{"gene":"ARL11","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2005,"finding":"Wild-type ARLTS1 transfected into A549 lung-cancer cells induced apoptosis via caspase-dependent mechanisms and suppressed tumor formation in immunodeficient mice; a truncated Trp149Stop variant had limited effect on apoptosis and tumor suppression, establishing a defined pro-apoptotic tumor-suppressor function for the wild-type protein.","method":"Transfection of full-length vs. truncated ARLTS1 into A549 cells, apoptosis assays, in vivo xenograft tumor formation, microarray expression profiling","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in cell lines plus in vivo xenograft, single lab, two orthogonal readouts (apoptosis + tumor suppression)","pmids":["15843669"],"is_preprint":false},{"year":2007,"finding":"Restoration of ARLTS1 expression by adenoviral transduction in ARLTS1-negative A549 and H1299 lung cancer cells induced apoptosis, inhibited cell growth, and reduced tumor formation in nude mice; microarray analysis identified ~650 differentially expressed transcripts in survival, proliferation, and signaling pathways.","method":"Adenoviral transduction, apoptosis and growth assays, in vivo nude mouse xenograft, microarray gene expression profiling","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional rescue experiments in two cell lines plus in vivo model, single lab, multiple orthogonal methods","pmids":["17699778"],"is_preprint":false},{"year":2006,"finding":"ARLTS1 expression is down-regulated in ovarian carcinomas by DNA promoter methylation; adenoviral restoration of ARLTS1 in ARLTS1-negative TOV-112 cells induced apoptosis and inhibited cell growth, and reduced in vivo tumorigenicity; the Trp149Stop polymorphism induced lower levels of apoptosis, indicating partial loss of function.","method":"Adenoviral transduction, promoter methylation analysis, apoptosis and growth assays, in vivo nude mouse xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function in two cell lines with in vivo validation, single lab, multiple orthogonal methods","pmids":["17079447"],"is_preprint":false},{"year":2010,"finding":"Stable expression of wild-type ARLTS1 in SKOV3 ovarian cancer cells increased sensitivity to chemotherapeutic agents (2-3 fold), enhanced apoptosis, and down-regulated caspase-3 and bcl-2 proteins, indicating ARLTS1 modulates the apoptosis signaling pathway involving caspase-3 and bcl-2.","method":"Stable transfection, MTT proliferation assay, flow cytometry (apoptosis/cell cycle), Western blot for caspase-3 and bcl-2","journal":"Archives of gynecology and obstetrics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, no in vivo validation, limited mechanistic depth","pmids":["21153650"],"is_preprint":false},{"year":2009,"finding":"Transfection of ARLTS1 into SKOV3 ovarian cancer cells inhibited proliferation, induced apoptosis (36.7% apoptotic index vs controls), increased S-phase fraction, and decreased caspase-3 and bcl-2 protein levels.","method":"Stable transfection, MTT assay, flow cytometry, Western blot for caspase-3 and bcl-2","journal":"Sichuan da xue xue bao. Yi xue ban","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, limited mechanistic depth","pmids":["19292033"],"is_preprint":false},{"year":2018,"finding":"ARL11 is endogenously expressed in mouse and human macrophages and promotes LPS-stimulated pro-inflammatory cytokine production and control of intracellular Salmonella replication by facilitating ERK1/2 and p38 MAPK activation; ARL11 forms a complex with phospho-ERK in macrophages within minutes of LPS stimulation; overexpression of ARL11 caused constitutive ERK1/2 phosphorylation and macrophage exhaustion.","method":"siRNA knockdown, LPS stimulation assays, phospho-ERK/p38 immunoblotting, co-immunoprecipitation of ARL11 with phospho-ERK, intracellular Salmonella replication assay, overexpression studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, KD with defined cellular phenotype, multiple orthogonal functional readouts in a single rigorous study","pmids":["29618517"],"is_preprint":false},{"year":2012,"finding":"Using an in-frame cDNA library combined with a protein complementation assay, two novel ARL11 binding partners were identified: cellular retinoic acid binding protein 2 (CRABP2) and phosphoglycerate mutase 1 (PGAM1).","method":"In-frame cDNA library, protein complementation assay (split-reporter)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (protein complementation assay), no functional validation of