Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003729 mRNA binding	IBA GO_REF:0000033	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0000398 mRNA splicing, via spliceosome	IBA GO_REF:0000033	MODIFY	Summary: The family-level annotation correctly places TRA2B in spliceosomal mRNA splicing, but describes it as core machinery rather than as a regulator of splice-site choice. Reason: TRA2B regulates both constitutive and alternative target exons, so the general regulatory parent GO:0048024 is more accurate here than the alternative-only child. It also avoids implying that TRA2B performs the core splicing reaction. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Proposed replacements: regulation of mRNA splicing, via spliceosome Supporting Evidence: PMID:25208576 Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β control.
GO:0005681 spliceosomal complex	IBA GO_REF:0000033	ACCEPT	Summary: Spliceosomal-complex association is consistent with phylogenetic, experimental, and pathway evidence and with TRA2B coupling enhancer-bound RNA to snRNP machinery. Reason: TRA2B functions in dynamic pre-mRNA processing assemblies, and independent mechanistic evidence connects ESE-bound TRA2 proteins to U1/U2 spliceosomal machinery. Supporting Evidence: PMID:10339552 The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound "activators" and the snRNP machinery of the spliceosome.
GO:0003676 nucleic acid binding	IEA GO_REF:0000002	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0003723 RNA binding	IEA GO_REF:0000002	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005515 protein binding	IPI PMID:17332742 Composition and three-dimensional EM structure of double aff...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: splicing factor binding
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: splicing factor binding
GO:0005515 protein binding	IPI PMID:22365833 Dynamic protein-protein interaction wiring of the human spli...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: splicing factor binding
GO:0005515 protein binding	IPI PMID:23602568 The protein interaction landscape of the human CMGC kinase g...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: protein kinase binding
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: A proteome-scale binary-interaction map yields many partners, but bare protein binding is uninformative and the mixed partner set cannot be represented by one precise molecular-function term. Reason: Four partners in this collapsed tuple recur in independent splicing-factor or kinase interaction datasets and can be classified in those source-specific rows. The other eleven span heterogeneous molecular classes, so no single informative replacement represents the full HuRI set. The binary interactions remain available in the source database without a generic GO term that overstates their functional interpretation.
GO:0005515 protein binding	IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: protein kinase binding
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: protein kinase binding
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: splicing factor binding
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	UNDECIDED	Summary: The HuRI-derived self-association is encoded by the IPI/WITH record, but the cached article does not expose the TRA2B-specific pair for direct verification. Reason: The interaction may be present in HuRI's underlying dataset, but the available text only describes the atlas globally. Keep the curated row undecided until the pair-level source data can be inspected rather than treating dataset-level evidence as positive support.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0032991 protein-containing complex	IDA PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	MODIFY	Summary: The experimental complex association is real but the generic protein-containing complex term does not identify the relevant RNA-processing assembly. Reason: TRA2B associates with splicing regulators and enhancer-dependent spliceosomal machinery. Spliceosomal complex is the more informative cellular-component term. Proposed replacements: spliceosomal complex Supporting Evidence: PMID:10339552 The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound "activators" and the snRNP machinery of the spliceosome.
GO:0003723 RNA binding	IMP PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0005515 protein binding	IPI PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: splicing factor binding
GO:0005634 nucleus	IDA PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0019904 protein domain specific binding	IPI PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	KEEP AS NON CORE	Summary: Domain-specific association with an RNA-splicing regulator is experimentally supported but is a partner interaction rather than TRA2B's defining RNA-recognition activity. Reason: The term is informative and more specific than protein binding, but the core activity remains sequence-specific pre-mRNA recognition and regulation of exon selection.
GO:0042802 identical protein binding	IDA PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	UNDECIDED	Summary: The curated IDA self-association cannot be verified from the cached abstract, which reports TRA2B interactions with RBM-family proteins but does not mention TRA2B self-binding. Reason: The experimental curator may have used data in the unavailable full text, so the annotation is not removed or called wrong. It remains undecided until the self-association experiment can be inspected directly.
GO:0043484 regulation of RNA splicing	IMP PMID:10749975 RBMY, a probable human spermatogenesis factor, and other hnR...	MODIFY	Summary: The experiment establishes regulation of enhancer-dependent pre-mRNA splicing but does not restrict TRA2B's regulatory program to alternative target exons. Reason: Perturbing the RBM interaction domain inhibited splicing of a TRA2B-bound enhancer substrate. The spliceosome-specific regulatory parent captures this result and remains compatible with later evidence that TRA2 proteins control both constitutive and alternative target exons. Proposed replacements: regulation of mRNA splicing, via spliceosome Supporting Evidence: PMID:10749975 Incubation with the protein interaction domain of RBM inhibited splicing in vitro of a specific pre-mRNA substrate containing an essential enhancer bound by Tra2beta.
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IMP PMID:25689357 Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its ...	ACCEPT	Summary: Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central biological process. Reason: Target-specific perturbation and biochemical studies show that TRA2B changes exon inclusion, with activating or repressive outcomes determined by target and partner context.
GO:0005681 spliceosomal complex	IMP PMID:25689357 Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its ...	ACCEPT	Summary: Spliceosomal-complex association is consistent with phylogenetic, experimental, and pathway evidence and with TRA2B coupling enhancer-bound RNA to snRNP machinery. Reason: TRA2B functions in dynamic pre-mRNA processing assemblies, and independent mechanistic evidence connects ESE-bound TRA2 proteins to U1/U2 spliceosomal machinery. Supporting Evidence: PMID:10339552 The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound "activators" and the snRNP machinery of the spliceosome.
GO:0036002 pre-mRNA binding	IDA PMID:25689357 Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its ...	ACCEPT	Summary: Direct pre-mRNA binding is a core TRA2B activity and is supported by target-specific RNA-binding and splicing assays. Reason: The annotation is accurate. Structural work further resolves the activity as sequence-specific recognition of purine-rich pre-mRNA elements. Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0071333 cellular response to glucose stimulus	IMP PMID:25689357 Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its ...	KEEP AS NON CORE	Summary: TRA2B abundance changes during glucose deprivation in the AGER/RAGE splicing experiment, but this is a condition-specific response rather than its core activity. Reason: The experimental observation is supported, yet it describes one regulatory context for TRA2B expression and downstream isoform balance, not the molecular role that defines TRA2B. Supporting Evidence: PMID:25689357 Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-72103	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770119	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770129	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770131	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770132	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770141	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770142	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770145	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770236	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9770847	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9794542	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970141	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970179	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970189	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970190	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970191	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970193	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970282	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970294	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970318	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970320	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970428	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970429	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9970431	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005634 nucleus	HDA PMID:16791210 Dynamic proteomics in individual human cells uncovers widesp...	