-loss phenotype, placing ACTR2 downstream of nuclear lamina integrity in regulating focal adhesion dynamics.","method":"siRNA-mediated LMNA knockdown, quantitative stable isotope labeling-based shotgun proteomics, quantitative immunofluorescence of focal adhesions, traction force microscopy, ARP2/3 complex chemical inhibition","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional validation with chemical inhibitor rescue, single lab, multiple orthogonal methods","pmids":["27791462"],"is_preprint":false},{"year":2023,"finding":"ACTR2 (ARP2) is a cellular binding partner of rotavirus VP4 that promotes viral replication in intestinal cells. Knockdown of ACTR2 reduced RV replication, antibody blocking and recombinant protein overexpression further confirmed that ACTR2 promotes RV entry/replication.","method":"Proximity labeling (BioID), siRNA knockdown, antibody blocking, recombinant protein overexpression, viral binding assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling identification followed by knockdown and overexpression validation, single lab, multiple orthogonal methods","pmids":["37991368"],"is_preprint":false},{"year":2024,"finding":"In mouse oocyte meiosis, PLD1 maintains ACTR2 levels and local distribution on MTOC, spindle, and vesicles; overexpression of ACTR2 rescues MTOC clustering, spindle assembly, and asymmetric spindle positioning in PLD1-depleted oocytes, placing ACTR2 downstream of PLD1 in regulating meiotic spindle dynamics.","method":"PLD1 genetic/chemical inhibition, overexpression of ACTR2 in PLD1-depleted oocytes, immunofluorescence for spindle and MTOC markers, proximity ligation assay for PLD1-ACTR2 interaction","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue by ACTR2 overexpression in loss-of-function context with defined cellular phenotype, PLA for interaction, single lab multiple methods","pmids":["38513669"],"is_preprint":false},{"year":2025,"finding":"CRLF3 physically binds ACTR2 (demonstrated by co-immunoprecipitation) and this interaction promotes proliferation, migration, and immune escape of hepatocellular carcinoma cells. Knockdown of CRLF3 increased CD8+ T cell effector function, and overexpression of ACTR2 reversed this effect, indicating CRLF3 acts through ACTR2 to suppress anti-tumor immunity.","method":"Co-immunoprecipitation, siRNA knockdown of CRLF3 and overexpression of ACTR2, MTT/colony assays, Transwell migration/invasion assays, flow cytometry for CD8+ T cell markers, xenograft mouse model","journal":"Cytotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction, epistasis rescue experiment with ACTR2 overexpression, single lab, multiple orthogonal methods","pmids":["40469577"],"is_preprint":false},{"year":2025,"finding":"KLF5 promotes ITCH transcription, and ITCH-mediated ubiquitination of ACTR2 leads to its degradation. KLF5 overexpression attenuates ACTR2-driven autophagy, apoptosis, and inflammation in adriamycin-injured podocytes. ACTR2 silencing reverses ADR-induced apoptosis and reduces autophagy markers, demonstrating ACTR2 as a promoter of excessive autophagy and podocyte injury downstream of the KLF5/ITCH axis.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, siRNA knockdown and overexpression, Western blot for autophagy markers, flow cytometry for apoptosis, ADR rat model","journal":"The Tohoku journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, ChIP, luciferase) establishing ubiquitination axis, single lab","pmids":["41062301"],"is_preprint":false},{"year":2022,"finding":"ACTR2 knockdown inhibits malignant behaviors of diffuse large B-cell lymphoma (DLBCL) cells, while ACTR2 overexpression promotes them. ACTR2 activates Wnt signaling in DLBCL, and its oncogenic influence is mediated through this pathway, confirmed in vitro and in vivo.","method":"siRNA knockdown and overexpression of ACTR2 in DLBCL cell lines, Wnt pathway reporter assays, xenograft mouse model","journal":"Computational and mathematical methods in medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function and gain-of-function with pathway reporter, single lab, limited mechanistic detail in abstract","pmids":["36570337"],"is_preprint":false},{"year":2016,"finding":"PKD2 (protein kinase D2) physically interacts with the entire seven-subunit Arp2/3 complex including ACTR2 and ACTR3, as identified by chemical cross-linking/mass spectrometry from Golgi-enriched subcellular fractions, providing evidence of a direct PKD2–Arp2/3 protein-protein interaction.","method":"Affinity enrichment, chemical cross-linking/mass spectrometry from cytosolic and Golgi-enriched subcellular fractions","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cross-linking MS identification without functional follow-up for ACTR2 specifically","pmids":["27559607"],"is_preprint":false},{"year":2024,"finding":"In bladder cancer, ACTR2/ARP2 