{"gene":"TRA2A","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1995,"finding":"TRA-2A (C. elegans ortholog) is a predicted multipass membrane protein whose intracellular carboxy-terminal domain is necessary and sufficient to promote hermaphrodite (female) somatic development by negatively regulating the FEM proteins, as shown by heat-shock-driven transgenic rescue of tra-2 loss-of-function mutants and feminization of XO animals.","method":"Transgenic overexpression (heat-shock promoter), loss-of-function rescue assay in C. elegans","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo genetic rescue with domain dissection, replicated across multiple genotypes (XX loss-of-function and XO animals)","pmids":["7555725"],"is_preprint":false},{"year":1999,"finding":"The carboxy-terminal intracellular region of C. elegans TRA-2A directly interacts with FEM-3 (a masculinizing protein), and this interaction is the mechanistic basis by which TRA-2A negatively regulates male development; overproduction of the TRA-2A C-terminal domain suppresses FEM-3-induced masculinization.","method":"Yeast two-hybrid, in vitro binding assay, genetic epistasis/suppression in C. elegans","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding + yeast two-hybrid + genetic epistasis with multiple genotypes, replicated across assays","pmids":["10364161"],"is_preprint":false},{"year":2000,"finding":"C. elegans TRA-3, an atypical calpain protease, cleaves TRA-2A in a calcium-dependent manner, generating a peptide predicted to have feminizing activity; this proteolytic cleavage is essential for TRA-3's in vivo function in female development.","method":"In vitro proteolytic assay with calcium dependence, active-site mutagenesis of TRA-3, genetic analysis in C. elegans","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of proteolytic activity plus mutagenesis plus in vivo genetic validation","pmids":["10783162"],"is_preprint":false},{"year":2004,"finding":"HER-1, a secreted ligand, inhibits TRA-2A function by directly binding to the extracellular face of TRA-2A (which acts as its receptor); crystal structure of HER-1 (1.5 Å) identified a localized surface region critical for this interaction, confirmed by binding assays with TRA-2A-expressing cells and HER-1 surface mutants.","method":"X-ray crystallography (MAD, 1.5 Å), cell-based binding assay with HER-1 surface mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus functional mutagenesis plus cell-based binding assay","pmids":["15289613"],"is_preprint":false},{"year":2017,"finding":"Human TRA2A promotes paclitaxel resistance in triple-negative breast cancer by controlling alternative splicing of RSRC2, CALU, and PALM; specifically, TRA2A binds an upstream intronic sequence of RSRC2 exon 4 to shift isoform usage from RSRC2s to RSRC2l, reducing RSRC2 protein levels and driving resistance.","method":"siRNA knockdown/overexpression, RNA immunoprecipitation (RIP), alternative splicing RT-PCR, functional cell viability assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP establishes direct RNA binding, splicing assays confirm isoform shift, functional rescue not fully completed with reconstitution","pmids":["28416606"],"is_preprint":false},{"year":2017,"finding":"ILDR1 and ILDR2 (angulin proteins) physically interact with TRA2A (and TRA2B/SRSF1), translocate to the nucleus when TRA2A is present, and modulate alternative splicing of TUBD1, IQCB1, and PCDH19; LSR (third angulin) does not bind TRA2A.","method":"Co-immunoprecipitation, siRNA knockdown, alternative splicing RT-PCR, subcellular localization imaging","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and localization with functional splicing readout, single lab but multiple orthogonal assays","pmids":["28785060"],"is_preprint":false},{"year":2020,"finding":"Human TRA2A regulates influenza A virus mRNA splicing by binding intronic splicing silencer motifs: in avian IAV (YS/H5N1) it binds the M mRNA to depress splicing (inhibiting replication), while in human IAV (PR8/H1N1) it binds the NS mRNA to depress splicing (benefiting replication); M-334 and NS-234/236 sites are critical for TRA2A binding, splicing, viral replication, and pathogenicity.","method":"RNA binding assays, viral splicing analysis, site-directed mutagenesis of viral RNA motifs, in vitro and in vivo viral replication assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of binding sites, in vitro and in vivo replication, multiple viral strains tested with mechanistic specificity","pmids":["32596447"],"is_preprint":false},{"year":2020,"finding":"TRA2A stabilizes LINC00662 lncRNA by directly binding to it (RBP-lncRNA interaction), which in an Alzheimer's disease BBB microenvironment model increases TRA2A/LINC00662 levels and reduces ELK4 mRNA via SMD pathway, thereby increasing BBB permeability.","method":"RNA immunoprecipitation (RIP), siRNA knockdown in vitro BBB model, mRNA stability assay","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP confirms direct binding, functional knockdown establishes pathway, single lab","pmids":["32372707"],"is_preprint":false},{"year":2021,"finding":"TRA2A directly binds MALAT1 lncRNA (confirmed by RIP and RNA pull-down), and its expression stabilizes MALAT1, which in turn modulates