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0005515 protein binding	IPI PMID:12165565 hnRNP-G promotes exon 7 inclusion of survival motor neuron (...	MODIFY	Summary: Direct interactions with RBMY1A1 and RBMX are more informatively represented as splicing factor binding than as generic protein binding. Reason: The WITH/FROM partners P0DJD3 and P38159 are RBMY1A1 and RBMX, and the paper directly shows specific binding of hnRNP-G/RBM proteins to Htra2-beta1 in an exon-inclusion mechanism. Splicing factor binding preserves that informative partner class. Proposed replacements: splicing factor binding Supporting Evidence: PMID:12165565 hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7 pre-mRNA.
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IDA PMID:12165565 hnRNP-G promotes exon 7 inclusion of survival motor neuron (...	ACCEPT	Summary: Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central biological process. Reason: Target-specific perturbation and biochemical studies show that TRA2B changes exon inclusion, with activating or repressive outcomes determined by target and partner context. Supporting Evidence: PMID:12165565 hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7 pre-mRNA.
GO:0003729 mRNA binding	IDA PMID:12165565 hnRNP-G promotes exon 7 inclusion of survival motor neuron (...	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0000381 regulation of alternative mRNA splicing, via spliceosome	IDA PMID:12761049 HnRNP G and Tra2beta: opposite effects on splicing matched b...	ACCEPT	Summary: Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central biological process. Reason: Target-specific perturbation and biochemical studies show that TRA2B changes exon inclusion, with activating or repressive outcomes determined by target and partner context. Supporting Evidence: PMID:12761049 We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor.
GO:0003729 mRNA binding	IDA PMID:12761049 HnRNP G and Tra2beta: opposite effects on splicing matched b...	MODIFY	Summary: The annotation captures TRA2B RNA recognition but is less specific than the established sequence-selective activity of its RNA-recognition motif. Reason: Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative than generic nucleic acid, RNA, or mRNA binding. Proposed replacements: sequence-specific mRNA binding Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0048026 positive regulation of mRNA splicing, via spliceosome	IDA PMID:15009664 Tau exon 10, whose missplicing causes frontotemporal dementi...	ACCEPT	Summary: Positive regulation of spliceosomal mRNA splicing is supported for MAPT exon 10 and other enhancer-dependent targets. Reason: The cached abstract for the original paper does not name TRA2B, so the curator's full-text assessment is retained and independently corroborated by direct TRA2B binding and RNA-interference studies on the same MAPT enhancer. Supporting Evidence: PMID:12649279 The interaction between Tra2 beta and the exonic splicing enhancer correlates with the activity of this enhancer element in stimulating splicing. PMID:16308321 Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta significantly reduces exon 10 splicing.
GO:0005515 protein binding	IPI PMID:19282290 Heterogeneous nuclear ribonucleoprotein G regulates splice s...	MODIFY	Summary: The WITH/FROM accession P84586 resolves to rat Rbmxrtl, an hnRNP G retrogene-like pre-mRNA splicing regulator, so the interaction is more informative than generic protein binding. Reason: The source paper characterizes hnRNP G-family proteins as supraspliceosomal regulators of alternative splice-site selection. Splicing factor binding therefore records the verified partner class while remaining secondary to TRA2B's RNA-binding activity. Proposed replacements: splicing factor binding Supporting Evidence: PMID:19282290 hnRNP G is part of the supraspliceosome, where it regulates alternative splice site selection in a concentration-dependent manner.
GO:0005515 protein binding	IPI PMID:17577209 The interactome of the histone gene regulatory factor HiNF-P...	MODIFY	Summary: The reported physical association is better described by the molecular class of the identified partner than by generic protein binding. Reason: The GOA WITH/FROM identifier records a DNA-binding transcription factor partner. Replacing protein binding preserves the interaction evidence while making the annotation biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory activity. Proposed replacements: DNA-binding transcription factor binding
GO:0005515 protein binding	IPI PMID:15169763 Distinct sequence motifs within the 68-kDa subunit of cleava...	MODIFY	Summary: CPSF6/CFIm68 binds TRA2B through a defined C-terminal alternating-charge domain, making domain-specific binding more informative than generic protein binding. Reason: PMID:15169763 maps the hTra2beta interaction specifically to the C-terminal alternating-charge domain of CFIm68. GO:0019904 captures that experimentally localized interface without elevating this secondary partner interaction to a core TRA2B function. Proposed replacements: protein domain specific binding Supporting Evidence: PMID:15169763 CF I(m)68 interacts with SRp20, 9G8, and hTra2beta, members of the SR family of splicing factors, via its C-terminal alternating charge domain.
GO:0000375 RNA splicing, via transesterification reactions	TAS PMID:9546399 Human Tra2 proteins are sequence-specific activators of pre-...	MODIFY	Summary: TRA2B regulates spliceosomal exon choice rather than catalysing constitutive pre-mRNA splicing. Reason: The founding biochemical study explicitly found no constitutive-splicing activity and instead demonstrated sequence-specific activation of enhancer-dependent splicing. The regulatory alternative-splicing term captures the activity without implying that TRA2B performs the core transesterification reaction. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome Supporting Evidence: PMID:9546399 Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition with competitor RNA.
GO:0000398 mRNA splicing, via spliceosome	IDA PMID:9546399 Human Tra2 proteins are sequence-specific activators of pre-...	MODIFY	Summary: TRA2B regulates spliceosomal exon choice rather than catalysing constitutive pre-mRNA splicing. Reason: The founding biochemical study explicitly found no constitutive-splicing activity and instead demonstrated sequence-specific activation of enhancer-dependent splicing. The regulatory alternative-splicing term captures the activity without implying that TRA2B performs the core transesterification reaction. Proposed replacements: regulation of alternative mRNA splicing, via spliceosome Supporting Evidence: PMID:9546399 Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition with competitor RNA.
GO:0005634 nucleus	IDA PMID:9546399 Human Tra2 proteins are sequence-specific activators of pre-...	ACCEPT	Summary: Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA splicing regulator. Reason: This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its RNA-splicing activity. Supporting Evidence: PMID:9212162 htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
GO:1990825 sequence-specific mRNA binding	IDA PMID:21399644 Molecular basis of purine-rich RNA recognition by the human ...	NEW	Summary: Direct structural and mutational evidence establishes sequence-specific recognition of an AGAA element by the TRA2B RNA-recognition motif. Reason: GOA contains only broader RNA- and mRNA-binding terms. This term captures the experimentally demonstrated molecular specificity and is the best representation of TRA2B's core molecular function. Supporting Evidence: PMID:21399644 The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
GO:0048025 negative regulation of mRNA splicing, via spliceosome	IDA PMID:12761049 HnRNP G and Tra2beta: opposite effects on splicing matched b...	NEW	Summary: TRA2B can repress exon incorporation as well as activate it, depending on the exon and cellular context. Reason: Existing GOA records the general and positive regulatory activities but omits the directly demonstrated repressive direction. The paper reports several exons for which hTra2beta acts as a repressor. Supporting Evidence: PMID:12761049 We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor.