is upregulated and forms part of the CTTN-ARP2 axis driving lamellipodia formation; sulforaphane (SFN) causes lamellipodia collapse by blocking the CTTN-ARP2 axis and downregulating ACTR2/ARP2 expression, suppressing bladder cancer metastasis in vivo.","method":"Overexpression of AKT1, cell morphology assays, bioluminescent imaging of lung metastases in nude mice, Western blot and qPCR for CTTN and ARP2","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological intervention with downstream marker readout, single lab, limited direct mechanistic dissection of ACTR2 specifically","pmids":["39084455"],"is_preprint":false},{"year":2024,"finding":"In anal fistula wound healing, IL-6+ macrophages promote WASF3 expression in fibroblasts which recruits ACTR2 (ARP2), facilitating fibroblast migration via JAK2/STAT3 signaling; this intercellular communication is modulated by Calvatia lilacina treatment.","method":"Single-cell RNA sequencing, cell co-culture, immunofluorescence, Western blot, flow cytometry","journal":"Chinese medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — scRNA-seq identification with limited direct functional validation of ACTR2 specifically, single lab","pmids":["41495793"],"is_preprint":false},{"year":2024,"finding":"CORO1C interacts with ACTR2/ARP2-ACTR3/ARP3 complex; this interaction is essential for branched actin network assembly, SQSTM1/p62 body formation, and autophagosome structural integrity in mammalian cells.","method":"Genome-wide loss-of-function screen, Co-immunoprecipitation, autophagy assays, electron microscopy, coro1c knockout mice","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ACTR2 mentioned as interaction partner of CORO1C without direct functional dissection of ACTR2 itself, single lab","pmids":["41968673"],"is_preprint":false},{"year":2024,"finding":"GJA1/Cx43 promotes exocytosis of damaged lysosomes through a mechanism that relies on ACTR2/ARP2-ACTR3/ARP3-dependent actin remodeling.","method":"Live imaging, siRNA knockdown, lysosomal damage assays, actin remodeling assays","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ACTR2 role inferred from ARP2/3-dependent actin remodeling without direct ACTR2-specific manipulation described in abstract, single lab","pmids":["39394955"],"is_preprint":false},{"year":2022,"finding":"Nuclear BRAFV600E interacts with Arp2/3 complex members including ACTR2 (ARP2) as identified by proteomic analysis; this nuclear interaction is associated with aggressive phenotypes and vemurafenib resistance in papillary thyroid cancer.","method":"Nuclear localization signal (NLS) BRAFV600E constructs, proteomic analysis of nuclear BRAFV600E binding partners, xenograft mouse model, IHC of PTC specimens","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic identification of interaction without direct functional follow-up specific to ACTR2, single lab","pmids":["35968344"],"is_preprint":false}],"current_model":"ACTR2 (ARP2, actin-related protein 2) is a core component of the ARP2/3 complex that nucleates branched actin networks; mechanistically it is regulated by PTENε-mediated dephosphorylation and PLK4-CEP85-STIL-driven phosphorylation to control filopodia/lamellipodia formation and directional cell migration, is transcriptionally regulated by YAP/TAZ to maintain the peri-nuclear actin cap and nuclear envelope integrity (suppressing cGAS-STING senescence signaling), is subject to ITCH-mediated ubiquitin-dependent degradation downstream of KLF5 to limit autophagy in podocytes, physically associates with CRLF3 to promote hepatocellular carcinoma immune escape, interacts with rotavirus VP4 to promote viral replication, and in its original biochemical context forms a high-affinity heterotrimeric signaling complex with type 1 and type 3 activin receptors on endothelial cell surfaces."},"narrative":{"mechanistic_narrative":"ACTR2 (ARP2) is a core subunit of the ARP2/3 complex that nucleates branched actin networks underlying cell migration, adhesion, and membrane protrusion [PMID:27791462, PMID:41968673]. Its actin-organizing output is tuned by opposing post-translational inputs: PTENε physically associates with and dephosphorylates ACTR2 to restrain filopodia formation and tumor cell metastasis [PMID:33755220], whereas a PLK4-CEP85-STIL module drives ACTR2 phosphorylation at the leading edge to support directional migration [PMID:32107292]. ACTR2 abundance is controlled at multiple levels — YAP/TAZ mechanotransduction directly activates ACTR2 transcription to build the peri-nuclear actin cap and preserve nuclear envelope integrity, thereby restraining cGAS-STING-driven senescence [PMID:35768505], while a KLF5/ITCH axis targets ACTR2 for ubiquitin-dependent degradation to limit excessive autophagy and injury in podocytes [PMID:41062301]. ACTR2-nucleated actin networks are integral to