the EZH2/β-catenin pathway to promote proliferation and migration of esophageal cancer cells.","method":"RNA immunoprecipitation (RIP), RNA pull-down, gain- and loss-of-function experiments","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding confirmed by two orthogonal RNA methods (RIP + pulldown), functional downstream validated, single lab","pmids":["34234858"],"is_preprint":false},{"year":2022,"finding":"E4B (a U-box E3 ubiquitin ligase) ubiquitinates TRA2A both in vitro and in HEK293 cells, forming K11-linked polyubiquitin chains on TRA2A, leading to its proteasomal degradation; E4B-mediated TRA2A degradation regulates TRA2A's alternative splicing function and affects RSRC2 transcription. E4B interacts with TRA2A via its variable region.","method":"In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor experiments, alternative splicing RT-PCR in HEK293 cells","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination reconstitution plus cellular Co-IP plus functional splicing readout, single lab but multiple orthogonal methods","pmids":["35669517"],"is_preprint":false},{"year":2023,"finding":"TRA2A interacts with METTL3 and RBMX (m6A writer complex components), and its depletion reduces m6A modification of MALAT1 lncRNA, causing structural alteration and reduced MALAT1 stability; TRA2A also affects KIAA1429 (WTAP) expression. This noncanonical m6A writer-associated function promotes esophageal cancer proliferation.","method":"Co-IP (TRA2A-METTL3/RBMX), MeRIP-qPCR, CLIP, RNA pull-down, stability assays, epitranscriptomic microarray","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP + CLIP + MeRIP-qPCR in single lab, multiple orthogonal methods confirming noncanonical m6A function","pmids":["37317053"],"is_preprint":false},{"year":2023,"finding":"Lnc-ZEB2-19 binds TRA2A and promotes its proteasomal degradation, thereby relieving TRA2A-mediated suppression of IL32 alternative splicing; TRA2A normally suppresses IL32 exon inclusion, and its degradation leads to enhanced IL-32 secretion that recruits M2-TAMs via ITGA5.","method":"RNA pull-down/RIP (lncRNA-TRA2A binding), proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding confirmed plus splicing functional assay plus in vivo model, single lab","pmids":["37564197"],"is_preprint":false},{"year":2025,"finding":"TRA2A and its paralog TRA2B function as synthetic lethal partners and largely redundant activators of both alternative and constitutive splicing; in cancer cell lines with TRA2B insufficiency, TRA2A depletion leads to defects in shared splicing targets, mitotic defects, and cell death; TRA2B overexpression rescues both aberrant splicing and lethality, demonstrating dosage-sensitive paralog compensation.","method":"CRISPR/shRNA loss-of-function screens, RNA-seq splicing analysis, TRA2B overexpression rescue, cell viability/mitosis phenotyping","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (synthetic lethality), transcriptome-wide splicing analysis, rescue experiments establishing dosage-sensitive redundancy","pmids":["40367120"],"is_preprint":false},{"year":2025,"finding":"CTSZ (cathepsin Z) overexpression in prostate cancer cells induces TRA2A degradation via the proteasome pathway, which relieves TRA2A-mediated suppression of IL32 alternative splicing, promoting M2-TAM recruitment and metastasis.","method":"Proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo metastasis models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteasomal degradation assay plus splicing analysis plus in vivo model, single lab","pmids":["40764928"],"is_preprint":false},{"year":2025,"finding":"H3K18 lactylation (H3K18la) is enriched at the TRA2A promoter and activates TRA2A transcription; upregulated TRA2A then acts as a splicing factor to promote inclusion of STIL-L isoform, which inhibits ferroptosis in ovarian cancer cells by modulating iron metabolism.","method":"ChIP (H3K18la at TRA2A promoter), qRT-PCR/WB, RT-PCR for alternative splicing, xenograft model, CCK8/clone/EdU assays","journal":"Cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP establishes epigenetic activation, splicing assay confirms isoform shift, in vivo xenograft validates functional consequence, single lab","pmids":["40907573"],"is_preprint":false}],"current_model":"TRA2A (human) is a serine/arginine-rich splicing factor that functions as a direct RNA-binding protein to regulate alternative and constitutive pre-mRNA splicing (acting largely redundantly with its paralog TRA2B in a dosage-sensitive manner); it is subject to proteasomal degradation via E4B-mediated K11-linked ubiquitination; it binds oncogenic lncRNAs such as MALAT1 to modulate their m6A methylation and stability through interaction with the METTL3/RBMX writer complex; it suppresses IL32 alternative splicing and is degraded by CTSZ or lnc-ZEB2-19 to relieve this suppression; and its C. elegans ortholog TRA-2A acts as a membrane receptor for HER-1 ligand, directly sequesters the masculinizing protein FEM-3 through its intracellular C-terminal domain, and is proteolytically activated by the calpain TRA-3 to promote female cell fate."