Core Functions

Binds purine-rich sequences in pre-mRNA exonic splicing enhancers through its RRM and cooperates with splicing factors and snRNP machinery to regulate exon selection. Sequence specificity is the defining molecular feature represented here; the accepted pre-mRNA binding annotation independently captures the precursor-RNA substrate. Depending on RNA and partner context, TRA2B promotes or represses exon inclusion, while TRA2A can compensate at many endogenous targets.

Molecular Function:

sequence-specific mRNA binding

Directly Involved In:

regulation of mRNA splicing, via spliceosome

Cellular Locations:

nucleoplasm

In Complex:

spliceosomal complex

Supporting Evidence:

PMID:21399644
The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM.
PMID:9546399
Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition with competitor RNA.
PMID:10339552
The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound "activators" and the snRNP machinery of the spliceosome.
PMID:12761049
We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor.
PMID:25208576
Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β control.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:10749975

RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins interact with Tra2beta and affect splicing.

TRA2B associates with hnRNP-G/RBMY-family proteins in enhancer-dependent splicing complexes.

"Endogenous hnRNP G and Tra2beta proteins are associated in HeLa nuclear extracts."

PMID:12165565

hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-beta1.

TRA2B binds the AG-rich SMN2 exon 7 enhancer and cooperates with hnRNP-G/RBM proteins to promote inclusion.

"hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7 pre-mRNA."

PMID:12761049

HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding.

TRA2B can activate or repress exon incorporation according to target context.

"We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor."

PMID:15009664

Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated by an intricate interplay of cis elements and trans factors.

The abstract reports a broad survey of MAPT exon 10 regulators but does not identify TRA2B.

"We also carried out a comprehensive survey of the influence of splicing regulators on exon 10 inclusion"

PMID:15169763

Distinct sequence motifs within the 68-kDa subunit of cleavage factor Im mediate RNA binding, protein-protein interactions, and subcellular localization.

CFIm68/CPSF6 interacts with TRA2B through its C-terminal alternating-charge domain.

"CF I(m)68 interacts with SRp20, 9G8, and hTra2beta, members of the SR family of splicing factors, via its C-terminal alternating charge domain."

PMID:16791210

Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins.

PMID:17332742

Composition and three-dimensional EM structure of double affinity-purified, human prespliceosomal A complexes.

PMID:17577209

The interactome of the histone gene regulatory factor HiNF-P suggests novel cell cycle related roles in transcriptional control and RNA processing.

PMID:19282290

Heterogeneous nuclear ribonucleoprotein G regulates splice site selection by binding to CC(A/C)-rich regions in pre-mRNA.

hnRNP G-family proteins are supraspliceosomal regulators of alternative splice-site choice.

"hnRNP G is part of the supraspliceosome, where it regulates alternative splice site selection in a concentration-dependent manner."

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22365833

Dynamic protein-protein interaction wiring of the human spliceosome.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:23602568

The protein interaction landscape of the human CMGC kinase group.

PMID:25689357

Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its potential role in AD pathogenesis.

TRA2B and hnRNP A1 antagonistically regulate alternative AGER/RAGE isoform splicing.

"hnRNP A1 and Transformer2β-1 (Tra2β-1) were involved in the alternative splicing of mRAGE and esRAGE. Functionally, two factors had an antagonistic effect"
Glucose deprivation reduces TRA2B abundance and changes the AGER/RAGE isoform ratio.

"Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1."

PMID:32296183

A reference map of the human binary protein interactome.

HuRI is a proteome-scale map of human binary protein interactions.

"Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'."

PMID:32707033

Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:9546399

Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing.

Human TRA2 proteins bind GAA-repeat enhancers and activate enhancer-dependent rather than constitutive splicing.

"Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition with competitor RNA."

PMID:10339552

The SRm160/300 splicing coactivator is required for exon-enhancer function.

ESE-bound TRA2 proteins are coupled to U1/U2 snRNP machinery through the SRm160/300 coactivator.

"The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound "activators" and the snRNP machinery of the spliceosome."

PMID:12649279

Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2 beta.

TRA2B directly binds the MAPT exon 10 enhancer and its binding tracks enhancer-dependent splicing.

"The interaction between Tra2 beta and the exonic splicing enhancer correlates with the activity of this enhancer element in stimulating splicing."

PMID:14709600

Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing of its pre-mRNA.

TRA2B binds four enhancers in its poison exon and promotes nonproductive exon inclusion in a negative-feedback loop.

"TRA2-BETA1 binds to four enhancers present in exon 2, which activates its inclusion. Inclusion of exon 2 generates mRNAs that are not translated into proteins."

PMID:16308321

Arginine/serine-rich protein interaction domain-dependent modulation of a tau exon 10 splicing enhancer: altered interactions and mechanisms for functionally antagonistic FTDP-17 mutations Delta280K AND N279K.

Reducing endogenous TRA2B decreases MAPT exon 10 splicing.

"Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta significantly reduces exon 10 splicing."

PMID:20190275

Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and has no impact on full-length SMN/Smn splicing.

Mouse Sfrs10/Tra2b loss did not alter full-length SMN2 splicing, demonstrating target and redundancy context.

"Surprisingly, deletion of Sfrs10 by recombinant Cre showed no impact on SMN2 splicing but increased SMN levels."

PMID:20926394

Structural basis for the dual RNA-recognition modes of human Tra2-β RRM.

The TRA2B RRM recognizes CAA and GAA-rich RNA through distinct structural modes.

"This study indicates that the hTra2-β RRM recognizes two types of RNA sequences in different RNA binding modes."

PMID:21399644

Molecular basis of purine-rich RNA recognition by the human SR-like protein Tra2-β1.

The TRA2B RRM specifically recognizes an AGAA motif, with RNA contacts validated in an SMN2 splicing assay.

"The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM."

PMID:25208576

Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons.

Endogenous TRA2A and TRA2B target exons show paralog compensation, with strong shifts after joint depletion.

"Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β control."

PMID:9212162

Molecular cloning of htra2-beta-1 and htra2-beta-2, two human homologs of tra-2 generated by alternative splicing.

TRA2B is nuclear, colocalizes with SC35-positive speckles, and interacts with SR proteins.

"htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern."