interactions","pmids":["23272234"],"is_preprint":false},{"year":2024,"finding":"ARL11 interacts with JAK2 and phospho-JAK2 and modulates their degradation, thereby activating the JAK2/STAT1 pathway; silencing ARL11 in macrophages reduced M1 polarization, inflammatory cytokine production, and lipid deposition in an atherosclerosis mouse model.","method":"Co-immunoprecipitation (ARL11 with JAK2/p-JAK2), Western blot, siRNA knockdown, ApoE−/− mouse model, ELISA for cytokines, immunofluorescence","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifies interaction, in vivo and in vitro loss-of-function with defined pathway readout, single lab","pmids":["39312826"],"is_preprint":false},{"year":2024,"finding":"ARL11 knockdown in microglia/BV2 cells inhibited M1 polarization and reduced phosphorylated ERK1/2 expression; the transcription factor ELF1 binds to the ARL11 promoter and activates ARL11 transcription, placing ELF1 upstream of ARL11 in neuroinflammation.","method":"siRNA knockdown, Western blot for p-ERK1/2, ChIP/promoter binding assay (ELF1 binding to ARL11 promoter), LPS/IFN-γ stimulation of BV2 cells, SCI mouse model with motor function assessment","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding assay plus KD with defined pathway and functional readout in vivo and in vitro, single lab","pmids":["39307293"],"is_preprint":false},{"year":2025,"finding":"ARL11 interacts with STING to enhance innate immune signaling and type I interferon induction, creating a positive feedback loop; ARL11 also interacts with the RUVBL1/RUVBL2 complex to facilitate DNA homologous recombination repair and reduce PARP-inhibitor-induced DNA double-strand damage, identified in a genome-wide CRISPR activation screen for PARPi resistance.","method":"Genome-wide CRISPR activation screen, co-immunoprecipitation (ARL11 with STING; ARL11 with RUVBL1/2), DNA damage assays, HR repair assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for two distinct interactions identified by orthogonal CRISPR screen, single lab, limited mutagenesis/reconstitution depth","pmids":["40123001"],"is_preprint":false}],"current_model":"ARL11 (ARLTS1) is a small GTPase that functions as a tumor suppressor by inducing apoptosis (involving caspase-dependent mechanisms and bcl-2 regulation) when re-expressed in cancer cells; in macrophages and microglia it acts as a positive regulator of ERK1/2 and p38 MAPK signaling downstream of LPS/TLR4 stimulation by forming a complex with phospho-ERK, promotes innate immune activation; it also interacts with JAK2/p-JAK2 to modulate their degradation and activate JAK2/STAT1 signaling in atherosclerotic inflammation; interacts with STING to amplify type I interferon responses and with the RUVBL1/2 complex to facilitate homologous recombination DNA repair, conferring resistance to PARP inhibitors; and its transcription is directly activated by the ELF1 transcription factor binding to its promoter."},"narrative":{"mechanistic_narrative":"ARL11 (ARLTS1) is a small GTPase with two distinct, context-dependent roles: a pro-apoptotic tumor suppressor in epithelial cancers and a positive regulator of innate immune signaling in macrophages and microglia [PMID:15843669, PMID:29618517]. As a tumor suppressor, re-expression of wild-type ARL11 in lung and ovarian cancer cells that have lost it induces caspase-dependent apoptosis, inhibits growth, and suppresses xenograft tumor formation, whereas a truncating Trp149Stop variant shows attenuated activity; loss of expression in tumors is driven in part by promoter methylation [PMID:15843669, PMID:17699778, PMID:17079447]. In immune cells, ARL11 acts downstream of LPS/TLR4 to drive pro-inflammatory activation: it forms a complex with phospho-ERK within minutes of stimulation and facilitates ERK1/2 and p38 MAPK activation, promoting cytokine production and control of intracellular Salmonella, while its overexpression causes constitutive ERK phosphorylation and macrophage exhaustion [PMID:29618517]. It further amplifies inflammatory signaling by binding JAK2/phospho-JAK2 to modulate their degradation and activate JAK2/STAT1 in atherosclerosis, and its expression is transcriptionally activated by ELF1 binding to its promoter in microglial neuroinflammation [PMID:39312826, PMID:39307293]. ARL11 also interacts with STING to amplify type I interferon responses and with the RUVBL1/RUVBL2 complex to facilitate homologous-recombination DNA repair, conferring PARP-inhibitor resistance [PMID:40123001]. How a single GTPase reconciles tumor-suppressive apoptosis with pro-survival immune and DNA-repair functions, and