},"narrative":{"mechanistic_narrative":"TRA2A is a sequence-specific RNA-binding splicing factor that controls alternative and constitutive pre-mRNA splicing, functioning as a largely redundant, dosage-sensitive partner of its paralog TRA2B such that the two are synthetic-lethal: in cells with low TRA2B, TRA2A loss produces shared splicing defects, mitotic failure, and death that TRA2B overexpression rescues [PMID:40367120]. TRA2A binds defined intronic regulatory motifs to direct isoform choice — for example shifting RSRC2 exon usage in triple-negative breast cancer to drive paclitaxel resistance [PMID:28416606] and binding intronic silencers in influenza A M and NS mRNAs to repress viral splicing with strain-specific consequences for replication [PMID:32596447]. Its splicing activity is modulated by interacting proteins, including the angulins ILDR1/ILDR2, which it draws into the nucleus to co-regulate target splicing [PMID:28785060]. TRA2A protein levels are set by proteasomal turnover: the U-box E3 ligase E4B builds K11-linked polyubiquitin chains on TRA2A to trigger its degradation and thereby tune its splicing output [PMID:35669517], and degradation through CTSZ or the lncRNA lnc-ZEB2-19 relieves TRA2A-mediated suppression of IL32 splicing, enhancing IL-32 secretion and M2-tumor-associated-macrophage recruitment [PMID:37564197, PMID:40764928]. TRA2A also acts on long noncoding RNAs, directly binding and stabilizing MALAT1 and, through interaction with the m6A writer components METTL3 and RBMX, modulating MALAT1 m6A methylation and stability to promote cancer cell proliferation [PMID:34234858, PMID:37317053]. The C. elegans ortholog TRA-2A is a multipass membrane protein whose intracellular C-terminal domain promotes female fate by directly sequestering the masculinizing protein FEM-3 [PMID:7555725, PMID:10364161]; it serves as the receptor for the secreted ligand HER-1 [PMID:15289613] and is proteolytically activated by the calpain TRA-3 [PMID:10783162].","teleology":[{"year":1995,"claim":"Established the founding sex-determination role of the ortholog by showing that the intracellular C-terminal domain of TRA-2A is necessary and sufficient to promote female somatic fate by repressing the FEM proteins.","evidence":"Heat-shock transgenic overexpression and loss-of-function rescue in C. elegans","pmids":["7555725"],"confidence":"High","gaps":["Did not identify the direct molecular target of the C-terminal domain","No connection yet to RNA-level function"]},{"year":1999,"claim":"Defined the molecular mechanism of FEM repression by showing the TRA-2A C-terminus directly binds and sequesters FEM-3.","evidence":"Yeast two-hybrid, in vitro binding, and genetic suppression in C. elegans","pmids":["10364161"],"confidence":"High","gaps":["Did not address how TRA-2A activity is switched on or off","Ortholog-specific; no human relevance established"]},{"year":2000,"claim":"Showed how TRA-2A feminizing activity is generated, identifying calcium-dependent calpain cleavage by TRA-3 as the activating proteolytic step.","evidence":"In vitro proteolysis with calcium dependence, active-site mutagenesis, and genetics in C. elegans","pmids":["10783162"],"confidence":"High","gaps":["Physiological trigger of the calcium signal unresolved","Fate of cleavage products in vivo not fully traced"]},{"year":2004,"claim":"Established TRA-2A as a ligand-gated receptor by resolving the HER-1 structure and the surface that contacts the TRA-2A extracellular face.","evidence":"1.5 Å X-ray crystallography of HER-1 plus cell-based binding assays with surface mutants","pmids":["15289613"],"confidence":"High","gaps":["No structure of the TRA-2A receptor itself","Signal transduction from receptor binding to FEM regulation not mapped"]},{"year":2017,"claim":"Connected human TRA2A to disease-relevant splicing by demonstrating direct RNA binding that shifts RSRC2 isoforms to drive chemoresistance, and identified protein partners that recruit it to the nucleus.","evidence":"RIP, splicing RT-PCR and viability assays; Co-IP and localization imaging of angulin partners","pmids":["28416606","28785060"],"confidence":"Medium","gaps":["Reconstituted functional rescue incomplete","Genome-wide TRA2A binding map not defined","Single-lab angulin findings"]},{"year":2020,"claim":"Showed TRA2A binds defined intronic silencer motifs to repress splicing, with strain-specific outcomes in viral mRNA and direct stabilization of lncRNA targets.","evidence":"RNA binding/mutagenesis with viral replication assays; RIP and mRNA-stability assays in a BBB model","pmids":["32596447","32372707"],"confidence":"High","gaps":["Structural basis of motif selectivity unknown","LINC00662/SMD pathway from a single model system"]},{"year":2021,"claim":"Extended TRA2A function to oncogenic lncRNA biology by showing direct MALAT1 binding and stabilization that feeds the EZH2/β-catenin axis.","evidence":"RIP and RNA pull-down with gain/loss-of-function in esophageal cancer cells","pmids":["34234858"],"confidence":"Medium","gaps":["Single-lab functional axis","Mechanism of MALAT1 stabilization not yet linked to methylation"]},{"year":2022,"claim":"Identified how TRA2A protein abundance is controlled, showing E4B builds K11-linked ubiquitin chains to drive proteasomal degradation and tune splicing output.","evidence":"In vitro ubiquitination, Co-IP, proteasome inhibition, and splicing RT-PCR in