Reactome:R-HSA-72103

Formation of pre-mRNPs

Reactome:R-HSA-9770119

Formation of the Spliceosomal E complex

Reactome:R-HSA-9770129

Formation of the Spliceosomal A complex

Reactome:R-HSA-9770131

Formation of the Spliceosomal B* complex

Reactome:R-HSA-9770132

Formation of the Spliceosomal Pre-B complex

Reactome:R-HSA-9770141

Formation of the Spliceosomal C* complex

Reactome:R-HSA-9770142

Formation of the Spliceosomal B complex

Reactome:R-HSA-9770145

Formation of the Spliceosomal Bact complex

Reactome:R-HSA-9770236

Formation of the Spliceosomal P complex and exon ligation

Reactome:R-HSA-9770847

Spliceosomal P complex dissociates yielding the intron-containing complex (ILS) and the spliced mRNP (new)

Reactome:R-HSA-9794542

Formation of the Spliceosomal C complex containing intron lariat

Reactome:R-HSA-9970141

Core CPA complex binds capped pre-mRNA

Reactome:R-HSA-9970179

Recruitment of other CPA components to pre-mRNA-bound CPA core

Reactome:R-HSA-9970189

PABPN1-stimulated PAPOL synthesizes polyA tail at distal 3'UTR PAS

Reactome:R-HSA-9970190

PP1 dephosphorylates RNA Pol II

Reactome:R-HSA-9970191

RBBP6 activates CPSF complex

Reactome:R-HSA-9970193

CPSF3 cleaves pre-mRNA at distal 3'UTR PAS

Reactome:R-HSA-9970282

U1 snRNP suppresses CPSF3-mediated pre-mRNA cleavage at intronic PAS

Reactome:R-HSA-9970294

CPSF3 cleaves pre-mRNA at proximal 3'UTR PAS

Reactome:R-HSA-9970318

PABPN1-stimulated PAPOL synthesizes polyA tail at proximal 3'UTR PAS

Reactome:R-HSA-9970320

PABPN1-stimulated PAPOL synthesizes polyA tail at intronic PAS

Reactome:R-HSA-9970428

CPA complex components dissociate from polyadenylated pre-mRNA (distal 3'UTR PAS)

Reactome:R-HSA-9970429

CPA complex components dissociate from polyadenylated pre-mRNA (intronic PAS)

Reactome:R-HSA-9970431

CPA complex components dissociate from polyadenylated pre-mRNA (proximal 3'UTR PAS)

Suggested Experiments

Experiment: Introduce rapid endogenous degrons for TRA2B and TRA2A in several differentiated human cell types and compare acute single and joint depletion by TRA2B/TRA2A eCLIP and short- plus long-read RNA sequencing. Rescue from a matched locus with wild-type TRA2B or an RRM RNA-contact-defective mutant, and classify as direct targets only events with nearby binding and wild-type-specific rescue.

Hypothesis: TRA2B has both paralog-redundant and cell-type-specific direct splicing targets that are masked by TRA2A compensation.

Type: Acute degron perturbation, eCLIP, and RNA sequencing

Experiment: Test a massively parallel minigene library varying AGAA/GAA and structured CAA elements, their position relative to splice sites, and adjacent regulator motifs under titrated TRA2B expression and perturbation of TRA2A, RBMX, SR proteins, CLK kinases, and SRPK kinases. Validate predictive sequence features by base editing representative endogenous exons.

Hypothesis: Motif position, local RNA architecture, partner abundance, and RS-domain phosphorylation determine whether TRA2B activates or represses exon inclusion.

Type: Massively parallel splicing reporter and endogenous base editing

Experiment: Establish endogenous expression of each isoform by long-read RNA sequencing and targeted proteomics, then perform matched single-copy isoform rescue in an acute TRA2B-depletion background. Compare nuclear localization, eCLIP profiles, protein interactomes, and rescue of direct splicing events.

Hypothesis: TRA2B isoform 3 retains RNA binding but has altered partner recruitment, whereas isoform 2 is unstable or lacks splicing-regulatory activity.

Type: Isoform-resolved proteomics, eCLIP, and functional rescue

Deep Research

Falcon

(TRA2B-deep-research-falcon.md)

Comprehensive Research Report: TRA2B (Transformer-2 Protein Homolog Beta) Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-29T14:20:31.179842

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: TRA2B (Transformer-2 Protein Homolog Beta)

1. Gene and Protein Identity

TRA2B (also known as SFRS10) encodes Transformer-2 protein homolog beta (TRA2β), a sequence-specific RNA-binding protein and splicing activator belonging to the serine/arginine-rich (SR)-like protein family (swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2, swarup2025dualroleof pages 1-2). The gene is located on human chromosome 3q27.2 and produces a protein (UniProt P62995) that is the mammalian homolog of the Drosophila sex-determination factor Transformer-2 (swarup2025dualroleof pages 1-2, xue2023tra2thedominant pages 1-3). In humans, the Tra2 family comprises two paralogs—TRA2A and TRA2B—which share approximately 75% overall sequence identity and have partially overlapping functions (xue2023tra2thedominant pages 5-7, xue2023tra2thedominant pages 1-3). TRA2B is typically expressed at substantially higher levels than TRA2A in most human cell types (best2014humantra2proteins pages 1-2).

The following table provides a structured summary of TRA2B's key properties:

Feature	TRA2B summary
Gene name	TRA2B; synonym SFRS10 (OpenTargets Search: -TRA2B, swarup2025dualroleof pages 2-4)
UniProt accession	P62995 (OpenTargets Search: -TRA2B, swarup2025dualroleof pages 2-4)
Chromosome location	3q27.2 (swarup2025dualroleof pages 1-2)
Protein family	SR-like / Tra2 family RNA-binding splicing factor; part of the broader serine/arginine-rich splicing regulator class (OpenTargets Search: -TRA2B, best2014humantra2proteins pages 1-2, xue2023tra2thedominant pages 1-3)
Domain architecture	RS1–RRM–RS2: N-terminal arginine/serine-rich domain, central RNA recognition motif, C-terminal arginine/serine-rich domain (swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2, xue2023tra2thedominant pages 1-3)
RNA-binding motif	Preferentially binds AGAA-rich / GAA-rich enhancer sequences; extended consensus includes AGAAGA; CAA-rich targets have also been reported (best2014humantra2proteins pages 1-2, grellscheid2011identificationofevolutionarily pages 4-5, swarup2025dualroleof pages 2-4)
Number of exons	9 exons reported for the canonical gene architecture in review literature (swarup2025dualroleof pages 2-4)
Key isoforms	TRA2β-L: full-length isoform containing RS1 + RRM + RS2; TRA2β-S: truncated isoform lacking exon 2 / lacking RS1 but retaining RRM + RS2 (swarup2025dualroleof pages 2-4)
Paralog	TRA2A; approximately 75% sequence identity with TRA2B (xue2023tra2thedominant pages 5-7, xue2023tra2thedominant pages 1-3)
Conservation	RRM ~85% identical to TRA2A; ~54% identical to Drosophila TRA2; TRA2B poison exon reported as 100% conserved in human, mouse, and rat (swarup2025dualroleof pages 1-2, swarup2025dualroleof pages 2-4)
Subcellular localization	Primarily nuclear; strong nucleolar staining reported; some cytoplasmic/membrane staining observed in certain contexts (grellscheid2011identificationofevolutionarily pages 4-5, xue2023tra2thedominant pages 5-7)
Primary function	Sequence-specific splicing activator that promotes exon inclusion by binding exonic splicing enhancers and facilitating spliceosome assembly; can also act as a co-activator, and RS1-lacking forms can repress some target exons (xue2023tra2thedominant pages 3-4, grellscheid2011identificationofevolutionarily pages 1-2, grellscheid2011identificationofevolutionarily pages 5-6)
Autoregulation	Negative-feedback control via a poison exon whose inclusion introduces a premature stop codon and triggers nonsense-mediated decay (NMD), limiting TRA2B protein accumulation (swarup2025dualroleof pages 2-4, dalgliesh2025anultraconservedpoison pages 1-2)

