Affinage

TRA2A

Transformer-2 protein homolog alpha · UniProt Q13595

Length
282 aa
Mass
32.7 kDa
Annotated
2026-06-13
16 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    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

    PMID:7555725

    Open questions at the time
    • Did not identify the direct molecular target of the C-terminal domain
    • No connection yet to RNA-level function
  2. 1999 High

    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

    PMID:10364161

    Open questions at the time
    • Did not address how TRA-2A activity is switched on or off
    • Ortholog-specific; no human relevance established
  3. 2000 High

    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

    PMID:10783162

    Open questions at the time
    • Physiological trigger of the calcium signal unresolved
    • Fate of cleavage products in vivo not fully traced
  4. 2004 High

    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

    PMID:15289613

    Open questions at the time
    • No structure of the TRA-2A receptor itself
    • Signal transduction from receptor binding to FEM regulation not mapped
  5. 2017 Medium

    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

    PMID:28416606 PMID:28785060

    Open questions at the time
    • Reconstituted functional rescue incomplete
    • Genome-wide TRA2A binding map not defined
    • Single-lab angulin findings
  6. 2020 High

    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

    PMID:32372707 PMID:32596447

    Open questions at the time
    • Structural basis of motif selectivity unknown
    • LINC00662/SMD pathway from a single model system
  7. 2021 Medium

    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

    PMID:34234858

    Open questions at the time
    • Single-lab functional axis
    • Mechanism of MALAT1 stabilization not yet linked to methylation
  8. 2022 High

    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

    PMID:35669517

    Open questions at the time
    • Upstream signals controlling E4B engagement unknown
    • Single-lab cellular validation
  9. 2023 Medium

    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

    PMID:37317053 PMID:37564197

    Open questions at the time
    • Whether m6A regulation is direct catalytic involvement vs. scaffolding unclear
    • Single-lab models for both mechanisms
  10. 2025 High

    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

    PMID:40367120 PMID:40764928 PMID:40907573

    Open questions at the time
    • Full set of essential shared TRA2A/TRA2B targets undefined
    • Mechanism of mitotic failure on co-depletion not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 1
Partners
E4BFEM-3HER-1ILDR1ILDR2METTL3RBMXTRA2B

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 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. Transgenic overexpression (heat-shock promoter), loss-of-function rescue assay in C. elegans Development (Cambridge, England) High 7555725
1999 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. Yeast two-hybrid, in vitro binding assay, genetic epistasis/suppression in C. elegans Genes & development High 10364161
2000 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. In vitro proteolytic assay with calcium dependence, active-site mutagenesis of TRA-3, genetic analysis in C. elegans Genes & development High 10783162
2004 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. X-ray crystallography (MAD, 1.5 Å), cell-based binding assay with HER-1 surface mutants Proceedings of the National Academy of Sciences of the United States of America High 15289613
2017 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. siRNA knockdown/overexpression, RNA immunoprecipitation (RIP), alternative splicing RT-PCR, functional cell viability assays Molecular cancer therapeutics Medium 28416606
2017 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. Co-immunoprecipitation, siRNA knockdown, alternative splicing RT-PCR, subcellular localization imaging Scientific reports Medium 28785060
2020 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. RNA binding assays, viral splicing analysis, site-directed mutagenesis of viral RNA motifs, in vitro and in vivo viral replication assays Science advances High 32596447
2020 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. RNA immunoprecipitation (RIP), siRNA knockdown in vitro BBB model, mRNA stability assay RNA biology Medium 32372707
2021 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. RNA immunoprecipitation (RIP), RNA pull-down, gain- and loss-of-function experiments Journal of Cancer Medium 34234858
2022 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. In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor experiments, alternative splicing RT-PCR in HEK293 cells Frontiers in cell and developmental biology High 35669517
2023 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. Co-IP (TRA2A-METTL3/RBMX), MeRIP-qPCR, CLIP, RNA pull-down, stability assays, epitranscriptomic microarray Cancer science Medium 37317053
2023 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. RNA pull-down/RIP (lncRNA-TRA2A binding), proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo rescue experiments International journal of biological sciences Medium 37564197
2025 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. CRISPR/shRNA loss-of-function screens, RNA-seq splicing analysis, TRA2B overexpression rescue, cell viability/mitosis phenotyping PLoS genetics High 40367120
2025 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. Proteasomal degradation assays, IL32 pre-mRNA splicing analysis, in vitro/in vivo metastasis models Journal of translational medicine Medium 40764928
2025 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. ChIP (H3K18la at TRA2A promoter), qRT-PCR/WB, RT-PCR for alternative splicing, xenograft model, CCK8/clone/EdU assays Cancer research and treatment Medium 40907573

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Negative regulation of male development in Caenorhabditis elegans by a protein-protein interaction between TRA-2A and FEM-3. Genes & development 86 10364161
2000 Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A by TRA-3. Genes & development 64 10783162
2017 TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing. Molecular cancer therapeutics 44 28416606
1995 A predicted membrane protein, TRA-2A, directs hermaphrodite development in Caenorhabditis elegans. Development (Cambridge, England) 39 7555725
2020 TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer's microenvironment. RNA biology 29 32372707
2020 Human TRA2A determines influenza A virus host adaptation by regulating viral mRNA splicing. Science advances 24 32596447
2021 TRA2A Binds With LncRNA MALAT1 To Promote Esophageal Cancer Progression By Regulating EZH2/β-catenin Pathway. Journal of Cancer 22 34234858
2017 Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1. Scientific reports 17 28785060
2018 TRA2A promotes proliferation, migration, invasion and epithelial mesenchymal transition of glioma cells. Brain research bulletin 16 30367895
2004 Crystal structure of Caenorhabditis elegans HER-1 and characterization of the interaction between HER-1 and TRA-2A. Proceedings of the National Academy of Sciences of the United States of America 14 15289613
2023 Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis. International journal of biological sciences 13 37564197
2023 Splicing factor TRA2A contributes to esophageal cancer progression via a noncanonical role in lncRNA m6 A methylation. Cancer science 12 37317053
2025 The CTSZ-TRA2A-IL32 axis defines a targetable macrophage-dependent pathway in metastatic prostate cancer. Journal of translational medicine 5 40764928
2022 Differential Degradation of TRA2A and PYCR2 Mediated by Ubiquitin E3 Ligase E4B. Frontiers in cell and developmental biology 5 35669517
2025 Incomplete paralog compensation generates selective dependency on TRA2A in cancer. PLoS genetics 1 40367120
2025 H3K18la Facilitates TRA2A-Mediated Alternative Splicing of STIL, Suppressing Ferroptosis and Cisplatin Treatment Sensitivity in Ovarian Cancer. Cancer research and treatment 1 40907573

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