HEK293","pmids":["35669517"],"confidence":"High","gaps":["Upstream signals controlling E4B engagement unknown","Single-lab cellular validation"]},{"year":2023,"claim":"Defined a noncanonical epitranscriptomic role and a degradation-coupled immune mechanism, linking TRA2A to the m6A writer complex and to IL32 splicing control via lncRNA-driven turnover.","evidence":"Co-IP with METTL3/RBMX, MeRIP-qPCR, CLIP; RNA pull-down with proteasomal degradation and IL32 splicing/in vivo assays","pmids":["37317053","37564197"],"confidence":"Medium","gaps":["Whether m6A regulation is direct catalytic involvement vs. scaffolding unclear","Single-lab models for both mechanisms"]},{"year":2025,"claim":"Established the core cellular logic of TRA2A as a dosage-sensitive, paralog-redundant splicing activator essential when TRA2B is limiting, and added transcriptional and degradation inputs that set its level in cancer.","evidence":"CRISPR/shRNA synthetic-lethality screens with RNA-seq and rescue; CTSZ degradation and H3K18la ChIP with splicing and in vivo models","pmids":["40367120","40764928","40907573"],"confidence":"High","gaps":["Full set of essential shared TRA2A/TRA2B targets undefined","Mechanism of mitotic failure on co-depletion not resolved"]},{"year":null,"claim":"How TRA2A's overlapping inputs — ubiquitin-mediated turnover, m6A-associated lncRNA regulation, transcriptional activation, and paralog dosage — are integrated to select specific target isoforms in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking abundance control to target specificity","No structural basis for RNA motif recognition","Most human mechanisms rest on single-lab studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,6,7,8,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,6,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,6,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14]}],"complexes":[],"partners":["TRA2B","METTL3","RBMX","ILDR1","ILDR2","E4B","FEM-3","HER-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13595","full_name":"Transformer-2 protein homolog alpha","aliases":["Transformer-2 protein homolog A"],"length_aa":282,"mass_kda":32.7,"function":"Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13595/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRA2A","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":4.0},{"gene":"SNRPA","stoichiometry":4.0},{"gene":"DDX21","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRA2A","total_profiled":1310},"omim":[{"mim_id":"602719","title":"TRANSFORMER 2 BETA HOMOLOG; TRA2B","url":"https://www.omim.org/entry/602719"},{"mim_id":"602718","title":"TRANSFORMER 2 ALPHA HOMOLOG; TRA2A","url":"https://www.omim.org/entry/602718"},{"mim_id":"602421","title":"CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; CFTR","url":"https://www.omim.org/entry/602421"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRA2A"},"hgnc":{"alias_symbol":["htra-2-alpha","AWMS1"],"prev_symbol":[]},"alphafold":{"accession":"Q13595","domains":[{"cath_id":"3.30.70.330","chopping":"113-193","consensus_level":"high","plddt":88.8531,"start":113,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13595","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13595-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13595-F1-predicted_aligned_error_v6.png","plddt_mean":58.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRA2A","jax_strain_url":"https://www.jax.org/strain/search?query=TRA2A"},"sequence":{"accession":"Q13595","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13595.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13595/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13595"}},"corpus_meta":[{"pmid":"10364161","id":"PMC_10364161","title":"Negative regulation of male development in Caenorhabditis elegans by a protein-protein interaction between TRA-2A and FEM-3.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10364161","citation_count":86,"is_preprint":false},{"pmid":"10783162","id":"PMC_10783162","title":"Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by TRA-3.","date":"2000","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10783162","citation_count":64,"is_preprint":false},{"pmid":"28416606","id":"PMC_28416606","title":"TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28416606","citation_count":44,"is_preprint":false},{"pmid":"7555725","id":"PMC_7555725","title":"A predicted membrane protein, TRA-2A, directs hermaphrodite development in Caenorhabditis elegans.","date":"1995","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7555725","citation_count":39,"is_preprint":false},{"pmid":"32372707","id":"PMC_32372707","title":"TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer's microenvironment.","date":"2020","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/32372707","citation_count":29,"is_preprint":false},{"pmid":"32596447","id":"PMC_32596447","title":"Human TRA2A determines influenza A virus host adaptation by regulating viral mRNA splicing.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32596447","citation_count":24,"is_preprint":false},{"pmid":"34234858","id":"PMC_34234858","title":"TRA2A Binds With LncRNA MALAT1 To Promote Esophageal Cancer Progression By Regulating EZH2/β-catenin Pathway.