Table: This table summarizes the validated structural features, localization, and core functional properties of human TRA2B/ SFRS10. It is useful as a quick-reference overview linking domain architecture and RNA-binding specificity to TRA2B’s role as an autoregulated splicing activator.

2. Protein Structure and Domain Architecture

TRA2β possesses a characteristic modular domain organization consisting of a single central RNA Recognition Motif (RRM) flanked by two arginine/serine-rich (RS) domains: RS1 at the N-terminus and RS2 at the C-terminus (swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2, xue2023tra2thedominant pages 1-3). The RRM domain is the primary determinant of RNA-binding specificity and directly interacts with target pre-mRNA sequences to facilitate spliceosome assembly (swarup2025dualroleof pages 2-4, swarup2025dualroleof pages 1-2). The RRM is highly conserved, sharing approximately 85% sequence identity with TRA2A and 54% identity with Drosophila TRA2 (swarup2025dualroleof pages 1-2). The RS domains mediate both protein–protein and protein–RNA interactions that are critical for splice site selection and exon inclusion; they also facilitate RNA–RNA base pairing and interaction with other RS-domain-containing proteins in the spliceosome (swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2).

The TRA2B gene produces multiple splice isoforms. The full-length isoform TRA2β-L contains all functional domains (RS1–RRM–RS2), while the truncated isoform TRA2β-S lacks exon 2 and consequently the RS1 domain, retaining only the RRM and RS2 (swarup2025dualroleof pages 2-4). Importantly, the N-terminal RS1 domain is essential for the splicing activator function of TRA2β: isoforms lacking this domain not only lose activator activity but can potently repress the same target exons that are activated by full-length TRA2β protein (grellscheid2011identificationofevolutionarily pages 1-2, grellscheid2011identificationofevolutionarily pages 5-6). This domain-dependent functional switch between activation and repression represents a key regulatory mechanism.

3. RNA Binding Specificity and Mechanism

TRA2β preferentially recognizes and binds AGAA-rich sequences, with the extended consensus motif AGAAGA representing the most frequently identified binding site in transcriptome-wide CLIP studies (~20% of CLIP tags) (grellscheid2011identificationofevolutionarily pages 4-5, swarup2025dualroleof pages 2-4). The GAA trinucleotide core is essential for efficient RNA-protein interaction: when only a single GAA triplet is present, 89% of binding events contain a downstream G residue (GAAG) (grellscheid2011identificationofevolutionarily pages 4-5). Modifications to the AGAA motif—such as replacing the first A with C, G, or T—reduce binding affinity approximately 2-fold (xue2023tra2thedominant pages 5-7). In addition to AGAA-rich sequences, CAA-rich single-stranded sequences have also been identified as TRA2β binding targets (best2014humantra2proteins pages 1-2, grellscheid2011identificationofevolutionarily pages 4-5). TRA2β can adopt alternative RNA-binding modes, including binding to stem-loop RNA structures (xue2023tra2thedominant pages 5-7).

HITS-CLIP analysis in mouse testis demonstrated that approximately 69% of Tra2β binding sites map to protein-coding genes, with 29% located specifically within exons (grellscheid2011identificationofevolutionarily pages 4-5). TRA2β binds to exonic splicing enhancers (ESEs) positioned close to regulatory splice sites, strengthening spliceosome assembly and promoting exon inclusion (xue2023tra2thedominant pages 3-4). Efficient splicing activation of target exons frequently requires multiple cooperative TRA2β binding sites, explaining why regulated exons tend to be longer than average and contain a high density of binding motifs (grellscheid2011identificationofevolutionarily pages 5-6, grellscheid2011identificationofevolutionarily pages 1-2). Electrophoretic mobility shift assays (EMSA) have demonstrated that very low concentrations of Tra2β protein (50 ng) can form large protein-RNA complexes, indicative of high-affinity binding (grellscheid2011identificationofevolutionarily pages 5-6).

4. Primary Function: Splicing Activation

The primary molecular function of TRA2β is as a sequence-specific splicing activator that promotes exon inclusion in pre-mRNAs (xue2023tra2thedominant pages 3-4, grellscheid2011identificationofevolutionarily pages 1-2). TRA2β activates cassette exons—the most common form of alternative splicing in human and mouse cells—and can activate both weak 3' and 5' splice sites (xue2023tra2thedominant pages 3-4). It achieves this by binding to ESE sequences and recruiting spliceosomal components to promote productive splice site recognition (xue2023tra2thedominant pages 3-4, swarup2025dualroleof pages 2-4).

Beyond direct RNA-binding-dependent activation, TRA2β can also function as a splicing co-activator independent of its own RRM-mediated RNA binding (grellscheid2011identificationofevolutionarily pages 1-2). This dual mechanism—direct activation via RNA binding and indirect co-activation—expands the repertoire of exons that TRA2β can regulate. Importantly, the N-terminal RS1 domain, which is conserved between flies and humans, is indispensable for splicing activation; versions of TRA2β lacking RS1 function as potent repressors rather than activators of the same target exons (grellscheid2011identificationofevolutionarily pages 1-2, grellscheid2011identificationofevolutionarily pages 5-6).

5. Subcellular Localization

TRA2β is predominantly a nuclear protein that carries out its splicing regulatory functions in the nucleus, consistent with its role in pre-mRNA processing (grellscheid2011identificationofevolutionarily pages 4-5). Immunohistochemistry of mouse testis sections using affinity-purified antibodies revealed strong nuclear staining in spermatocytes, round spermatids, and elongating spermatids (grellscheid2011identificationofevolutionarily pages 4-5). Immunohistochemistry across 79 standard tissue cell types revealed strong nucleolar staining, with some cytoplasmic and membrane localization also observed (xue2023tra2thedominant pages 5-7). The nuclear localization is consistent with the protein's function at sites of pre-mRNA splicing, where it interacts with the spliceosome and other SR-domain-containing proteins.

