Affinage

TRA2B

Transformer-2 protein homolog beta · UniProt P62995

Length
288 aa
Mass
33.7 kDa
Annotated
2026-06-10
25 papers in source corpus 19 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRA2B (Htra2-beta/SFRS10) is a nuclear SR-like splicing factor that directs alternative exon usage across developmental and disease-relevant pre-mRNAs by binding AG/GAA-rich exonic splicing enhancers (PMID:10931943, PMID:25261467). It promotes inclusion of target exons through direct ESE recognition—demonstrated for SMN exon 7 and PKCδ exon 9—and serves as an adaptor that tethers other SR proteins such as SRp30c, which lack intrinsic affinity for these enhancers, to the regulated RNA (PMID:10931943, PMID:11875052, PMID:25261467). The factor localizes to nuclear speckles with SC35 and interacts with multiple SR proteins, and it is expressed as distinct isoforms differing in their RS domains (PMID:9212162, PMID:9790768). Its splicing program governs a broad set of targets—CD44, LPIN1, TGFBR2, wnt11b, Tubulinδ1, Shugoshin-like2, and androgen receptor (AR-V7)—linking TRA2B to cell growth, hepatic lipogenesis, myogenic and cardiac/pronephric development, and prostate cancer progression (PMID:19439532, PMID:21803291, PMID:25620705, PMID:37705195, PMID:41919500). TRA2B is essential in vivo: ubiquitous deletion causes early embryonic lethality, and neural-specific loss triggers neural progenitor apoptosis through p21 (CDKN1A) upregulation (PMID:20190275, PMID:23818142, PMID:24586484). Its abundance is homeostatically buffered by a conserved poison exon, and disruption of this feedback—elevating TRA2B protein—produces aberrant hyper-responsive splicing incompatible with meiotic prophase and causes azoospermia (PMID:39748121). TRA2B activity is further modulated by oxidative-stress-induced phosphorylation and nucleocytoplasmic relocalization, and its transcription is controlled by an hnRNPA1–G-quadruplex switch in its promoter (PMID:19439532, PMID:31311954).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 Medium

    Establishing TRA2B as a bona fide SR-family splicing factor required showing where it acts and what it associates with; nuclear speckle co-localization with SC35 and SR-protein interactions defined it as a spliceosome-associated regulator with alternatively spliced isoforms.

    Evidence Yeast two-hybrid with SC35 bait, immunofluorescence localization, and cloning of an isoform lacking an SR domain

    PMID:9212162 PMID:9790768

    Open questions at the time
    • Yeast two-hybrid interactions not confirmed by Co-IP
    • Functional consequence of the SR-domain-less isoform not yet defined
    • No direct RNA targets identified at this stage
  2. 2000 High

    The central question of how TRA2B regulates splicing was answered by showing direct binding to an AG-rich exonic splicing enhancer, establishing sequence-specific ESE recognition as its core mechanism with disease relevance to SMN.

    Evidence SMN2 minigene expression in human/mouse cells with RNA-binding assay to the exon 7 AG-rich ESE

    PMID:10931943

    Open questions at the time
    • Did not resolve which co-factors are recruited downstream of ESE binding
    • Endogenous (non-minigene) regulation not fully established
  3. 2002 High

    How TRA2B cooperates with other splicing factors was clarified by showing it acts as an adaptor: SRp30c cannot bind the ESE itself but is recruited via direct protein–protein contact with TRA2B.

    Evidence Co-IP of hTra2β1–SRp30c plus binding-site mutagenesis in SMN minigene splicing assay

    PMID:11875052

    Open questions at the time
    • Generality of the adaptor mechanism beyond SMN exon 7 not tested
    • Stoichiometry and structure of the TRA2B–SRp30c–RNA complex unknown
  4. 2009 Medium

    Whether TRA2B regulation extends to disease-relevant targets and responds to cellular state was addressed by showing bidirectional control of CD44 variable-exon splicing tied to growth, and stress-induced phosphorylation/relocalization.

    Evidence siRNA knockdown and overexpression in AGS gastric cancer cells with CD44 RT-PCR; arsenite stress with immunofluorescence and phospho-western

    PMID:19439532

    Open questions at the time
    • Kinase mediating stress phosphorylation not identified
    • Direct binding to CD44 pre-mRNA not demonstrated
    • Single cell line
  5. 2010 High

    The in vivo necessity of TRA2B was established by ubiquitous knockout causing early embryonic lethality, while showing its role in Smn splicing is more limited endogenously than minigene studies implied.