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34234858","citation_count":22,"is_preprint":false},{"pmid":"28785060","id":"PMC_28785060","title":"Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28785060","citation_count":17,"is_preprint":false},{"pmid":"30367895","id":"PMC_30367895","title":"TRA2A promotes proliferation, migration, invasion and epithelial mesenchymal transition of glioma cells.","date":"2018","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/30367895","citation_count":16,"is_preprint":false},{"pmid":"15289613","id":"PMC_15289613","title":"Crystal structure of Caenorhabditis elegans HER-1 and characterization of the interaction between HER-1 and TRA-2A.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15289613","citation_count":14,"is_preprint":false},{"pmid":"37564197","id":"PMC_37564197","title":"Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37564197","citation_count":13,"is_preprint":false},{"pmid":"37317053","id":"PMC_37317053","title":"Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m6 A methylation.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37317053","citation_count":12,"is_preprint":false},{"pmid":"40764928","id":"PMC_40764928","title":"The CTSZ-TRA2A-IL32 axis defines a targetable macrophage-dependent pathway in metastatic prostate cancer.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40764928","citation_count":5,"is_preprint":false},{"pmid":"35669517","id":"PMC_35669517","title":"Differential Degradation of TRA2A and PYCR2 Mediated by Ubiquitin E3 Ligase E4B.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35669517","citation_count":5,"is_preprint":false},{"pmid":"40907573","id":"PMC_40907573","title":"H3K18la Facilitates TRA2A-Mediated Alternative Splicing of STIL, Suppressing Ferroptosis and Cisplatin Treatment Sensitivity in Ovarian Cancer.","date":"2025","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/40907573","citation_count":1,"is_preprint":false},{"pmid":"40367120","id":"PMC_40367120","title":"Incomplete paralog compensation generates selective dependency on TRA2A in cancer.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40367120","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18370,"output_tokens":3804,"usd":0.09833,"retried_sync":true},"stage2":{"model":"claude-opus-4-8","input_tokens":11505,"output_tokens":3383,"usd":0.07105,"stage2_stop_reason":"end_turn"},"total_usd":0.16938,"stage1_batch_id":"msgbatch_0147LFpL5iCPFZF66xp23BqC","stage2_batch_id":"msgbatch_01Crtwc6eCsZh1CrnfJhY7J7","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"TRA-2A (C. elegans ortholog) is a predicted multipass membrane protein whose intracellular carboxy-terminal domain is necessary and sufficient to promote hermaphrodite (female) somatic development by negatively regulating the FEM proteins, as shown by heat-shock-driven transgenic rescue of tra-2 loss-of-function mutants and feminization of XO animals.\",\n      \"method\": \"Transgenic overexpression (heat-shock promoter), loss-of-function rescue assay in C. elegans\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo genetic rescue with domain dissection, replicated across multiple genotypes (XX loss-of-function and XO animals)\",\n      \"pmids\": [\"7555725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The carboxy-terminal intracellular region of C. elegans TRA-2A directly interacts with FEM-3 (a masculinizing protein), and this interaction is the mechanistic basis by which TRA-2A negatively regulates male development; overproduction of the TRA-2A C-terminal domain suppresses FEM-3-induced masculinization.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, genetic epistasis/suppression in C. elegans\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding + yeast two-hybrid + genetic epistasis with multiple genotypes, replicated across assays\",\n      \"pmids\": [\"10364161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"C. elegans TRA-3, an atypical calpain protease, cleaves TRA-2A in a calcium-dependent manner, generating a peptide predicted to have feminizing activity; this proteolytic cleavage is essential for TRA-3's in vivo function in female development.\",\n      \"method\": \"In vitro proteolytic assay with calcium dependence, active-site mutagenesis of TRA-3, genetic analysis in C. elegans\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of proteolytic activity plus mutagenesis plus in vivo genetic validation\",\n      \"pmids\": [\"10783162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HER-1, a secreted ligand, inhibits TRA-2A function by directly binding to the extracellular face of TRA-2A (which acts as its receptor); crystal structure of HER-1 (1.5 Å) identified a localized surface region critical for this interaction, confirmed by binding assays with TRA-2A-expressing cells and HER-1 surface mutants.\",\n      \"method\": \"X-ray crystallography (MAD, 1.5 Å), cell-based binding assay with HER-1 surface mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus functional mutagenesis plus cell-based binding assay\",\n      \"pmids\": [\"15289613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human TRA2A promotes paclitaxel resistance in triple-negative breast cancer by controlling alternative splicing of RSRC2, CALU, and PALM; specifically, TRA2A binds an upstream intronic sequence of RSRC2 exon 4 to shift isoform usage from RSRC2s to RSRC2l, reducing RSRC2 protein levels and driving resistance.