6. Autoregulation via Poison Exon and Paralog Compensation

A critical feature of TRA2β biology is its autoregulatory negative feedback mechanism. TRA2β regulates its own expression by promoting inclusion of an ultra-conserved poison exon (PE) located between exons 1 and 2 of its own TRA2B pre-mRNA (swarup2025dualroleof pages 2-4, dalgliesh2025anultraconservedpoison pages 1-2). When TRA2β protein levels rise, the protein binds to its own PE and activates its inclusion, introducing a premature stop codon that targets the resulting transcript for nonsense-mediated decay (NMD) (dalgliesh2025anultraconservedpoison pages 1-2, dalgliesh2025ultra‐conservedpoisonexons pages 2-4). This limits further protein accumulation and prevents toxic overexpression. The PE is remarkably conserved: it is 100% identical in sequence between humans, mice, and rats, and 96% conserved across approximately 300 million years of vertebrate evolution, underscoring its functional importance (swarup2025dualroleof pages 2-4).

In addition to self-regulation, TRA2β cross-regulates its paralog TRA2A via a poison exon mechanism: TRA2β activates inclusion of a poison exon in TRA2A mRNA, thereby repressing TRA2A protein expression (best2014humantra2proteins pages 1-2). This paralog compensation system ensures that simultaneous depletion of both proteins—but not individual depletion—produces substantial shifts in splicing of endogenous target exons, as the remaining paralog can compensate for loss of the other (best2014humantra2proteins pages 1-2).

7. Key Splicing Targets and Biological Pathways

TRA2β regulates the alternative splicing of a diverse set of target transcripts across multiple biological pathways. The following table summarizes the major validated targets:

Target Gene	Exon/Isoform	Splicing Effect of TRA2B	Biological Pathway	Disease Association
CHEK1	Exon 3 / full-length CHK1	Promotes exon 3 inclusion and supports production of full-length CHK1; TRA2A/TRA2B depletion reduces productive CHEK1 splicing, lowers CHK1 protein, and increases DNA-damage marker γH2AX (swarup2025dualroleof pages 7-9, swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2)	DNA damage response, chromosome biology, cell viability (swarup2025dualroleof pages 2-4, best2014humantra2proteins pages 1-2)	Genome instability/cell-death phenotypes; aberrant TRA2B isoforms linked to neurodevelopmental disease and cancer-related survival pathways (swarup2025dualroleof pages 14-15, swarup2025dualroleof pages 7-9, best2014humantra2proteins pages 1-2)
LPIN1	Exon 6; LPIN1a vs LPIN1b	High TRA2B/SFRS10 promotes exon 6 skipping and favors LPIN1a; reduced TRA2B increases exon 6 inclusion and the lipogenic LPIN1b isoform (pihlajamaki2011expressionofthe pages 1-2, pihlajamaki2011expressionofthe pages 4-5)	Hepatic lipogenesis, triglyceride synthesis, VLDL secretion, metabolic regulation (pihlajamaki2011expressionofthe pages 1-2, pihlajamaki2011expressionofthe pages 4-5, pihlajamaki2011expressionofthe pages 3-4)	Obesity, fatty liver/metabolic dysfunction, hypertriglyceridemia (pihlajamaki2011expressionofthe pages 1-2, pihlajamaki2011expressionofthe pages 4-5, pihlajamaki2011expressionofthe pages 3-4)
SMN2	Exon 7	Promotes exon 7 inclusion, increasing the productive SMN2 isoform in vitro; effect in vivo appears limited unless strongly overexpressed (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 7-9)	snRNP/SMN pathway, motor-neuron RNA processing (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 7-9)	Spinal muscular atrophy (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 7-9)
RAGE (AGER)	esRAGE vs mRAGE splice products	Shifts splicing toward soluble esRAGE and away from membrane mRAGE; functionally opposes hnRNP A1-driven mRAGE production (swarup2025dualroleof pages 7-9)	AGE/RAGE signaling, inflammatory and neurodegenerative response modulation (swarup2025dualroleof pages 7-9)	Alzheimer’s disease and related neuroinflammatory pathology (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 7-9)
CD44	Variant exons v4/v5	Promotes inclusion of CD44 v4/v5 exons in a concentration-dependent manner (xue2023tra2thedominant pages 5-7)	Cell adhesion, migration, invasion, metastatic behavior (xue2023tra2thedominant pages 5-7, swarup2025dualroleof pages 9-10)	Cancer progression and metastasis, especially breast and other epithelial cancers (xue2023tra2thedominant pages 5-7, swarup2025dualroleof pages 9-10)
AR / AR-V7	Cryptic exon CE3 / AR-V7	Enhances CE3 inclusion, promoting AR-V7 synthesis at the expense of full-length AR; depletion reduces AR-V7 and suppresses growth of AR-V7-positive cells (brittain2026splicingfactortra2b pages 9-10, brittain2026splicingfactortra2b pages 1-2)	Androgen receptor signaling, therapy resistance in advanced prostate cancer (brittain2026splicingfactortra2b pages 9-10, brittain2026splicingfactortra2b pages 1-2)	Castration-resistant prostate cancer (brittain2026splicingfactortra2b pages 9-10, brittain2026splicingfactortra2b pages 1-2)
Nasp	Meiotic exon / Nasp-T	Activates inclusion of the conserved meiotic exon producing Nasp-T; target exons often require multiple cooperative TRA2B-binding sites for efficient activation (grellscheid2011identificationofevolutionarily pages 4-5, grellscheid2011identificationofevolutionarily pages 5-6, grellscheid2011identificationofevolutionarily pages 1-2)	Germ-cell development, chromatin/histone handling, meiotic DNA double-strand break monitoring (grellscheid2011identificationofevolutionarily pages 4-5, grellscheid2011identificationofevolutionarily pages 1-2)	Spermatogenesis and developmental defects when TRA2B-dependent splicing is perturbed (grellscheid2011identificationofevolutionarily pages 4-5, grellscheid2011identificationofevolutionarily pages 1-2)
MYPT1 (PPP1R12A)	Smooth-muscle regulatory isoforms	Regulates alternative splicing of MYPT1 isoforms that determine smooth muscle properties/contractility phenotypes (swarup2025dualroleof pages 4-6)	Smooth muscle differentiation and contractility control (swarup2025dualroleof pages 4-6)	Functional relevance to muscle physiology; disease context inferred from smooth-muscle dysfunction rather than a single monogenic disorder in the cited evidence (swarup2025dualroleof pages 4-6)
TRA2A	Poison exon	Activates TRA2A poison exon inclusion, thereby repressing TRA2A protein output through unproductive splicing/NMD; part of paralog compensation and feedback regulation between Tra2 proteins (best2014humantra2proteins pages 1-2, grellscheid2011identificationofevolutionarily pages 1-2)	Splicing-factor homeostasis, paralog cross-regulation, concentration buffering (best2014humantra2proteins pages 1-2, grellscheid2011identificationofevolutionarily pages 1-2)	Splicing-network robustness; dysregulation may contribute to broader developmental and disease phenotypes driven by altered TRA2 dosage (best2014humantra2proteins pages 1-2, grellscheid2011identificationofevolutionarily pages 1-2)