whether nucleotide-dependent GTPase cycling governs these roles, has not been resolved in the available corpus.","teleology":[{"year":2005,"claim":"Established that ARL11 has an intrinsic pro-apoptotic tumor-suppressor function and that a natural truncating variant impairs it, distinguishing wild-type from variant activity.","evidence":"Transfection of full-length vs Trp149Stop ARLTS1 into A549 lung cancer cells with apoptosis assays and xenograft tumor formation","pmids":["15843669"],"confidence":"Medium","gaps":["No molecular mechanism for how the GTPase triggers apoptosis","Effector and nucleotide-state dependence not defined"]},{"year":2006,"claim":"Showed that ARL11 silencing in tumors occurs via promoter methylation and that restoring it is sufficient to induce apoptosis and reduce tumorigenicity in ovarian cancer.","evidence":"Promoter methylation analysis and adenoviral restoration in TOV-112 ovarian cells with apoptosis and xenograft assays","pmids":["17079447"],"confidence":"Medium","gaps":["Downstream apoptotic effectors not identified","Generality of methylation silencing across tumor types unestablished"]},{"year":2007,"claim":"Confirmed tumor-suppressor rescue across multiple lung cancer lines and broadened the affected transcriptional program.","evidence":"Adenoviral transduction of A549 and H1299 cells, growth/apoptosis assays, nude mouse xenografts, microarray profiling","pmids":["17699778"],"confidence":"Medium","gaps":["~650 differentially expressed transcripts not resolved into direct vs indirect targets","No physical effector linked to the apoptotic phenotype"]},{"year":2010,"claim":"Connected ARL11 re-expression to chemosensitization and specific apoptotic regulators caspase-3 and bcl-2.","evidence":"Stable transfection of SKOV3 ovarian cells, MTT, flow cytometry, Western blot for caspase-3 and bcl-2","pmids":["21153650","19292033"],"confidence":"Low","gaps":["Single cell line, no in vivo validation","Whether bcl-2/caspase-3 changes are direct or downstream is unknown"]},{"year":2012,"claim":"Provided the first candidate physical partners (CRABP2, PGAM1) for ARL11, raising the question of which interactions are functional.","evidence":"In-frame cDNA library screen with split-reporter protein complementation assay","pmids":["23272234"],"confidence":"Low","gaps":["Single method, no functional validation of either interaction","No reciprocal confirmation or cellular consequence demonstrated"]},{"year":2018,"claim":"Defined a positive signaling role distinct from tumor suppression: ARL11 drives LPS/TLR4-induced MAPK activation in macrophages by complexing with phospho-ERK.","evidence":"siRNA knockdown, LPS stimulation, phospho-ERK/p38 immunoblotting, reciprocal co-IP of ARL11 with phospho-ERK, Salmonella replication and overexpression assays","pmids":["29618517"],"confidence":"High","gaps":["Whether ARL11 binds phospho-ERK directly or via an adaptor not established","Role of GTPase activity in the interaction undefined"]},{"year":2024,"claim":"Extended pro-inflammatory function to JAK2/STAT1 signaling and atherosclerosis, and placed ELF1 as a direct transcriptional activator of ARL11 in neuroinflammation.","evidence":"Co-IP of ARL11 with JAK2/p-JAK2, siRNA knockdown, ApoE-/- and SCI mouse models, ChIP/promoter binding for ELF1","pmids":["39312826","39307293"],"confidence":"Medium","gaps":["Mechanism by which ARL11 modulates JAK2 degradation not resolved","Whether MAPK and JAK2 pathways are engaged independently is unclear"]},{"year":2025,"claim":"Identified two new interaction-based functions—STING-mediated type I IFN amplification and RUVBL1/2-dependent homologous recombination—linking ARL11 to PARP-inhibitor resistance.","evidence":"Genome-wide CRISPR activation screen, co-IP of ARL11 with STING and with RUVBL1/2, DNA damage and HR repair assays","pmids":["40123001"],"confidence":"Medium","gaps":["Limited mutagenesis/reconstitution depth for either interaction","Direct vs indirect nature of RUVBL1/2 and STING binding not dissected"]},{"year":null,"claim":"How a single GTPase reconciles tumor-suppressive apoptosis with pro-survival immune signaling and DNA-repair functions, and whether nucleotide-dependent GTPase cycling controls these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or nucleotide-state characterization of ARL11","No identified GEF/GAP or canonical effector","Context determinants switching between tumor-suppressor and pro-inflammatory roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,5]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]}],"complexes":[],"partners":["JAK2","STING1","RUVBL1","RUVBL2","CRABP2","PGAM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969Q4","full_name":"ADP-ribosylation factor-like protein 11","aliases":["ADP-ribosylation factor-like tumor suppressor protein 1"],"length_aa":196,"mass_kda":21.4,"function":"May play a role in apoptosis. May act as a tumor suppressor","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q969Q4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARL11","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARL11","total_profiled":1310},"omim":[{"mim_id":"609351","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 11; ARL11","url":"https://www.omim.org/entry/609351"},{"mim_id":"151400","title":"LEUKEMIA, CHRONIC LYMPHOCYTIC; CLL","url":"https://www.omim.org/entry/151400"},{"mim_id":"109543","title":"LEUKEMIA, CHRONIC LYMPHOCYTIC, SUSCEPTIBILITY TO, 2","url":"https://www.omim.org/entry/109543"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":6.4}],"url":"https://www.proteinatlas.org/search/ARL11"},"hgnc":{"alias_symbol":["ARLTS1","FLJ33930"],"prev_symbol":[]},"alphafold":{"accession":"Q969Q4","domains":[{"cath_id":"3.40.50.300","chopping":"13-185","consensus_level":"high","plddt":93.3003,"start":13,"end":185}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Q4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Q4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969Q4-F1-predicted_aligned_error_v6.png","plddt_mean":87.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARL11","jax_strain_url":"https://www.jax.org/strain/search?query=ARL11"},"sequence":{"accession":"Q969Q4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969Q4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969Q4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969Q4"}},"corpus_meta":[{"pmid":"15843669","id":"PMC_15843669","title":"Familial cancer associated with a polymorphism in ARLTS1.","date":"2005","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15843669","citation_count":104,"is_preprint":false},{"pmid":"17079447","id":"PMC_17079447","title":"Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17079447","citation_count":40,"is_preprint":false},{"pmid":"29618517","id":"PMC_29618517","title":"ARL11 regulates lipopolysaccharide-stimulated macrophage activation by promoting mitogen-activated protein kinase (MAPK) signaling.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29618517","citation_count":27,"is_preprint":false},{"pmid":"16353159","id":"PMC_16353159","title":"Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16353159","citation_count":26,"is_preprint":false},{"pmid":"20358297","id":"PMC_20358297","title":"ARLTS1, MDM2 and RAD51 gene variations are associated with familial breast cancer.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/20358297","citation_count":26,"is_preprint":false},{"pmid":"18375053","id":"PMC_18375053","title":"ARLTS1 - a novel tumor suppressor gene.","date":"2008","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/18375053","citation_count":23,"is_preprint":false},{"pmid":"16488076","id":"PMC_16488076","title":"ARLTS1 variants and risk of colorectal cancer.","date":"2006","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/16488076","citation_count":23,"is_preprint":false},{"pmid":"16646072","id":"PMC_16646072","title":"ARLTS1 variants and melanoma risk.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16646072","citation_count":21,"is_preprint":false},{"pmid":"16581122","id":"PMC_16581122","title":"Relationship between ARLTS1 polymorphisms and risk of chronic lymphocytic leukemia.","date":"2006","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/16581122","citation_count":19,"is_preprint":false},{"pmid":"17699778","id":"PMC_17699778","title":"Tumor suppressor functions of ARLTS1 in lung cancers.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17699778","citation_count":17,"is_preprint":false},{"pmid":"16570116","id":"PMC_16570116","title":"Cancer Familial Aggregation (CFA) and G446A polymorphism in ARLTS1 gene.","date":"2006","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/16570116","citation_count":14,"is_preprint":false},{"pmid":"17449901","id":"PMC_17449901","title":"Association of the ARLTS1 Cys148Arg variant with sporadic and familial colorectal cancer.","date":"2007","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17449901","citation_count":14,"is_preprint":false},{"pmid":"23940804","id":"PMC_23940804","title":"ARLTS1 and prostate cancer risk--analysis of expression and