focal adhesion dynamics downstream of the nuclear lamina [PMID:27791462] and to branched-actin-dependent autophagosome assembly [PMID:41968673]. Beyond its cytoskeletal role, ACTR2 was originally characterized as a kinase-independent component of a high-affinity heterotrimeric activin receptor complex on endothelial cells [PMID:8307945], and its function is co-opted in disease, serving as a binding partner of rotavirus VP4 to promote viral replication [PMID:37991368] and acting downstream of CRLF3 to promote hepatocellular carcinoma immune escape [PMID:40469577]. Actr2 haploinsufficiency is lethal in mice, underscoring its essentiality [PMID:28827327].","teleology":[{"year":1994,"claim":"Established ACTR2's earliest molecular identity by showing it participates in a high-affinity activin receptor complex independent of its kinase domain, defining a non-catalytic mode of complex assembly.","evidence":"125I-activin-A affinity labeling and reciprocal immunoprecipitation with full-length and kinase-dead ACTR2 constructs in bovine aortic endothelial cells","pmids":["8307945"],"confidence":"High","gaps":["Does not connect this receptor role to the later-defined ARP2/3 actin-nucleation function","Downstream signaling consequences not resolved"]},{"year":2016,"claim":"Placed ACTR2 downstream of nuclear lamina integrity, linking ARP2/3-dependent actin assembly to focal adhesion size and cell motility control.","evidence":"LMNA siRNA knockdown with quantitative proteomics, focal adhesion immunofluorescence, traction force microscopy, and ARP2/3 chemical inhibitor rescue","pmids":["27791462"],"confidence":"Medium","gaps":["Mechanism linking lamina loss to ARP2/3 subunit reduction unresolved","ACTR2-specific contribution not separated from the whole complex"]},{"year":2017,"claim":"Demonstrated ACTR2 essentiality and a role in thrombosis regulation via genetic epistasis, distinguishing a hypomorphic/gain-of-function point allele from lethal haploinsufficiency.","evidence":"ENU mutagenesis screen with whole-exome sequencing and independent CRISPR/Cas9 alleles in Factor V Leiden/Tfpi mice","pmids":["28827327"],"confidence":"Medium","gaps":["Molecular mechanism by which p.R258G suppresses thrombosis unknown","Cellular pathway connecting ACTR2 to coagulation not defined"]},{"year":2020,"claim":"Identified a kinase-driven activating input on ACTR2 by showing PLK4-recruited CEP85/STIL promote ACTR2 phosphorylation needed for directional migration.","evidence":"siRNA knockdown of CEP85/STIL with ACTR2 phosphorylation assays, live-cell migration assays, and interaction mutagenesis","pmids":["32107292"],"confidence":"Medium","gaps":["Phosphorylation site on ACTR2 not mapped","Whether PLK4 directly phosphorylates ACTR2 not established"]},{"year":2021,"claim":"Defined an opposing dephosphorylation input, showing PTENε directly dephosphorylates ACTR2 to restrain filopodia formation and metastasis.","evidence":"Co-immunoprecipitation, in vitro dephosphorylation assay, and loss-of-function with filopodia and metastasis readouts","pmids":["33755220"],"confidence":"High","gaps":["Phospho-residues controlled by PTENε not identified","Interplay with the PLK4/CEP85/STIL phosphorylation axis untested"]},{"year":2022,"claim":"Connected ACTR2 transcriptional control to nuclear mechanics, showing YAP/TAZ directly drives ACTR2 expression to maintain the peri-nuclear actin cap and suppress cGAS-STING senescence.","evidence":"Genetic YAP/TAZ inactivation, transcriptional reporter and ChIP for direct ACTR2 regulation, nuclear envelope integrity assays, STING inhibition rescue","pmids":["35768505"],"confidence":"Medium","gaps":["Whether actin cap defect is solely ACTR2-dependent not isolated","Quantitative contribution of ACTR2 versus other YAP/TAZ targets unclear"]},{"year":2023,"claim":"Revealed pathogen co-option of ACTR2, identifying it as a VP4-binding partner required for rotavirus replication.","evidence":"BioID proximity labeling, siRNA knockdown, antibody blocking, recombinant protein overexpression, and viral binding assays","pmids":["37991368"],"confidence":"Medium","gaps":["Step of viral life cycle requiring ACTR2 (entry vs replication) not fully resolved","Whether ARP2/3 actin nucleation mediates the effect untested"]},{"year":2024,"claim":"Extended ACTR2's reach to meiotic spindle dynamics, placing it downstream of PLD1 in regulating MTOC clustering and asymmetric spindle positioning.","evidence":"PLD1 inhibition with ACTR2 overexpression rescue, spindle/MTOC immunofluorescence, and PLD1-ACTR2 proximity ligation in mouse oocytes","pmids":["38513669"],"confidence":"Medium","gaps":["Whether PLD1-ACTR2 association is direct not established","Mechanism by which PLD1 maintains ACTR2 levels unclear"]},{"year":2025,"claim":"Defined a degradative control axis, showing KLF5-induced ITCH ubiquitinates