Table: This table summarizes experimentally supported TRA2B-regulated splicing targets, the direction of their splicing regulation, and the biological and disease contexts in which those targets are relevant. It provides a compact map of TRA2B’s best-supported functional outputs across DNA damage response, metabolism, neurobiology, fertility, and cancer.

7.1 DNA Damage Response: CHEK1

A landmark study published in Nature Communications demonstrated that TRA2α and TRA2β jointly control splicing of CHEK1 exon 3, which is required for production of full-length CHK1 protein, a key DNA damage checkpoint kinase (best2014humantra2proteins pages 1-2). Dual depletion of both Tra2 proteins reduces full-length CHK1 protein levels, causes accumulation of the DNA damage marker γH2AX, and decreases cell viability (swarup2025dualroleof pages 7-9, best2014humantra2proteins pages 1-2). Target exons regulated by Tra2 proteins are enriched in genes associated with chromosome biology (best2014humantra2proteins pages 1-2).

7.2 Hepatic Lipogenesis and Metabolic Regulation: LPIN1

In a highly cited study in Cell Metabolism, Pihlajamäki et al. (2011) demonstrated that expression of SFRS10/TRA2B is reduced in liver and skeletal muscle of obese humans, and that this reduction contributes to enhanced lipogenesis (pihlajamaki2011expressionofthe pages 1-2). TRA2β directly regulates LPIN1 splicing by binding to GGAA motifs in the alternatively spliced exon 6: when TRA2β levels are high, it promotes exon 6 skipping and favors the LPIN1a isoform, whereas reduced TRA2β levels increase LPIN1b (the lipogenic isoform) (pihlajamaki2011expressionofthe pages 4-5). In Sfrs10 heterozygous mice with approximately 30% reduced mRNA levels, there was increased hepatic lipogenic gene expression (Srebp1c, Fasn, Scd1, Dgat2, Agpat2), elevated VLDL secretion, and hypertriglyceridemia (pihlajamaki2011expressionofthe pages 1-2, pihlajamaki2011expressionofthe pages 4-5, pihlajamaki2011expressionofthe pages 3-4). Critically, LPIN1b-specific siRNA abolished the lipogenic effects of reduced SFRS10, establishing LPIN1 splicing as a direct mediator (pihlajamaki2011expressionofthe pages 1-2).

7.3 Neurodevelopment and Neuronal Survival

TRA2β is essential for brain development. Neuronal-specific Tra2b knockout mice (Sfrs10fl/fl; Nestin-Cretg/+) die immediately after birth and exhibit severe cortical malformations caused by massive apoptosis in ventricular layers of the cortex (grellscheid2011identificationofevolutionarily pages 1-2). In vivo exon array analysis identified Tubulinδ1 and Shugoshin-like2 as neuronal Tra2b splicing targets, and loss of Tra2b led to upregulation of the cyclin-dependent kinase inhibitor p21, functionally linked to neuronal precursor cell death (grellscheid2011identificationofevolutionarily pages 1-2). Clustered variants in the 5' coding region of TRA2B have been identified as causing a distinctive neurodevelopmental syndrome in humans, further establishing TRA2β's essential role in neurogenesis (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 14-15). OpenTargets data associate TRA2B with syndromic complex neurodevelopmental disorder, schizophrenia, and blindness among other conditions (OpenTargets Search: -TRA2B).

7.4 Spinal Muscular Atrophy: SMN2 Exon 7

TRA2β promotes inclusion of SMN2 exon 7 in vitro, which is the critical splicing event determining the severity of spinal muscular atrophy (SMA) (swarup2025dualroleof pages 12-14, swarup2025dualroleof pages 7-9). However, the in vivo effect appears limited unless TRA2β is highly overexpressed, suggesting that TRA2β contributes to but is not the sole determinant of SMN2 exon 7 inclusion in the SMA context (swarup2025dualroleof pages 7-9).

7.5 Alzheimer's Disease: RAGE Splicing

TRA2β regulates splicing of the receptor for advanced glycation end-products (RAGE/AGER), promoting production of the soluble decoy receptor esRAGE at the expense of the membrane-bound mRAGE isoform (swarup2025dualroleof pages 7-9). This activity functionally opposes hnRNP A1, which promotes mRAGE splicing, positioning TRA2β as a modulator of the AGE/RAGE inflammatory signaling axis in neurodegeneration (swarup2025dualroleof pages 7-9).

7.6 Male Fertility and Meiosis: Poison Exon Function

A 2025 study in The EMBO Journal established that the ultra-conserved TRA2B poison exon is essential for male fertility and meiotic cell division (dalgliesh2025anultraconservedpoison pages 1-2). Genetic deletion of the Tra2b PE in mice causes azoospermia due to catastrophic cell death during meiotic prophase (dalgliesh2025anultraconservedpoison pages 1-2, dalgliesh2025ultra‐conservedpoisonexons pages 2-4). Without the PE to limit TRA2β concentration, protein levels become excessive in pachytene cells, driving aberrant hyper-responsive splice patterns and activating cryptic splice sites in meiosis-critical genes such as Ptbp2, generating unstable mRNAs that compromise cell function (dalgliesh2025ultra‐conservedpoisonexons pages 2-4). Notably, earlier mitotically active germ cells are spared despite still requiring Tra2b gene function, indicating that the PE-mediated concentration control is specifically critical during the meiotic transition (dalgliesh2025anultraconservedpoison pages 1-2). Deletion of the TRA2B PE also has cell-type-specific effects beyond the germline: in activated T cells, it enhances proliferation but reduces long-term survival (dalgliesh2025ultra‐conservedpoisonexons pages 6-7).

8. Role in Cancer

TRA2β functions as a proto-oncogene when upregulated in multiple cancer types. The TRA2B gene is amplified in tumors of the lung, ovary, cervix, stomach, head, and neck (swarup2025dualroleof pages 9-10, xue2023tra2thedominant pages 5-7). Both TRA2B mRNA and TRA2β protein are upregulated in breast, cervical, ovarian, and colon cancers, and overexpression is associated with poor prognosis (swarup2025dualroleof pages 9-10, swarup2025dualroleof pages 12-14). TRA2B transcription is regulated by the proto-oncogene ETS-1, which may drive its elevated expression in cancer cells (xue2023tra2thedominant pages 7-8).