\",\n      \"method\": \"siRNA knockdown/overexpression, RNA immunoprecipitation (RIP), alternative splicing RT-PCR, functional cell viability assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP establishes direct RNA binding, splicing assays confirm isoform shift, functional rescue not fully completed with reconstitution\",\n      \"pmids\": [\"28416606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILDR1 and ILDR2 (angulin proteins) physically interact with TRA2A (and TRA2B/SRSF1), translocate to the nucleus when TRA2A is present, and modulate alternative splicing of TUBD1, IQCB1, and PCDH19; LSR (third angulin) does not bind TRA2A.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, alternative splicing RT-PCR, subcellular localization imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and localization with functional splicing readout, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"28785060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human TRA2A regulates influenza A virus mRNA splicing by binding intronic splicing silencer motifs: in avian IAV (YS/H5N1) it binds the M mRNA to depress splicing (inhibiting replication), while in human IAV (PR8/H1N1) it binds the NS mRNA to depress splicing (benefiting replication); M-334 and NS-234/236 sites are critical for TRA2A binding, splicing, viral replication, and pathogenicity.\",\n      \"method\": \"RNA binding assays, viral splicing analysis, site-directed mutagenesis of viral RNA motifs, in vitro and in vivo viral replication assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of binding sites, in vitro and in vivo replication, multiple viral strains tested with mechanistic specificity\",\n      \"pmids\": [\"32596447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRA2A stabilizes LINC00662 lncRNA by directly binding to it (RBP-lncRNA interaction), which in an Alzheimer's disease BBB microenvironment model increases TRA2A/LINC00662 levels and reduces ELK4 mRNA via SMD pathway, thereby increasing BBB permeability.\",\n      \"method\": \"RNA immunoprecipitation (RIP), siRNA knockdown in vitro BBB model, mRNA stability assay\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP confirms direct binding, functional knockdown establishes pathway, single lab\",\n      \"pmids\": [\"32372707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRA2A directly binds MALAT1 lncRNA (confirmed by RIP and RNA pull-down), and its expression stabilizes MALAT1, which in turn modulates the EZH2/β-catenin pathway to promote proliferation and migration of esophageal cancer cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down, gain- and loss-of-function experiments\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding confirmed by two orthogonal RNA methods (RIP + pulldown), functional downstream validated, single lab\",\n      \"pmids\": [\"34234858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E4B (a U-box E3 ubiquitin ligase) ubiquitinates TRA2A both in vitro and in HEK293 cells, forming K11-linked polyubiquitin chains on TRA2A, leading to its proteasomal degradation; E4B-mediated TRA2A degradation regulates TRA2A's alternative splicing function and affects RSRC2 transcription. E4B interacts with TRA2A via its variable region.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor experiments, alternative splicing RT-PCR in HEK293 cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination reconstitution plus cellular Co-IP plus functional splicing readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35669517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRA2A interacts with METTL3 and RBMX (m6A writer complex components), and its depletion reduces m6A modification of MALAT1 lncRNA, causing structural alteration and reduced MALAT1 stability; TRA2A also affects KIAA1429 (WTAP) expression. This noncanonical m6A writer-associated function promotes esophageal cancer proliferation.\",\n      \"method\": \"Co-IP (TRA2A-METTL3/RBMX), MeRIP-qPCR, CLIP, RNA pull-down, stability assays, epitranscriptomic microarray\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP + CLIP + MeRIP-qPCR in single lab, multiple orthogonal methods confirming noncanonical m6A function\",\n      \"pmids\": [\"37317053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lnc-ZEB2-19 binds TRA2A and promotes its proteasomal degradation, thereby relieving TRA2A-mediated suppression of IL32 alternative splicing; TRA2A normally suppresses IL32 exon inclusion, and its degradation leads to enhanced IL-32 secretion that recruits M2-TAMs via ITGA5.\",\n      \"method\": \"RNA pull-down/RIP (lncRNA-TRA2A binding), proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding confirmed plus splicing functional assay plus in vivo model, single lab\",\n      \"pmids\": [\"37564197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRA2A and its paralog TRA2B function as synthetic lethal partners and largely redundant activators of both alternative and constitutive splicing; in cancer cell lines with TRA2B insufficiency, TRA2A depletion leads to defects in shared splicing targets, mitotic defects, and cell death; TRA2B overexpression rescues both aberrant splicing and lethality, demonstrating dosage-sensitive paralog compensation.