ACTR2 to limit ACTR2-driven autophagy and podocyte injury.","evidence":"Co-IP, ChIP, dual-luciferase reporter, knockdown/overexpression, autophagy and apoptosis assays, ADR rat model","pmids":["41062301"],"confidence":"Medium","gaps":["Ubiquitination sites on ACTR2 not mapped","How ACTR2 promotes autophagy mechanistically not defined"]},{"year":2025,"claim":"Implicated ACTR2 in tumor immune evasion, showing CRLF3 binds ACTR2 to suppress CD8+ T cell effector function in hepatocellular carcinoma.","evidence":"Co-immunoprecipitation, CRLF3 knockdown with ACTR2 overexpression rescue, proliferation/migration assays, flow cytometry, and xenografts","pmids":["40469577"],"confidence":"Medium","gaps":["Mechanism linking ACTR2 to immune escape signaling not defined","Whether actin nucleation is required for immune effect untested"]},{"year":null,"claim":"How the competing phosphorylation, dephosphorylation, transcriptional, and ubiquitin-degradation inputs are integrated to set ACTR2 activity in a given cellular context remains unresolved.","evidence":"No single study reconciles the PLK4/CEP85/STIL, PTENε, YAP/TAZ, and KLF5/ITCH regulatory layers","pmids":[],"confidence":"Low","gaps":["No unified model of ACTR2 regulatory hierarchy","Phospho-sites and ubiquitination sites remain unmapped","Structural basis of regulation within the ARP2/3 complex not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,14]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,12]}],"pathway":[],"complexes":["ARP2/3 complex"],"partners":["ACTR3","PTENΕ","CEP85","STIL","CRLF3","ITCH","CORO1C","WASF3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61160","full_name":"Actin-related protein 2","aliases":["Actin-like protein 2"],"length_aa":394,"mass_kda":44.8,"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)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection; Nucleus","url":"https://www.uniprot.org/uniprotkb/P61160/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTR2","classification":"Common 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DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 9; CDCBM9","url":"https://www.omim.org/entry/618174"},{"mim_id":"605952","title":"SORTING NEXIN 9; SNX9","url":"https://www.omim.org/entry/605952"},{"mim_id":"605144","title":"ACTIN-RELATED PROTEIN 1B; ACTR1B","url":"https://www.omim.org/entry/605144"},{"mim_id":"604227","title":"ACTIN-RELATED PROTEIN 2/3 COMPLEX, SUBUNIT 5; ARPC5","url":"https://www.omim.org/entry/604227"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACTR2"},"hgnc":{"alias_symbol":["ARP2"],"prev_symbol":[]},"alphafold":{"accession":"P61160","domains":[{"cath_id":"3.30.420.40","chopping":"153-183_276-349","consensus_level":"medium","plddt":95.5984,"start":153,"end":349},{"cath_id":"3.90.640.10","chopping":"185-264","consensus_level":"high","plddt":94.8261,"start":185,"end":264},{"cath_id":"3.40.5","chopping":"35-71","consensus_level":"medium","plddt":86.5638,"start":35,"end":71}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61160","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61160-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61160-F1-predicted_aligned_error_v6.png","plddt_mean":93.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTR2","jax_strain_url":"https://www.jax.org/strain/search?query=ACTR2"},"sequence":{"accession":"P61160","fasta_url":"https://rest.uniprot.org/uniprotkb/P61160.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61160/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61160"}},"corpus_meta":[{"pmid":"35768505","id":"PMC_35768505","title":"YAP/TAZ 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Complex formation does not require the kinase domain of ACTR2. Two classes of 125I-activin-A binding sites were identified: high affinity (Kd ~250 pM) and low affinity (Kd ~6.5–16 nM). Affinity labeling revealed labeled species of 55, 95, 100, and 160 kDa, all immunoprecipitated by anti-ACTR2 antibody.\",\n      \"method\": \"125I-activin-A affinity labeling, immunoprecipitation with anti-ACTR2 monoclonal antibody, transfection of full-length and kinase-dead truncated ACTR2 constructs in bovine aortic endothelial cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding assay with mutagenesis (kinase domain truncation), reciprocal immunoprecipitation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8307945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTENε (PTEN5), a novel N-terminal-extended PTEN isoform, physically associates with and dephosphorylates ACTR2, governing filopodia formation and cell motility. Endogenous depletion of PTENε promotes filopodia formation and enhances metastasis of tumor cells.