    Evidence Conditional Sfrs10 knockout mice (Cre/loxP, Hb9-Cre) and MEF deletion with RT-PCR for Smn isoforms

    PMID:20190275

    Open questions at the time
    • Molecular cause of embryonic lethality not pinned to specific targets
    • Discrepancy with minigene SMN2 results unresolved
  6. 2011 High

    TRA2B's role in metabolism was defined by demonstrating it controls LPIN1 isoform choice, with a genetic rescue establishing LPIN1β as the causal downstream effector of its lipogenic phenotype.

    Evidence SFRS10 siRNA in hepatocytes, Sfrs10 heterozygous mice, and LPIN1β-siRNA rescue with VLDL/triglyceride measurement

    PMID:21803291

    Open questions at the time
    • Direct ESE binding within LPIN1 not mapped
    • Tissue-specificity of metabolic effect not fully delineated
  7. 2014 High

    The mechanism of TRA2B essentiality in the nervous system was resolved by neural conditional knockouts that linked its loss to neural progenitor apoptosis via p21 upregulation, and identified in vivo splicing targets.

    Evidence Cortex-specific and Nestin-Cre conditional knockouts, exon microarray (Tubulinδ1, Shugoshin-like2), and p21 functional assay in NSC34 cells; PKCδ exon 9 binding mapped by RIP/mutagenesis

    PMID:23818142 PMID:24586484 PMID:25261467

    Open questions at the time
    • Direct splicing target driving apoptosis vs. p21 induction not fully separated
    • Whether p21 upregulation is a direct splicing consequence unknown
  8. 2015 High

    TRA2B's developmental splicing program was extended to morphogenesis by showing it controls wnt11b intron retention, generating a dominant-negative isoform that governs cardiac and pronephric gene programs.

    Evidence Morpholino knockdown in Xenopus, RNA-seq (142 splicing changes), forced-intron-retention minigenes, and functional cardiac/pronephric assays

    PMID:25620705

    Open questions at the time
    • Conservation of wnt11b regulation in mammals not tested
    • Direct binding to wnt11b not mapped
  9. 2016 Medium

    A pathogenic role beyond normal splicing was shown via a TRA2B-DNAH5 gene fusion driving lung squamous carcinoma through a SIRT6-ERK1/2-MMP1 axis targetable by ERK inhibition.

    Evidence Exon array, fusion transcript cloning, cell line functional studies, and selumetinib treatment

    PMID:27670699

    Open questions at the time
    • Mechanism connecting fusion to SIRT6-ERK axis incompletely defined
    • Single lab; in vivo validation limited
  10. 2017 Medium

    A novel mode of TRA2B regulation was identified by showing angulin proteins ILDR1/ILDR2 physically bind TRA2B, undergo TRA2B-dependent nuclear translocation, and influence specific splicing targets.

    Evidence Co-IP, subcellular localization, ILDR1/2 siRNA knockdown, and RT-PCR of TUBD1/IQCB1/Pcdh19

    PMID:28785060

    Open questions at the time
    • Reciprocal validation and direct vs. indirect binding not fully established
    • Functional significance of angulin-TRA2B axis in tissue unclear
  11. 2019 High

    How TRA2B levels are transcriptionally set was addressed by showing a promoter G-quadruplex represses transcription and that hnRNPA1 binding to the G4 relieves repression.

    Evidence Circular dichroism, EMSA, ChIP, promoter activity and minigene assays

    PMID:31311954

    Open questions at the time
    • In vivo physiological relevance of G4 control not established
    • Whether this couples to the poison-exon feedback unknown
  12. 2022 Medium

    The functional distinction between TRA2B isoforms was sharpened by showing 5' coding variants shift expression toward the RS1-lacking Tra2β-3 isoform, which acts as a dominant-negative repressor of CHEK1 exon 3 inclusion.

    Evidence RNA-seq/western on patient-derived cells and isoform/CHEK1 minigene transfection in HEK-293

    PMID:36549593

    Open questions at the time
    • Clinical phenotype causally linked only via cell models
    • Range of Tra2β-3-repressed targets not defined
  13. 2023 Medium

    Isoform-specific function was further established in development by showing the two TRA2B isoforms differentially regulate TGFBR2 splicing to tune canonical TGF-β signaling during myogenesis.