regulation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23940804","citation_count":12,"is_preprint":false},{"pmid":"18337727","id":"PMC_18337727","title":"ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer.","date":"2008","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/18337727","citation_count":12,"is_preprint":false},{"pmid":"22028916","id":"PMC_22028916","title":"Contribution of ARLTS1 Cys148Arg (T442C) variant with prostate cancer risk and ARLTS1 function in prostate cancer cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22028916","citation_count":10,"is_preprint":false},{"pmid":"27866680","id":"PMC_27866680","title":"ARLTS1, potential candidate gene in familial aggregation of hematological malignancies.","date":"2016","source":"Bulletin du cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27866680","citation_count":8,"is_preprint":false},{"pmid":"19509554","id":"PMC_19509554","title":"Association of the ARLTS1 variants with familial ovarian cancer risk in China.","date":"2009","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/19509554","citation_count":6,"is_preprint":false},{"pmid":"39312826","id":"PMC_39312826","title":"Silencing ARL11 relieved atherosclerotic inflammation and lipid deposition via retraining JAK2/STAT1 pathway.","date":"2024","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/39312826","citation_count":4,"is_preprint":false},{"pmid":"21153650","id":"PMC_21153650","title":"Involvement of ARLTS1 in chemotherapy and apoptosis in ovarian cancer cell line.","date":"2010","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/21153650","citation_count":4,"is_preprint":false},{"pmid":"19723348","id":"PMC_19723348","title":"ARLTS1 polymorphisms and basal cell carcinoma of the skin.","date":"2007","source":"Hereditary cancer in clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/19723348","citation_count":2,"is_preprint":false},{"pmid":"19292033","id":"PMC_19292033","title":"[Effects of ARLTS1 gene on growth and apoptosis of epithelial ovarian cancer SKOV3 cells].","date":"2009","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/19292033","citation_count":2,"is_preprint":false},{"pmid":"23272234","id":"PMC_23272234","title":"In-frame cDNA library combined with protein complementation assay identifies ARL11-binding partners.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23272234","citation_count":2,"is_preprint":false},{"pmid":"40123001","id":"PMC_40123001","title":"Genome-wide CRISPR activation screen identifies ARL11 as a sensitivity determinant of PARP inhibitor therapy.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40123001","citation_count":0,"is_preprint":false},{"pmid":"28630657","id":"PMC_28630657","title":"ARLTS1 polymorphism is associated with an increased risk of familial cancer: evidence from a meta-analysis.","date":"2017","source":"Hereditary cancer in clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/28630657","citation_count":0,"is_preprint":false},{"pmid":"39307293","id":"PMC_39307293","title":"ARL11 knockdown alleviates spinal cord injury by inhibiting neuroinflammation and M1 activation of microglia in mice.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39307293","citation_count":0,"is_preprint":false},{"pmid":"20067102","id":"PMC_20067102","title":"[Polymorphism of ARLTS1 gene in early-onset ovarian cancer].","date":"2009","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/20067102","citation_count":0,"is_preprint":false},{"pmid":"41734586","id":"PMC_41734586","title":"Ginsenoside Rg3 synergizes with near-infrared photothermal therapy to suppress prostate cancer progression by inhibiting RAS signaling and enhancing ARL11-mediated macrophage reprogramming.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41734586","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14562,"output_tokens":2648,"usd":0.041703,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9857,"output_tokens":2958,"usd":0.061617,"stage2_stop_reason":"end_turn"},"total_usd":0.10332,"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\": 2005,\n      \"finding\": \"Wild-type ARLTS1 transfected into A549 lung-cancer cells induced apoptosis via caspase-dependent mechanisms and suppressed tumor formation in immunodeficient mice; a truncated Trp149Stop variant had limited effect on apoptosis and tumor suppression, establishing a defined pro-apoptotic tumor-suppressor function for the wild-type protein.