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase assay (in vitro dephosphorylation of ACTR2), loss-of-function with filopodia and metastasis phenotypic readouts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP demonstrating physical association, in vitro dephosphorylation assay, loss-of-function with defined cellular phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33755220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLK4 drives recruitment of CEP85 and STIL to the leading edge of migrating cells, and downregulation of CEP85 and STIL leads to reduced ARP2 (ACTR2) phosphorylation and reorganization of the actin cytoskeleton, impairing directional cell migration.\",\n      \"method\": \"siRNA knockdown of CEP85/STIL, phosphorylation assay for ACTR2, live-cell migration assays, mutational analysis of CEP85-STIL-PLK4 interactions\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phosphorylation readout and migration phenotype, single lab, multiple methods\",\n      \"pmids\": [\"32107292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"YAP/TAZ mechanotransduction directly transcriptionally regulates ACTR2, which is involved in building the peri-nuclear actin cap; loss of YAP/TAZ reduces ACTR2 expression, compromises nuclear envelope integrity, and unleashes cGAS-STING signaling leading to tissue senescence.\",\n      \"method\": \"Genetic inactivation of YAP/TAZ in stromal cells, transcriptional reporter and ChIP assays for direct regulation of ACTR2, nuclear envelope integrity assays, STING inhibition rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular and cellular phenotypes, direct transcriptional regulation evidence, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35768505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An Actr2 point mutation (p.R258G) identified in a sensitized ENU mutagenesis screen is associated with suppression of lethal thrombosis in Factor V Leiden/Tfpi haploinsufficient mice, suggesting ACTR2 plays a role in thrombosis regulation. Actr2 haploinsufficiency is lethal, supporting a hypomorphic or gain-of-function mechanism for the p.R258G variant.\",\n      \"method\": \"ENU mutagenesis screen, whole-exome sequencing, CRISPR/Cas9 knockin/knockout to generate independent Actr2 alleles, genetic epistasis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by mutagenesis screen, validated by independent CRISPR allele, single lab, two orthogonal genetic methods\",\n      \"pmids\": [\"28827327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of A-type lamins (LMNA knockdown) leads to reduced levels of ACTR2/3 (ARP2/3 complex subunits), reduced focal adhesion size, decreased early cell adhesion, and increased cell motility. Chemical inhibition of the ARP2/3 complex partly recapitulates the lamin-loss phenotype, placing ACTR2 downstream of nuclear lamina integrity in regulating focal adhesion dynamics.\",\n      \"method\": \"siRNA-mediated LMNA knockdown, quantitative stable isotope labeling-based shotgun proteomics, quantitative immunofluorescence of focal adhesions, traction force microscopy, ARP2/3 complex chemical inhibition\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional validation with chemical inhibitor rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27791462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACTR2 (ARP2) is a cellular binding partner of rotavirus VP4 that promotes viral replication in intestinal cells. Knockdown of ACTR2 reduced RV replication, antibody blocking and recombinant protein overexpression further confirmed that ACTR2 promotes RV entry/replication.\",\n      \"method\": \"Proximity labeling (BioID), siRNA knockdown, antibody blocking, recombinant protein overexpression, viral binding assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling identification followed by knockdown and overexpression validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37991368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In mouse oocyte meiosis, PLD1 maintains ACTR2 levels and local distribution on MTOC, spindle, and vesicles; overexpression of ACTR2 rescues MTOC clustering, spindle assembly, and asymmetric spindle positioning in PLD1-depleted oocytes, placing ACTR2 downstream of PLD1 in regulating meiotic spindle dynamics.