    Evidence Iso-seq and scRNA-seq during myogenesis with isoform-specific functional and TGFBR2 splicing assays

    PMID:37705195

    Open questions at the time
    • Direct binding to TGFBR2 not mapped
    • Single lab
  14. 2025 High

    The mechanism maintaining TRA2B homeostasis and the consequence of its breakdown were defined by showing a conserved poison exon buffers protein levels, with its deletion causing hyper-responsive splicing, meiotic-prophase cell death, and azoospermia.

    Evidence Mouse poison-exon deletion knock-in with RNA analysis, spermatogenesis phenotyping, and Tra2β western blot

    PMID:39748121

    Open questions at the time
    • Specific hyper-responsive splice targets driving meiotic failure not enumerated
    • Generality of poison-exon buffering across tissues not fully tested
  15. 2026 Medium

    TRA2B's role in oncogenic splicing was extended by showing it binds AR-V7 mRNA and promotes constitutively active androgen receptor variant synthesis, supporting prostate cancer growth.

    Evidence RNA-targeting CasRx interactor screen, splicing assays, and growth assays upon TRA2B attenuation

    PMID:41919500

    Open questions at the time
    • ESE site within AR transcripts not mapped
    • Relative contributions of TRA2B vs. TRA2A not separated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRA2B substrate selectivity, isoform-specific target repertoires, and the structural basis of its adaptor-mediated SR-protein recruitment are integrated into a unified code remains unresolved.
  • No structural model of TRA2B–ESE–SR-protein complex
  • Genome-wide direct binding map not consolidated across tissues
  • Mechanism distinguishing inclusion-promoting vs. dominant-negative isoform activities incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0140110 transcription regulator activity 3 GO:0045182 translation regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3
Partners
HNRNPA1ILDR1ILDR2SC35SRP30CTRA2A

