{"gene":"ACTR1A","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2019,"finding":"ACTR1A (alpha-centractin), a subunit of the dynactin complex, physically interacts with TLR2 and functions as a regulator of TLR2-mediated pro-inflammatory cytokine induction. The interaction was identified by cross-linking co-immunoprecipitation proteomics and validated by biochemical methods; RNA interference knockdown of ACTR1A reduced pro-inflammatory cytokine induction downstream of TLR2.","method":"Cross-linking co-immunoprecipitation proteomics, biochemical validation (co-IP), RNAi knockdown with cytokine readout","journal":"Molecular & Cellular Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical validation of interaction plus functional RNAi knockdown with defined cytokine phenotype, single lab","pmids":["31221720"],"is_preprint":false},{"year":2025,"finding":"ACTR1A (alpha-centractin) is an in vitro substrate of the SETD3 protein histidine methyltransferase. SETD3 was identified as a proximal interactor of ACTR1A by TurboID proximity labeling, and recombinant SETD3 methylated ACTR1A in a radiochemical in vitro methylation assay, extending SETD3's known substrate repertoire beyond β-actin to this dynactin subunit.","method":"TurboID proximity labeling, mass spectrometry, radiochemical in vitro methylation assay with recombinant SETD3, CRISPR/Cas9 SETD3 knockout cell lines, fluorography","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with recombinant proteins plus proximity labeling, but single lab and in vitro methylation only (no in-cell confirmation of modification site)","pmids":["41142317"],"is_preprint":false}],"current_model":"ACTR1A (alpha-centractin), a core subunit of the dynactin complex, physically associates with TLR2 at the plasma membrane and is required for TLR2-mediated pro-inflammatory cytokine signaling, and is also an in vitro substrate of the SETD3 protein histidine methyltransferase, suggesting that dynein-mediated intracellular transport and cytoskeletal regulation may be modulated through SETD3-dependent methylation of this dynactin subunit."},"narrative":{"mechanistic_narrative":"ACTR1A (alpha-centractin) is a subunit of the dynactin complex that additionally participates in innate immune signaling and is subject to post-translational regulation [PMID:31221720, PMID:41142317]. ACTR1A physically associates with TLR2 and is required for TLR2-mediated pro-inflammatory cytokine induction, since its knockdown reduces cytokine output downstream of the receptor [PMID:31221720]. ACTR1A is also an in vitro substrate of the SETD3 protein histidine methyltransferase, which methylates recombinant ACTR1A and contacts it in cells, extending SETD3's substrate repertoire beyond beta-actin to this dynactin subunit [PMID:41142317]. Beyond these findings, the structural basis of these interactions, the in-cell methylation site, and the link between ACTR1A modification and dynactin function have not been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Established that the dynactin subunit ACTR1A has a role in innate immune signaling by physically engaging TLR2 and being required for downstream cytokine induction, a function not predicted by its cytoskeletal role.","evidence":"Cross-linking co-immunoprecipitation proteomics with biochemical validation and RNAi knockdown read out by pro-inflammatory cytokine induction","pmids":["31221720"],"confidence":"Medium","gaps":["Reciprocal interaction validated in a single lab; direct vs. indirect binding to TLR2 not resolved","Mechanism by which ACTR1A promotes TLR2 signaling (receptor trafficking, scaffolding) not defined","No structural or domain-mapping data for the ACTR1A-TLR2 association"]},{"year":2025,"claim":"Identified ACTR1A as a post-translationally modified target by showing it is methylated in vitro by SETD3, raising the possibility that dynactin function is regulated by histidine methylation.","evidence":"TurboID proximity labeling and mass spectrometry, radiochemical in vitro methylation with recombinant SETD3, and CRISPR/Cas9 SETD3 knockout cell lines","pmids":["41142317"],"confidence":"Medium","gaps":["In vitro methylation only; no in-cell confirmation of the modification or its site","Functional consequence of ACTR1A methylation for dynactin or dynein-mediated transport not tested","Single-lab finding without independent replication"]},{"year":null,"claim":"How ACTR1A's dynactin/cytoskeletal role, its TLR2-associated signaling function, and its SETD3-dependent methylation are mechanistically connected remains unknown.","evidence":"No discovery in the corpus links the methylation event to TLR2 signaling or to dynactin-dependent transport","pmids":[],"confidence":"Low","gaps":["No in-cell methylation site identified","No structural model of ACTR1A interactions","No demonstrated effect of methylation on transport or immune signaling"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["dynactin"],"partners":["TLR2","SETD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61163","full_name":"Alpha-centractin","aliases":["ARP1","Actin-RPV","Centrosome-associated actin homolog"],"length_aa":376,"mass_kda":42.6,"function":"Part of the ACTR1A/ACTB filament around which the dynactin complex is built. The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cell cortex","url":"https://www.uniprot.org/uniprotkb/P61163/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTR1A","classification":"Common