\",\n      \"method\": \"CRISPR/shRNA loss-of-function screens, RNA-seq splicing analysis, TRA2B overexpression rescue, cell viability/mitosis phenotyping\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (synthetic lethality), transcriptome-wide splicing analysis, rescue experiments establishing dosage-sensitive redundancy\",\n      \"pmids\": [\"40367120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTSZ (cathepsin Z) overexpression in prostate cancer cells induces TRA2A degradation via the proteasome pathway, which relieves TRA2A-mediated suppression of IL32 alternative splicing, promoting M2-TAM recruitment and metastasis.\",\n      \"method\": \"Proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo metastasis models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteasomal degradation assay plus splicing analysis plus in vivo model, single lab\",\n      \"pmids\": [\"40764928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H3K18 lactylation (H3K18la) is enriched at the TRA2A promoter and activates TRA2A transcription; upregulated TRA2A then acts as a splicing factor to promote inclusion of STIL-L isoform, which inhibits ferroptosis in ovarian cancer cells by modulating iron metabolism.\",\n      \"method\": \"ChIP (H3K18la at TRA2A promoter), qRT-PCR/WB, RT-PCR for alternative splicing, xenograft model, CCK8/clone/EdU assays\",\n      \"journal\": \"Cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP establishes epigenetic activation, splicing assay confirms isoform shift, in vivo xenograft validates functional consequence, single lab\",\n      \"pmids\": [\"40907573\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRA2A (human) is a serine/arginine-rich splicing factor that functions as a direct RNA-binding protein to regulate alternative and constitutive pre-mRNA splicing (acting largely redundantly with its paralog TRA2B in a dosage-sensitive manner); it is subject to proteasomal degradation via E4B-mediated K11-linked ubiquitination; it binds oncogenic lncRNAs such as MALAT1 to modulate their m6A methylation and stability through interaction with the METTL3/RBMX writer complex; it suppresses IL32 alternative splicing and is degraded by CTSZ or lnc-ZEB2-19 to relieve this suppression; and its C. elegans ortholog TRA-2A acts as a membrane receptor for HER-1 ligand, directly sequesters the masculinizing protein FEM-3 through its intracellular C-terminal domain, and is proteolytically activated by the calpain TRA-3 to promote female cell fate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRA2A is a sequence-specific RNA-binding splicing factor that controls alternative and constitutive pre-mRNA splicing, functioning as a largely redundant, dosage-sensitive partner of its paralog TRA2B such that the two are synthetic-lethal: in cells with low TRA2B, TRA2A loss produces shared splicing defects, mitotic failure, and death that TRA2B overexpression rescues [#12]. TRA2A binds defined intronic regulatory motifs to direct isoform choice — for example shifting RSRC2 exon usage in triple-negative breast cancer to drive paclitaxel resistance [#4] and binding intronic silencers in influenza A M and NS mRNAs to repress viral splicing with strain-specific consequences for replication [#6]. Its splicing activity is modulated by interacting proteins, including the angulins ILDR1/ILDR2, which it draws into the nucleus to co-regulate target splicing [#5]. TRA2A protein levels are set by proteasomal turnover: the U-box E3 ligase E4B builds K11-linked polyubiquitin chains on TRA2A to trigger its degradation and thereby tune its splicing output [#9], and degradation through CTSZ or the lncRNA lnc-ZEB2-19 relieves TRA2A-mediated suppression of IL32 splicing, enhancing IL-32 secretion and M2-tumor-associated-macrophage recruitment [#11, #13]. TRA2A also acts on long noncoding RNAs, directly binding and stabilizing MALAT1 and, through interaction with the m6A writer components METTL3 and RBMX, modulating MALAT1 m6A methylation and stability to promote cancer cell proliferation [#8, #10]. The C. elegans ortholog TRA-2A is a multipass membrane protein whose intracellular C-terminal domain promotes female fate by directly sequestering the masculinizing protein FEM-3 [#0, #1]; it serves as the receptor for the secreted ligand HER-1 [#3] and is proteolytically activated by the calpain TRA-3 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding sex-determination role of the ortholog by showing that the intracellular C-terminal domain of TRA-2A is necessary and sufficient to promote female somatic fate by repressing the FEM proteins.\",\n      \"evidence\": \"Heat-shock transgenic overexpression and loss-of-function rescue in C. elegans\",\n      \"pmids\": [\"7555725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the direct molecular target of the C-terminal domain\", \"No connection yet to RNA-level function\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the molecular mechanism of FEM repression by showing the TRA-2A C-terminus directly binds and sequesters FEM-3.