\",\n      \"method\": \"PLD1 genetic/chemical inhibition, overexpression of ACTR2 in PLD1-depleted oocytes, immunofluorescence for spindle and MTOC markers, proximity ligation assay for PLD1-ACTR2 interaction\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue by ACTR2 overexpression in loss-of-function context with defined cellular phenotype, PLA for interaction, single lab multiple methods\",\n      \"pmids\": [\"38513669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRLF3 physically binds ACTR2 (demonstrated by co-immunoprecipitation) and this interaction promotes proliferation, migration, and immune escape of hepatocellular carcinoma cells. Knockdown of CRLF3 increased CD8+ T cell effector function, and overexpression of ACTR2 reversed this effect, indicating CRLF3 acts through ACTR2 to suppress anti-tumor immunity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of CRLF3 and overexpression of ACTR2, MTT/colony assays, Transwell migration/invasion assays, flow cytometry for CD8+ T cell markers, xenograft mouse model\",\n      \"journal\": \"Cytotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction, epistasis rescue experiment with ACTR2 overexpression, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40469577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLF5 promotes ITCH transcription, and ITCH-mediated ubiquitination of ACTR2 leads to its degradation. KLF5 overexpression attenuates ACTR2-driven autophagy, apoptosis, and inflammation in adriamycin-injured podocytes. ACTR2 silencing reverses ADR-induced apoptosis and reduces autophagy markers, demonstrating ACTR2 as a promoter of excessive autophagy and podocyte injury downstream of the KLF5/ITCH axis.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, siRNA knockdown and overexpression, Western blot for autophagy markers, flow cytometry for apoptosis, ADR rat model\",\n      \"journal\": \"The Tohoku journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (Co-IP, ChIP, luciferase) establishing ubiquitination axis, single lab\",\n      \"pmids\": [\"41062301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTR2 knockdown inhibits malignant behaviors of diffuse large B-cell lymphoma (DLBCL) cells, while ACTR2 overexpression promotes them. ACTR2 activates Wnt signaling in DLBCL, and its oncogenic influence is mediated through this pathway, confirmed in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown and overexpression of ACTR2 in DLBCL cell lines, Wnt pathway reporter assays, xenograft mouse model\",\n      \"journal\": \"Computational and mathematical methods in medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function and gain-of-function with pathway reporter, single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"36570337\"],\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 ACTR2 and ACTR3, as identified by chemical cross-linking/mass spectrometry from Golgi-enriched subcellular fractions, providing evidence of a direct PKD2–Arp2/3 protein-protein interaction.\",\n      \"method\": \"Affinity enrichment, chemical cross-linking/mass spectrometry from cytosolic and Golgi-enriched subcellular fractions\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cross-linking MS identification without functional follow-up for ACTR2 specifically\",\n      \"pmids\": [\"27559607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In bladder cancer, ACTR2/ARP2 is upregulated and forms part of the CTTN-ARP2 axis driving lamellipodia formation; sulforaphane (SFN) causes lamellipodia collapse by blocking the CTTN-ARP2 axis and downregulating ACTR2/ARP2 expression, suppressing bladder cancer metastasis in vivo.\",\n      \"method\": \"Overexpression of AKT1, cell morphology assays, bioluminescent imaging of lung metastases in nude mice, Western blot and qPCR for CTTN and ARP2\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological intervention with downstream marker readout, single lab, limited direct mechanistic dissection of ACTR2 specifically\",\n      \"pmids\": [\"39084455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In anal fistula wound healing, IL-6+ macrophages promote WASF3 expression in fibroblasts which recruits ACTR2 (ARP2), facilitating fibroblast migration via JAK2/STAT3 signaling; this intercellular communication is modulated by Calvatia lilacina treatment.\",\n      \"method\": \"Single-cell RNA sequencing, cell co-culture, immunofluorescence, Western blot, flow cytometry\",\n      \"journal\": \"Chinese medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — scRNA-seq identification with limited direct functional validation of ACTR2 specifically, single lab\",\n      \"pmids\": [\"41495793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CORO1C interacts with ACTR2/ARP2-ACTR3/ARP3 complex; this interaction is essential for branched actin network assembly, SQSTM1/p62 body formation, and autophagosome structural integrity in mammalian cells.\",\n      \"method\": \"Genome-wide loss-of-function screen, Co-immunoprecipitation, autophagy assays, electron microscopy, coro1c knockout mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ACTR2 mentioned as interaction partner of CORO1C without direct functional dissection of ACTR2 itself, single lab\",\n      \"pmids\": [\"41968673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GJA1/Cx43 promotes exocytosis of damaged lysosomes through a mechanism that relies on ACTR2/ARP2-ACTR3/ARP3-dependent actin remodeling.