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Htra2-beta1 (TRA2B) promotes inclusion of SMN exon 7 by directly binding an AG-rich exonic splicing enhancer (ESE) within SMN exon 7, stimulating full-length SMN2 expression in human and mouse cells. Transient expression in human/mouse cells carrying SMN2 minigene; RNA binding assay showing direct interaction with AG-rich ESE in exon 7 Proceedings of the National Academy of Sciences of the United States of America High 10931943
2002 SRp30c stimulates SMN exon 7 inclusion through direct protein–protein interaction with hTra2β1; SRp30c does not directly bind SMN exon 7 RNA but requires hTra2β1 as an adaptor to associate with the AG-rich ESE. Co-immunoprecipitation demonstrating direct hTra2β1–SRp30c interaction; minigene splicing assay with mutations in hTra2β1 binding site abolishing SRp30c association Human molecular genetics High 11875052
1997 hTra2β1 is a nuclear protein that co-localizes with SC35 in a speckled pattern and interacts with multiple SR proteins in yeast two-hybrid assays; a second isoform hTra2β2 generated by alternative splicing lacks an SR domain. Yeast two-hybrid screen using SC35 as bait; subcellular localization by immunofluorescence; molecular cloning DNA and cell biology Medium 9212162
1998 The TRA2B isoform htra2-beta3, which lacks the first SR domain, is expressed in the nucleus and interacts with a subset of SR proteins. Yeast two-hybrid and in vivo interaction assay; RT-PCR; subcellular localization Genomics Medium 9790768
2009 TRA2B (Tra2β) regulates alternative splicing of CD44 pre-mRNA: knockdown of Tra2β caused skipping of the central variable region of CD44, while overexpression stimulated combinatorial inclusion of multiple variable exons, and this was linked to regulation of cell growth. siRNA knockdown and overexpression in gastric cancer cells (AGS); RT-PCR of CD44 splicing; cell growth assay American journal of physiology. Cell physiology Medium 19439532
2009 Under oxidative stress, Tra2β undergoes enhanced phosphorylation and translocates from the nucleus to the cytoplasm during an acute phase, followed by re-accumulation in the nucleus. Arsenite treatment of AGS cells; immunofluorescence; western blot for phosphorylation American journal of physiology. Cell physiology Medium 19439532
2010 Ubiquitous homozygous deletion of Sfrs10 in mice causes early embryonic lethality around E7.5, establishing an essential role during embryogenesis. In murine embryonic fibroblasts, deletion of Sfrs10 increased SmnΔ7 isoform 3–4-fold but showed no impact on full-length SMN2 splicing. Conditional Sfrs10 knockout mice (Cre/loxP); Hb9-Cre motor neuron-specific knockout; MEF-based Cre-mediated deletion; RT-PCR for Smn isoforms Human molecular genetics High 20190275
2011 TRA2B (SFRS10) regulates alternative splicing of LPIN1; reduced SFRS10 favors the lipogenic LPIN1β isoform, leading to increased lipogenesis and lipid accumulation in hepatocytes. SFRS10-specific siRNA knockdown in hepatocytes; Sfrs10 heterozygous mice; LPIN1β-specific siRNA rescue experiment; measurement of VLDL secretion and triglycerides Cell metabolism High 21803291
2012 Digitoxin treatment depletes TRA2B (Tra2-β) protein from cells, and re-expression of TRA2B after digitoxin treatment restores normal splicing of its targets, demonstrating that digitoxin-induced splicing changes are directly caused by TRA2B depletion. Transcriptome-wide splicing analysis; re-expression rescue experiments; identification of Tra2-β binding sites enriched at regulated exons RNA (New York, N.Y.) Medium 22456266
2014 TRA2B depletion in cortex-specific Tra2b mutant mice results in apoptosis of neural progenitor cells and disorganization of the cortical plate, establishing TRA2B as essential for neural progenitor survival during cortical neurogenesis. Cortex-specific Tra2b conditional knockout mice; histology; apoptosis assays The Journal of comparative neurology High 23818142
2014 Neuronal-specific Tra2b knockout mice (Nestin-Cre) die at birth and show massive apoptosis in cortical ventricular layers. Exon array analysis identified Tubulinδ1 and Shugoshin-like2 as in vivo splicing targets of Tra2b, and loss of Tra2b leads to upregulation of p21 (CDKN1A), which was functionally linked to cell death in NSC34 neuronal cells. Nestin-Cre conditional knockout; exon microarray; p21 functional assay in NSC34 cells PloS one High 24586484
2014 TRA2B regulates alternative splicing of PKCδ exon 9: TRA2B directly binds PKCδI exon 9 (mapped by mutagenesis and RNA-immunoprecipitation), and this binding is required for PKCδI splice variant expression during preadipocyte cell cycle progression. Heterologous PKCδ minigene splicing assay; mutagenesis; RNA-immunoprecipitation (RIP); siRNA knockdown in 3T3L1 preadipocytes The Journal of biological chemistry High 25261467
2015 Tra2b knockdown in Xenopus causes defective somitogenesis and multiple developmental defects. RNA-seq identified 142 splicing changes; Tra2b promotes skipping of the last intron of wnt11b, and retention of this intron produces a truncated dominant-negative Wnt11b-short isoform that impairs cardiac gene induction and pronephric tubule formation. Morpholino knockdown in Xenopus; RNA-seq; minigene/forced-intron-retention experiments; functional cardiac and pronephric assays Cell reports High 25620705
2016 A TRA2B-DNAH5 gene fusion occurs in lung squamous cell carcinoma and drives malignant progression through a SIRT6-ERK1/2-MMP1 signaling axis; ERK1/2 inhibition with selumetinib suppresses growth of cells expressing this fusion. Exon array analyses; molecular cloning of fusion transcript; functional studies in cell lines; ERK1/2 inhibitor treatment Cell research Medium 27670699
2017 ILDR1 and ILDR2 (angulin proteins) physically bind TRA2B and translocate to the nucleus when TRA2B is present; this interaction mediates alternative splicing of TUBD1, IQCB1, and Pcdh19. Co-immunoprecipitation; subcellular localization assays; siRNA knockdown of ILDR1/ILDR2; RT-PCR for alternative splicing targets Scientific reports Medium 28785060
2019 hnRNPA1 interacts with a G-quadruplex (G4) structure in the TRA2B promoter to stimulate TRA2B transcription; G4 formation suppresses TRA2B transcription, while hnRNPA1 binding to G4 relieves this repression. Circular dichroism; EMSA; chromatin immunoprecipitation (ChIP); minigene assays; promoter activity assay Scientific reports High 31311954
2022 Variants in the 5' coding region of TRA2B decrease expression of the canonical Tra2β-1 isoform and increase expression of the shorter Tra2β-3 isoform (lacking the N-terminal RS1 domain); overexpression of Tra2β-3 interferes with incorporation of CHEK1 exon 3, acting as a dominant-negative splicing repressor. RNA sequencing and western blot on patient-derived cells; transfection of Tra2β1-GFP, Tra2β3-GFP, and CHEK1 exon 3 plasmids into HEK-293 cells; minigene splicing assay Genetics in medicine Medium 36549593
2023 Two isoforms of TRA2B play distinct roles in myogenic differentiation by differentially regulating alternative splicing of TGFBR2 to modulate canonical TGF-β signaling cascades. Iso-seq and scRNA-seq during myogenesis; isoform-specific functional analysis; splicing assays for TGFBR2 Cell proliferation Medium 37705195
2025 A poison exon (PE) in the Tra2b gene controls TRA2B protein concentration via a homeostatic feedback mechanism; deletion of the ultra-conserved PE causes increased Tra2β protein levels that drive aberrant hyper-responsive splice patterns incompatible with meiotic prophase, leading to catastrophic cell death and azoospermia. Mouse genetics (PE deletion knock-in); RNA analysis; phenotypic analysis of spermatogenesis; western blot for Tra2β protein levels The EMBO journal High 39748121
2026 TRA2B (and its paralog TRA2A) bind AR-V7 mRNA and facilitate alternative splicing of androgen receptor transcripts, promoting synthesis of constitutively active AR splice variants (including AR-V7) at the expense of full-length AR; attenuation of TRA2-mediated splicing diminishes prostate cancer cell growth. RNA-targeting CasRx approach to identify AR-V7 mRNA protein interactors; splicing assays; cell growth assays upon TRA2B attenuation The Journal of clinical investigation Medium 41919500