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, and genetic suppression in C. elegans\",\n      \"pmids\": [\"10364161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how TRA-2A activity is switched on or off\", \"Ortholog-specific; no human relevance established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed how TRA-2A feminizing activity is generated, identifying calcium-dependent calpain cleavage by TRA-3 as the activating proteolytic step.\",\n      \"evidence\": \"In vitro proteolysis with calcium dependence, active-site mutagenesis, and genetics in C. elegans\",\n      \"pmids\": [\"10783162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of the calcium signal unresolved\", \"Fate of cleavage products in vivo not fully traced\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established TRA-2A as a ligand-gated receptor by resolving the HER-1 structure and the surface that contacts the TRA-2A extracellular face.\",\n      \"evidence\": \"1.5 Å X-ray crystallography of HER-1 plus cell-based binding assays with surface mutants\",\n      \"pmids\": [\"15289613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the TRA-2A receptor itself\", \"Signal transduction from receptor binding to FEM regulation not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected human TRA2A to disease-relevant splicing by demonstrating direct RNA binding that shifts RSRC2 isoforms to drive chemoresistance, and identified protein partners that recruit it to the nucleus.\",\n      \"evidence\": \"RIP, splicing RT-PCR and viability assays; Co-IP and localization imaging of angulin partners\",\n      \"pmids\": [\"28416606\", \"28785060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconstituted functional rescue incomplete\", \"Genome-wide TRA2A binding map not defined\", \"Single-lab angulin findings\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed TRA2A binds defined intronic silencer motifs to repress splicing, with strain-specific outcomes in viral mRNA and direct stabilization of lncRNA targets.\",\n      \"evidence\": \"RNA binding/mutagenesis with viral replication assays; RIP and mRNA-stability assays in a BBB model\",\n      \"pmids\": [\"32596447\", \"32372707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of motif selectivity unknown\", \"LINC00662/SMD pathway from a single model system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TRA2A function to oncogenic lncRNA biology by showing direct MALAT1 binding and stabilization that feeds the EZH2/β-catenin axis.\",\n      \"evidence\": \"RIP and RNA pull-down with gain/loss-of-function in esophageal cancer cells\",\n      \"pmids\": [\"34234858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional axis\", \"Mechanism of MALAT1 stabilization not yet linked to methylation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified how TRA2A protein abundance is controlled, showing E4B builds K11-linked ubiquitin chains to drive proteasomal degradation and tune splicing output.\",\n      \"evidence\": \"In vitro ubiquitination, Co-IP, proteasome inhibition, and splicing RT-PCR in HEK293\",\n      \"pmids\": [\"35669517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling E4B engagement unknown\", \"Single-lab cellular validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a noncanonical epitranscriptomic role and a degradation-coupled immune mechanism, linking TRA2A to the m6A writer complex and to IL32 splicing control via lncRNA-driven turnover.\",\n      \"evidence\": \"Co-IP with METTL3/RBMX, MeRIP-qPCR, CLIP; RNA pull-down with proteasomal degradation and IL32 splicing/in vivo assays\",\n      \"pmids\": [\"37317053\", \"37564197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A regulation is direct catalytic involvement vs. scaffolding unclear\", \"Single-lab models for both mechanisms\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the core cellular logic of TRA2A as a dosage-sensitive, paralog-redundant splicing activator essential when TRA2B is limiting, and added transcriptional and degradation inputs that set its level in cancer.\",\n      \"evidence\": \"CRISPR/shRNA synthetic-lethality screens with RNA-seq and rescue; CTSZ degradation and H3K18la ChIP with splicing and in vivo models\",\n      \"pmids\": [\"40367120\", \"40764928\", \"40907573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of essential shared TRA2A/TRA2B targets undefined\", \"Mechanism of mitotic failure on co-depletion not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRA2A's overlapping inputs — ubiquitin-mediated turnover, m6A-associated lncRNA regulation, transcriptional activation, and paralog dosage — are integrated to select specific target isoforms in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking abundance control to target specificity\", \"No structural basis for RNA motif recognition\", \"Most human mechanisms rest on single-lab studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 6, 7, 8, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 6, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 6, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRA2B\", \"METTL3\", \"RBMX\", \"ILDR1\", \"ILDR2\", \"E4B\", \"FEM-3\", \"HER-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}