\",\n      \"method\": \"Transfection of full-length vs. truncated ARLTS1 into A549 cells, apoptosis assays, in vivo xenograft tumor formation, microarray expression profiling\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in cell lines plus in vivo xenograft, single lab, two orthogonal readouts (apoptosis + tumor suppression)\",\n      \"pmids\": [\"15843669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Restoration of ARLTS1 expression by adenoviral transduction in ARLTS1-negative A549 and H1299 lung cancer cells induced apoptosis, inhibited cell growth, and reduced tumor formation in nude mice; microarray analysis identified ~650 differentially expressed transcripts in survival, proliferation, and signaling pathways.\",\n      \"method\": \"Adenoviral transduction, apoptosis and growth assays, in vivo nude mouse xenograft, microarray gene expression profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional rescue experiments in two cell lines plus in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17699778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ARLTS1 expression is down-regulated in ovarian carcinomas by DNA promoter methylation; adenoviral restoration of ARLTS1 in ARLTS1-negative TOV-112 cells induced apoptosis and inhibited cell growth, and reduced in vivo tumorigenicity; the Trp149Stop polymorphism induced lower levels of apoptosis, indicating partial loss of function.\",\n      \"method\": \"Adenoviral transduction, promoter methylation analysis, apoptosis and growth assays, in vivo nude mouse xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function in two cell lines with in vivo validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17079447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Stable expression of wild-type ARLTS1 in SKOV3 ovarian cancer cells increased sensitivity to chemotherapeutic agents (2-3 fold), enhanced apoptosis, and down-regulated caspase-3 and bcl-2 proteins, indicating ARLTS1 modulates the apoptosis signaling pathway involving caspase-3 and bcl-2.\",\n      \"method\": \"Stable transfection, MTT proliferation assay, flow cytometry (apoptosis/cell cycle), Western blot for caspase-3 and bcl-2\",\n      \"journal\": \"Archives of gynecology and obstetrics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, no in vivo validation, limited mechanistic depth\",\n      \"pmids\": [\"21153650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transfection of ARLTS1 into SKOV3 ovarian cancer cells inhibited proliferation, induced apoptosis (36.7% apoptotic index vs controls), increased S-phase fraction, and decreased caspase-3 and bcl-2 protein levels.\",\n      \"method\": \"Stable transfection, MTT assay, flow cytometry, Western blot for caspase-3 and bcl-2\",\n      \"journal\": \"Sichuan da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, limited mechanistic depth\",\n      \"pmids\": [\"19292033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARL11 is endogenously expressed in mouse and human macrophages and promotes LPS-stimulated pro-inflammatory cytokine production and control of intracellular Salmonella replication by facilitating ERK1/2 and p38 MAPK activation; ARL11 forms a complex with phospho-ERK in macrophages within minutes of LPS stimulation; overexpression of ARL11 caused constitutive ERK1/2 phosphorylation and macrophage exhaustion.\",\n      \"method\": \"siRNA knockdown, LPS stimulation assays, phospho-ERK/p38 immunoblotting, co-immunoprecipitation of ARL11 with phospho-ERK, intracellular Salmonella replication assay, overexpression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, KD with defined cellular phenotype, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"29618517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Using an in-frame cDNA library combined with a protein complementation assay, two novel ARL11 binding partners were identified: cellular retinoic acid binding protein 2 (CRABP2) and phosphoglycerate mutase 1 (PGAM1).\",\n      \"method\": \"In-frame cDNA library, protein complementation assay (split-reporter)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (protein complementation assay), no functional validation of interactions\",\n      \"pmids\": [\"23272234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARL11 interacts with JAK2 and phospho-JAK2 and modulates their degradation, thereby activating the JAK2/STAT1 pathway; silencing ARL11 in macrophages reduced M1 polarization, inflammatory cytokine production, and lipid deposition in an atherosclerosis mouse model.