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proceedings of the National Academy of Sciences of the United States of America 274 10931943
2011 Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell metabolism 136 21803291
2002 SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2 beta 1. Human molecular genetics 121 11875052
2020 Bone marrow mesenchymal stem cell-derived exosomal miR-206 inhibits osteosarcoma progression by targeting TRA2B. Cancer letters 110 32682951
1998 Human transformer-2-beta gene (SFRS10): complete nucleotide sequence, chromosomal localization, and generation of a tissue-specific isoform. Genomics 77 9790768
1997 Molecular cloning of htra2-beta-1 and htra2-beta-2, two human homologs of tra-2 generated by alternative splicing. DNA and cell biology 72 9212162
2012 The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B. RNA (New York, N.Y.) 56 22456266
2010 Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and has no impact on full-length SMN/Smn splicing. Human molecular genetics 53 20190275
2019 HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. Scientific reports 43 31311954
2014 Splicing factor TRA2B is required for neural progenitor survival. The Journal of comparative neurology 37 23818142
2009 Oxidative stress-induced alternative splicing of transformer 2beta (SFRS10) and CD44 pre-mRNAs in gastric epithelial cells. American journal of physiology. Cell physiology 37 19439532
2015 The alternative splicing regulator Tra2b is required for somitogenesis and regulates splicing of an inhibitory Wnt11b isoform. Cell reports 31 25620705
2014 Neuronal-specific deficiency of the splicing factor Tra2b causes apoptosis in neurogenic areas of the developing mouse brain. PloS one 29 24586484
2016 Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma. Cell research 27 27670699
2014 Transformer 2β (Tra2β/SFRS10) positively regulates the progression of NSCLC via promoting cell proliferation. Journal of molecular histology 20 24952301
2017 Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1. Scientific reports 17 28785060
2019 Expression of TRA2B in endometrial carcinoma and its regulatory roles in endometrial carcinoma cells. Oncology letters 11 31452736
2014 Transformer 2β homolog (Drosophila) (TRA2B) regulates protein kinase C δI (PKCδI) splice variant expression during 3T3L1 preadipocyte cell cycle. The Journal of biological chemistry 10 25261467
2023 Bulk and single-cell alternative splicing analyses reveal roles of TRA2B in myogenic differentiation. Cell proliferation 9 37705195
2013 Expression analysis of an evolutionarily conserved alternative splicing factor, Sfrs10, in age-related macular degeneration. PloS one 8 24098751
2025 An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division. The EMBO journal 6 39748121
2022 Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 6 36549593
2013 The expression analysis of Sfrs10 and Celf4 during mouse retinal development. Gene expression patterns : GEP 3 23932931
2026 Splicing factor TRA2B enhances synthesis of androgen receptor variant AR-V7 in prostate cancer cells. The Journal of clinical investigation 1 41919500
2023 TRA2B Gene Splice Variant Linked to Seizures and Neurodevelopmental Delay: A Second Case Study. International journal of molecular sciences 1 37958557

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