Essential","n_dependent_lines":971,"n_total_lines":1208,"dependency_fraction":0.8038079470198676},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":10.0},{"gene":"DCTN2","stoichiometry":10.0},{"gene":"DYNC1LI1","stoichiometry":10.0},{"gene":"CLASP1","stoichiometry":4.0},{"gene":"DYNC1H1","stoichiometry":4.0},{"gene":"DYNC1I2","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CLASP2","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ACTR1A","total_profiled":1310},"omim":[{"mim_id":"619731","title":"ACTIN-RELATED PROTEIN 10; ACTR10","url":"https://www.omim.org/entry/619731"},{"mim_id":"614758","title":"DYNACTIN 4; DCTN4","url":"https://www.omim.org/entry/614758"},{"mim_id":"605144","title":"ACTIN-RELATED PROTEIN 1B; ACTR1B","url":"https://www.omim.org/entry/605144"},{"mim_id":"605143","title":"ACTIN-RELATED PROTEIN 1A; ACTR1A","url":"https://www.omim.org/entry/605143"},{"mim_id":"601143","title":"DYNACTIN 1; DCTN1","url":"https://www.omim.org/entry/601143"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACTR1A"},"hgnc":{"alias_symbol":["ARP1","Arp1A"],"prev_symbol":[]},"alphafold":{"accession":"P61163","domains":[{"cath_id":"3.30.420.40","chopping":"11-38_73-142_339-372","consensus_level":"high","plddt":95.3043,"start":11,"end":372},{"cath_id":"3.30.420.40","chopping":"148-184_273-330","consensus_level":"medium","plddt":96.7509,"start":148,"end":330},{"cath_id":"3.90.640.10","chopping":"186-267","consensus_level":"medium","plddt":93.1743,"start":186,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61163","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61163-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61163-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTR1A","jax_strain_url":"https://www.jax.org/strain/search?query=ACTR1A"},"sequence":{"accession":"P61163","fasta_url":"https://rest.uniprot.org/uniprotkb/P61163.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61163/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61163"}},"corpus_meta":[{"pmid":"18303113","id":"PMC_18303113","title":"Transcriptome sequencing of malignant pleural mesothelioma tumors.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18303113","citation_count":107,"is_preprint":false},{"pmid":"17016645","id":"PMC_17016645","title":"Correlation of glypican-1 expression with TGF-beta, BMP, and activin receptors in pancreatic ductal adenocarcinoma.","date":"2006","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17016645","citation_count":39,"is_preprint":false},{"pmid":"28348047","id":"PMC_28348047","title":"Genome-Wide Association Study Meta-Analysis of Long-Term Average Blood Pressure in East Asians.","date":"2017","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28348047","citation_count":26,"is_preprint":false},{"pmid":"33065998","id":"PMC_33065998","title":"Mutational Profile of Malignant Pleural Mesothelioma (MPM) in the Phase II RAMES Study.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33065998","citation_count":19,"is_preprint":false},{"pmid":"31221720","id":"PMC_31221720","title":"Cross-linking Proteomics Indicates Effects of Simvastatin on the TLR2 Interactome and Reveals ACTR1A as a Novel Regulator of the TLR2 Signal Cascade.","date":"2019","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/31221720","citation_count":16,"is_preprint":false},{"pmid":"31280474","id":"PMC_31280474","title":"Identification of Potential Biomarkers with Diagnostic Value in Pituitary Adenomas Using Prediction Analysis for Microarrays Method.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/31280474","citation_count":11,"is_preprint":false},{"pmid":"26662454","id":"PMC_26662454","title":"Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26662454","citation_count":7,"is_preprint":false},{"pmid":"35882953","id":"PMC_35882953","title":"Reference gene selection in bovine caruncular epithelial cells under pregnancy-associated hormones exposure.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35882953","citation_count":5,"is_preprint":false},{"pmid":"26422100","id":"PMC_26422100","title":"Application of serex-analysis for identification of human colon cancer antigens.","date":"2015","source":"Experimental oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26422100","citation_count":5,"is_preprint":false},{"pmid":"39417182","id":"PMC_39417182","title":"Uncovering the role of FXYD3 as a potential oncogene and early biomarker in pancreatic cancer.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39417182","citation_count":4,"is_preprint":false},{"pmid":"22457812","id":"PMC_22457812","title":"Progesterone receptor activates Msx2 expression by downregulating TNAP/Akp2 and activating the Bmp pathway in EpH4 mouse mammary epithelial cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22457812","citation_count":3,"is_preprint":false},{"pmid":"40951946","id":"PMC_40951946","title":"Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures.","date":"2025","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/40951946","citation_count":1,"is_preprint":false},{"pmid":"41142317","id":"PMC_41142317","title":"Alpha-centractin is a novel substrate of SETD3 methyltransferase in vitro.","date":"2025","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/41142317","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9650,"output_tokens":694,"usd":0.01968,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7052,"output_tokens":1214,"usd":0.032805,"stage2_stop_reason":"end_turn"},"total_usd":0.052485,"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\": 2019,\n      \"finding\": \"ACTR1A (alpha-centractin), a subunit of the dynactin complex, physically interacts with TLR2 and functions as a regulator of TLR2-mediated pro-inflammatory cytokine induction. The interaction was identified by cross-linking co-immunoprecipitation proteomics and validated by biochemical methods; RNA interference knockdown of ACTR1A reduced pro-inflammatory cytokine induction downstream of TLR2.