\",\n      \"method\": \"Co-immunoprecipitation (ARL11 with JAK2/p-JAK2), Western blot, siRNA knockdown, ApoE−/− mouse model, ELISA for cytokines, immunofluorescence\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifies interaction, in vivo and in vitro loss-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"39312826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ARL11 knockdown in microglia/BV2 cells inhibited M1 polarization and reduced phosphorylated ERK1/2 expression; the transcription factor ELF1 binds to the ARL11 promoter and activates ARL11 transcription, placing ELF1 upstream of ARL11 in neuroinflammation.\",\n      \"method\": \"siRNA knockdown, Western blot for p-ERK1/2, ChIP/promoter binding assay (ELF1 binding to ARL11 promoter), LPS/IFN-γ stimulation of BV2 cells, SCI mouse model with motor function assessment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding assay plus KD with defined pathway and functional readout in vivo and in vitro, single lab\",\n      \"pmids\": [\"39307293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARL11 interacts with STING to enhance innate immune signaling and type I interferon induction, creating a positive feedback loop; ARL11 also interacts with the RUVBL1/RUVBL2 complex to facilitate DNA homologous recombination repair and reduce PARP-inhibitor-induced DNA double-strand damage, identified in a genome-wide CRISPR activation screen for PARPi resistance.\",\n      \"method\": \"Genome-wide CRISPR activation screen, co-immunoprecipitation (ARL11 with STING; ARL11 with RUVBL1/2), DNA damage assays, HR repair assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for two distinct interactions identified by orthogonal CRISPR screen, single lab, limited mutagenesis/reconstitution depth\",\n      \"pmids\": [\"40123001\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARL11 (ARLTS1) is a small GTPase that functions as a tumor suppressor by inducing apoptosis (involving caspase-dependent mechanisms and bcl-2 regulation) when re-expressed in cancer cells; in macrophages and microglia it acts as a positive regulator of ERK1/2 and p38 MAPK signaling downstream of LPS/TLR4 stimulation by forming a complex with phospho-ERK, promotes innate immune activation; it also interacts with JAK2/p-JAK2 to modulate their degradation and activate JAK2/STAT1 signaling in atherosclerotic inflammation; interacts with STING to amplify type I interferon responses and with the RUVBL1/2 complex to facilitate homologous recombination DNA repair, conferring resistance to PARP inhibitors; and its transcription is directly activated by the ELF1 transcription factor binding to its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARL11 (ARLTS1) is a small GTPase with two distinct, context-dependent roles: a pro-apoptotic tumor suppressor in epithelial cancers and a positive regulator of innate immune signaling in macrophages and microglia [#0, #5]. As a tumor suppressor, re-expression of wild-type ARL11 in lung and ovarian cancer cells that have lost it induces caspase-dependent apoptosis, inhibits growth, and suppresses xenograft tumor formation, whereas a truncating Trp149Stop variant shows attenuated activity; loss of expression in tumors is driven in part by promoter methylation [#0, #1, #2]. In immune cells, ARL11 acts downstream of LPS/TLR4 to drive pro-inflammatory activation: it forms a complex with phospho-ERK within minutes of stimulation and facilitates ERK1/2 and p38 MAPK activation, promoting cytokine production and control of intracellular Salmonella, while its overexpression causes constitutive ERK phosphorylation and macrophage exhaustion [#5]. It further amplifies inflammatory signaling by binding JAK2/phospho-JAK2 to modulate their degradation and activate JAK2/STAT1 in atherosclerosis, and its expression is transcriptionally activated by ELF1 binding to its promoter in microglial neuroinflammation [#7, #8]. ARL11 also interacts with STING to amplify type I interferon responses and with the RUVBL1/RUVBL2 complex to facilitate homologous-recombination DNA repair, conferring PARP-inhibitor resistance [#9]. How a single GTPase reconciles tumor-suppressive apoptosis with pro-survival immune and DNA-repair functions, and whether nucleotide-dependent GTPase cycling governs these roles, has not been resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that ARL11 has an intrinsic pro-apoptotic tumor-suppressor function and that a natural truncating variant impairs it, distinguishing wild-type from variant activity.