\",\n      \"method\": \"Live imaging, siRNA knockdown, lysosomal damage assays, actin remodeling assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ACTR2 role inferred from ARP2/3-dependent actin remodeling without direct ACTR2-specific manipulation described in abstract, single lab\",\n      \"pmids\": [\"39394955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear BRAFV600E interacts with Arp2/3 complex members including ACTR2 (ARP2) as identified by proteomic analysis; this nuclear interaction is associated with aggressive phenotypes and vemurafenib resistance in papillary thyroid cancer.\",\n      \"method\": \"Nuclear localization signal (NLS) BRAFV600E constructs, proteomic analysis of nuclear BRAFV600E binding partners, xenograft mouse model, IHC of PTC specimens\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic identification of interaction without direct functional follow-up specific to ACTR2, single lab\",\n      \"pmids\": [\"35968344\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTR2 (ARP2, actin-related protein 2) is a core component of the ARP2/3 complex that nucleates branched actin networks; mechanistically it is regulated by PTENε-mediated dephosphorylation and PLK4-CEP85-STIL-driven phosphorylation to control filopodia/lamellipodia formation and directional cell migration, is transcriptionally regulated by YAP/TAZ to maintain the peri-nuclear actin cap and nuclear envelope integrity (suppressing cGAS-STING senescence signaling), is subject to ITCH-mediated ubiquitin-dependent degradation downstream of KLF5 to limit autophagy in podocytes, physically associates with CRLF3 to promote hepatocellular carcinoma immune escape, interacts with rotavirus VP4 to promote viral replication, and in its original biochemical context forms a high-affinity heterotrimeric signaling complex with type 1 and type 3 activin receptors on endothelial cell surfaces.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTR2 (ARP2) is a core subunit of the ARP2/3 complex that nucleates branched actin networks underlying cell migration, adhesion, and membrane protrusion [#5, #14]. Its actin-organizing output is tuned by opposing post-translational inputs: PTENε physically associates with and dephosphorylates ACTR2 to restrain filopodia formation and tumor cell metastasis [#1], whereas a PLK4-CEP85-STIL module drives ACTR2 phosphorylation at the leading edge to support directional migration [#2]. ACTR2 abundance is controlled at multiple levels — YAP/TAZ mechanotransduction directly activates ACTR2 transcription to build the peri-nuclear actin cap and preserve nuclear envelope integrity, thereby restraining cGAS-STING-driven senescence [#3], while a KLF5/ITCH axis targets ACTR2 for ubiquitin-dependent degradation to limit excessive autophagy and injury in podocytes [#9]. ACTR2-nucleated actin networks are integral to focal adhesion dynamics downstream of the nuclear lamina [#5] and to branched-actin-dependent autophagosome assembly [#14]. Beyond its cytoskeletal role, ACTR2 was originally characterized as a kinase-independent component of a high-affinity heterotrimeric activin receptor complex on endothelial cells [#0], and its function is co-opted in disease, serving as a binding partner of rotavirus VP4 to promote viral replication [#6] and acting downstream of CRLF3 to promote hepatocellular carcinoma immune escape [#8]. Actr2 haploinsufficiency is lethal in mice, underscoring its essentiality [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established ACTR2's earliest molecular identity by showing it participates in a high-affinity activin receptor complex independent of its kinase domain, defining a non-catalytic mode of complex assembly.\",\n      \"evidence\": \"125I-activin-A affinity labeling and reciprocal immunoprecipitation with full-length and kinase-dead ACTR2 constructs in bovine aortic endothelial cells\",\n      \"pmids\": [\"8307945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not connect this receptor role to the later-defined ARP2/3 actin-nucleation function\", \"Downstream signaling consequences not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ACTR2 downstream of nuclear lamina integrity, linking ARP2/3-dependent actin assembly to focal adhesion size and cell motility control.\",\n      \"evidence\": \"LMNA siRNA knockdown with quantitative proteomics, focal adhesion immunofluorescence, traction force microscopy, and ARP2/3 chemical inhibitor rescue\",\n      \"pmids\": [\"27791462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking lamina loss to ARP2/3 subunit reduction unresolved\", \"ACTR2-specific contribution not separated from the whole complex\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated ACTR2 essentiality and a role in thrombosis regulation via genetic epistasis, distinguishing a hypomorphic/gain-of-function point allele from lethal haploinsufficiency.