\",\n      \"method\": \"Cross-linking co-immunoprecipitation proteomics, biochemical validation (co-IP), RNAi knockdown with cytokine readout\",\n      \"journal\": \"Molecular & Cellular Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical validation of interaction plus functional RNAi knockdown with defined cytokine phenotype, single lab\",\n      \"pmids\": [\"31221720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACTR1A (alpha-centractin) is an in vitro substrate of the SETD3 protein histidine methyltransferase. SETD3 was identified as a proximal interactor of ACTR1A by TurboID proximity labeling, and recombinant SETD3 methylated ACTR1A in a radiochemical in vitro methylation assay, extending SETD3's known substrate repertoire beyond β-actin to this dynactin subunit.\",\n      \"method\": \"TurboID proximity labeling, mass spectrometry, radiochemical in vitro methylation assay with recombinant SETD3, CRISPR/Cas9 SETD3 knockout cell lines, fluorography\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with recombinant proteins plus proximity labeling, but single lab and in vitro methylation only (no in-cell confirmation of modification site)\",\n      \"pmids\": [\"41142317\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTR1A (alpha-centractin), a core subunit of the dynactin complex, physically associates with TLR2 at the plasma membrane and is required for TLR2-mediated pro-inflammatory cytokine signaling, and is also an in vitro substrate of the SETD3 protein histidine methyltransferase, suggesting that dynein-mediated intracellular transport and cytoskeletal regulation may be modulated through SETD3-dependent methylation of this dynactin subunit.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTR1A (alpha-centractin) is a subunit of the dynactin complex that additionally participates in innate immune signaling and is subject to post-translational regulation [#0, #1]. ACTR1A physically associates with TLR2 and is required for TLR2-mediated pro-inflammatory cytokine induction, since its knockdown reduces cytokine output downstream of the receptor [#0]. ACTR1A is also an in vitro substrate of the SETD3 protein histidine methyltransferase, which methylates recombinant ACTR1A and contacts it in cells, extending SETD3's substrate repertoire beyond beta-actin to this dynactin subunit [#1]. Beyond these findings, the structural basis of these interactions, the in-cell methylation site, and the link between ACTR1A modification and dynactin function have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that the dynactin subunit ACTR1A has a role in innate immune signaling by physically engaging TLR2 and being required for downstream cytokine induction, a function not predicted by its cytoskeletal role.\",\n      \"evidence\": \"Cross-linking co-immunoprecipitation proteomics with biochemical validation and RNAi knockdown read out by pro-inflammatory cytokine induction\",\n      \"pmids\": [\"31221720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal interaction validated in a single lab; direct vs. indirect binding to TLR2 not resolved\",\n        \"Mechanism by which ACTR1A promotes TLR2 signaling (receptor trafficking, scaffolding) not defined\",\n        \"No structural or domain-mapping data for the ACTR1A-TLR2 association\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified ACTR1A as a post-translationally modified target by showing it is methylated in vitro by SETD3, raising the possibility that dynactin function is regulated by histidine methylation.\",\n      \"evidence\": \"TurboID proximity labeling and mass spectrometry, radiochemical in vitro methylation with recombinant SETD3, and CRISPR/Cas9 SETD3 knockout cell lines\",\n      \"pmids\": [\"41142317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro methylation only; no in-cell confirmation of the modification or its site\",\n        \"Functional consequence of ACTR1A methylation for dynactin or dynein-mediated transport not tested\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACTR1A's dynactin/cytoskeletal role, its TLR2-associated signaling function, and its SETD3-dependent methylation are mechanistically connected remains unknown.\",\n      \"evidence\": \"No discovery in the corpus links the methylation event to TLR2 signaling or to dynactin-dependent transport\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in-cell methylation site identified\",\n        \"No structural model of ACTR1A interactions\",\n        \"No demonstrated effect of methylation on transport or immune signaling\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [\"dynactin\"],\n    \"partners\": [\"TLR2\", \"SETD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}