\",\n      \"evidence\": \"Transfection of full-length vs Trp149Stop ARLTS1 into A549 lung cancer cells with apoptosis assays and xenograft tumor formation\",\n      \"pmids\": [\"15843669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for how the GTPase triggers apoptosis\", \"Effector and nucleotide-state dependence not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed that ARL11 silencing in tumors occurs via promoter methylation and that restoring it is sufficient to induce apoptosis and reduce tumorigenicity in ovarian cancer.\",\n      \"evidence\": \"Promoter methylation analysis and adenoviral restoration in TOV-112 ovarian cells with apoptosis and xenograft assays\",\n      \"pmids\": [\"17079447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream apoptotic effectors not identified\", \"Generality of methylation silencing across tumor types unestablished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Confirmed tumor-suppressor rescue across multiple lung cancer lines and broadened the affected transcriptional program.\",\n      \"evidence\": \"Adenoviral transduction of A549 and H1299 cells, growth/apoptosis assays, nude mouse xenografts, microarray profiling\",\n      \"pmids\": [\"17699778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"~650 differentially expressed transcripts not resolved into direct vs indirect targets\", \"No physical effector linked to the apoptotic phenotype\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected ARL11 re-expression to chemosensitization and specific apoptotic regulators caspase-3 and bcl-2.\",\n      \"evidence\": \"Stable transfection of SKOV3 ovarian cells, MTT, flow cytometry, Western blot for caspase-3 and bcl-2\",\n      \"pmids\": [\"21153650\", \"19292033\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single cell line, no in vivo validation\", \"Whether bcl-2/caspase-3 changes are direct or downstream is unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the first candidate physical partners (CRABP2, PGAM1) for ARL11, raising the question of which interactions are functional.\",\n      \"evidence\": \"In-frame cDNA library screen with split-reporter protein complementation assay\",\n      \"pmids\": [\"23272234\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method, no functional validation of either interaction\", \"No reciprocal confirmation or cellular consequence demonstrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a positive signaling role distinct from tumor suppression: ARL11 drives LPS/TLR4-induced MAPK activation in macrophages by complexing with phospho-ERK.\",\n      \"evidence\": \"siRNA knockdown, LPS stimulation, phospho-ERK/p38 immunoblotting, reciprocal co-IP of ARL11 with phospho-ERK, Salmonella replication and overexpression assays\",\n      \"pmids\": [\"29618517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARL11 binds phospho-ERK directly or via an adaptor not established\", \"Role of GTPase activity in the interaction undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended pro-inflammatory function to JAK2/STAT1 signaling and atherosclerosis, and placed ELF1 as a direct transcriptional activator of ARL11 in neuroinflammation.\",\n      \"evidence\": \"Co-IP of ARL11 with JAK2/p-JAK2, siRNA knockdown, ApoE-/- and SCI mouse models, ChIP/promoter binding for ELF1\",\n      \"pmids\": [\"39312826\", \"39307293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ARL11 modulates JAK2 degradation not resolved\", \"Whether MAPK and JAK2 pathways are engaged independently is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified two new interaction-based functions—STING-mediated type I IFN amplification and RUVBL1/2-dependent homologous recombination—linking ARL11 to PARP-inhibitor resistance.\",\n      \"evidence\": \"Genome-wide CRISPR activation screen, co-IP of ARL11 with STING and with RUVBL1/2, DNA damage and HR repair assays\",\n      \"pmids\": [\"40123001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mutagenesis/reconstitution depth for either interaction\", \"Direct vs indirect nature of RUVBL1/2 and STING binding not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GTPase reconciles tumor-suppressive apoptosis with pro-survival immune signaling and DNA-repair functions, and whether nucleotide-dependent GTPase cycling controls these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or nucleotide-state characterization of ARL11\", \"No identified GEF/GAP or canonical effector\", \"Context determinants switching between tumor-suppressor and pro-inflammatory roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAK2\", \"STING1\", \"RUVBL1\", \"RUVBL2\", \"CRABP2\", \"PGAM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}