\",\n      \"evidence\": \"ENU mutagenesis screen with whole-exome sequencing and independent CRISPR/Cas9 alleles in Factor V Leiden/Tfpi mice\",\n      \"pmids\": [\"28827327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which p.R258G suppresses thrombosis unknown\", \"Cellular pathway connecting ACTR2 to coagulation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a kinase-driven activating input on ACTR2 by showing PLK4-recruited CEP85/STIL promote ACTR2 phosphorylation needed for directional migration.\",\n      \"evidence\": \"siRNA knockdown of CEP85/STIL with ACTR2 phosphorylation assays, live-cell migration assays, and interaction mutagenesis\",\n      \"pmids\": [\"32107292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site on ACTR2 not mapped\", \"Whether PLK4 directly phosphorylates ACTR2 not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an opposing dephosphorylation input, showing PTENε directly dephosphorylates ACTR2 to restrain filopodia formation and metastasis.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro dephosphorylation assay, and loss-of-function with filopodia and metastasis readouts\",\n      \"pmids\": [\"33755220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-residues controlled by PTENε not identified\", \"Interplay with the PLK4/CEP85/STIL phosphorylation axis untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ACTR2 transcriptional control to nuclear mechanics, showing YAP/TAZ directly drives ACTR2 expression to maintain the peri-nuclear actin cap and suppress cGAS-STING senescence.\",\n      \"evidence\": \"Genetic YAP/TAZ inactivation, transcriptional reporter and ChIP for direct ACTR2 regulation, nuclear envelope integrity assays, STING inhibition rescue\",\n      \"pmids\": [\"35768505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether actin cap defect is solely ACTR2-dependent not isolated\", \"Quantitative contribution of ACTR2 versus other YAP/TAZ targets unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed pathogen co-option of ACTR2, identifying it as a VP4-binding partner required for rotavirus replication.\",\n      \"evidence\": \"BioID proximity labeling, siRNA knockdown, antibody blocking, recombinant protein overexpression, and viral binding assays\",\n      \"pmids\": [\"37991368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Step of viral life cycle requiring ACTR2 (entry vs replication) not fully resolved\", \"Whether ARP2/3 actin nucleation mediates the effect untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended ACTR2's reach to meiotic spindle dynamics, placing it downstream of PLD1 in regulating MTOC clustering and asymmetric spindle positioning.\",\n      \"evidence\": \"PLD1 inhibition with ACTR2 overexpression rescue, spindle/MTOC immunofluorescence, and PLD1-ACTR2 proximity ligation in mouse oocytes\",\n      \"pmids\": [\"38513669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PLD1-ACTR2 association is direct not established\", \"Mechanism by which PLD1 maintains ACTR2 levels unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a degradative control axis, showing KLF5-induced ITCH ubiquitinates ACTR2 to limit ACTR2-driven autophagy and podocyte injury.\",\n      \"evidence\": \"Co-IP, ChIP, dual-luciferase reporter, knockdown/overexpression, autophagy and apoptosis assays, ADR rat model\",\n      \"pmids\": [\"41062301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on ACTR2 not mapped\", \"How ACTR2 promotes autophagy mechanistically not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ACTR2 in tumor immune evasion, showing CRLF3 binds ACTR2 to suppress CD8+ T cell effector function in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, CRLF3 knockdown with ACTR2 overexpression rescue, proliferation/migration assays, flow cytometry, and xenografts\",\n      \"pmids\": [\"40469577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ACTR2 to immune escape signaling not defined\", \"Whether actin nucleation is required for immune effect untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing phosphorylation, dephosphorylation, transcriptional, and ubiquitin-degradation inputs are integrated to set ACTR2 activity in a given cellular context remains unresolved.\",\n      \"evidence\": \"No single study reconciles the PLK4/CEP85/STIL, PTENε, YAP/TAZ, and KLF5/ITCH regulatory layers\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model of ACTR2 regulatory hierarchy\", \"Phospho-sites and ubiquitination sites remain unmapped\", \"Structural basis of regulation within the ARP2/3 complex not addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"ARP2/3 complex\"],\n    \"partners\": [\"ACTR3\", \"PTENε\", \"CEP85\", \"STIL\", \"CRLF3\", \"ITCH\", \"CORO1C\", \"WASF3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}