Key oncogenic splicing events regulated by TRA2β include: promoting CD44 exon v4/v5 inclusion to enhance cancer cell invasiveness (xue2023tra2thedominant pages 5-7); activating the PI3K/AKT pathway in laryngeal carcinoma (xue2023tra2thedominant pages 7-8); and regulating genes involved in cell cycle progression, cell adhesion, and angiogenesis in ovarian cancer (swarup2025dualroleof pages 9-10). In prostate cancer, a landmark study published in the Journal of Clinical Investigation demonstrated that TRA2B enhances synthesis of the androgen receptor splice variant AR-V7, a constitutively active receptor variant that drives treatment resistance in castration-resistant prostate cancer (CRPC) (brittain2026splicingfactortra2b pages 9-10, brittain2026splicingfactortra2b pages 1-2). The AR cryptic exon CE3, which encodes AR-V7, contains an elevated frequency of AGAA binding motifs (2.4-fold above average), and depletion of TRA2A/B reduces AR-V7 protein and suppresses growth of AR-V7-positive prostate cancer cells by 50–70% (brittain2026splicingfactortra2b pages 9-10). Antisense oligonucleotides targeting TRA2β (ASO-1570) have shown anti-cancer effects in glioblastoma, triple-negative breast cancer, and colorectal cancer models (swarup2025dualroleof pages 12-14).

9. Summary of Signaling and Biochemical Context

TRA2β operates at the nexus of post-transcriptional gene regulation, controlling the output of biologically critical splicing decisions across multiple cellular contexts. It does not function as an enzyme catalyzing a chemical reaction; rather, it is a sequence-specific RNA-binding adapter protein that facilitates spliceosome assembly at target exons by recognizing AGAA-rich exonic splicing enhancers through its RRM domain and recruiting spliceosomal components via its RS domains (swarup2025dualroleof pages 2-4, xue2023tra2thedominant pages 3-4). Its concentration-dependent activity, controlled by an ultra-conserved poison exon autoregulatory mechanism and paralog compensation with TRA2A, ensures precise splicing regulation across developmental stages and cell types (best2014humantra2proteins pages 1-2, dalgliesh2025anultraconservedpoison pages 1-2, dalgliesh2025ultra‐conservedpoisonexons pages 2-4). Dysregulation of this tightly controlled system—whether through gene amplification in cancer, reduced expression in obesity, or coding-region mutations in neurodevelopmental disorders—has profound pathological consequences that illuminate TRA2β's central role in splicing homeostasis.

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swarup2025dualroleof pages 1-2
swarup2025dualroleof pages 2-4
grellscheid2011identificationofevolutionarily pages 4-5
grellscheid2011identificationofevolutionarily pages 5-6
grellscheid2011identificationofevolutionarily pages 1-2
swarup2025dualroleof pages 7-9
swarup2025dualroleof pages 4-6
pihlajamaki2011expressionofthe pages 1-2
pihlajamaki2011expressionofthe pages 4-5
dalgliesh2025anultraconservedpoison pages 1-2
swarup2025dualroleof pages 9-10
swarup2025dualroleof pages 12-14
swarup2025dualroleof pages 14-15
pihlajamaki2011expressionofthe pages 3-4
https://doi.org/10.3390/ijms26188805,
https://doi.org/10.1038/ncomms5760,
https://doi.org/10.1016/j.heliyon.2023.e15516,
https://doi.org/10.1371/journal.pgen.1002390,
https://doi.org/10.1038/s44318-024-00344-6,
https://doi.org/10.1002/bies.70081,
https://doi.org/10.1016/j.cmet.2011.06.007,
https://doi.org/10.1172/jci198264,

📚 Additional Documentation

Notes

(TRA2B-notes.md)

TRA2B review notes

Core molecular activity

TRA2B (historically HTRA2-BETA1/SFRS10) is an SR-like nuclear splicing regulator with a single RNA-recognition motif flanked by two arginine/serine-rich regions. Two independent structures show sequence-specific RNA recognition: the RRM recognizes an AGAA tetranucleotide in extended RNA and can also recognize CAA presented in a stem-loop [PMID:21399644, "The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of the RRM and by residues from both extremities flanking the RRM."] [PMID:20926394, "This study indicates that the hTra2-β RRM recognizes two types of RNA sequences in different RNA binding modes."]
The founding biochemical study found preferential binding to GAA-repeat exonic enhancers and sequence-specific activation of enhancer-dependent, but not constitutive, splicing [PMID:9546399, "Indeed, both purified proteins bound preferentially to RNA sequences containing GAA repeats, characteristic of many enhancer elements."] [PMID:9546399, "Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition with competitor RNA."]
Human iCLIP/depletion data support a broad target program with substantial TRA2A compensation: only joint TRA2A/TRA2B depletion caused large shifts across endogenous constitutive and alternative target exons [PMID:25208576, "Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β control."]

Direction and mechanism of splicing regulation

TRA2B is not exclusively an activator. It can promote or repress exon incorporation depending on the target, partner balance, and isoform [PMID:12761049, "We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor."]
In MAPT, TRA2B binding to an AG-rich exon-10 enhancer correlates with enhancer activity, and RNAi-mediated reduction of TRA2B reduces exon-10 inclusion [PMID:12649279, "The interaction between Tra2 beta and the exonic splicing enhancer correlates with the activity of this enhancer element in stimulating splicing."] [PMID:16308321, "Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta significantly reduces exon 10 splicing."]
In SMN2, TRA2B contacts the AG-rich exon-7 enhancer and cooperates with hnRNP-G/RBMX-family proteins to promote exon inclusion [PMID:12165565, "hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7 pre-mRNA."] This is a supported biochemical target, but mouse Tra2b loss did not change full-length SMN2 splicing, indicating redundancy/context dependence [PMID:20190275, "Surprisingly, deletion of Sfrs10 by recombinant Cre showed no impact on SMN2 splicing but increased SMN levels."]
ESE-bound TRA2 proteins can be coupled to spliceosome assembly through SRm160/300, U1 snRNP, and U2 snRNP [PMID:10339552, "The results suggest a model for ESE function in which the SRm160/300 splicing coactivator promotes critical interactions between ESE-bound \"activators\" and the snRNP machinery of the spliceosome."]

Localization and regulation

TRA2B is a nuclear protein that colocalizes with the splicing-speckle marker SC35 [PMID:9212162, "htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern."] Its nuclear/nucleoplasmic and spliceosomal-complex annotations are consistent with its mechanism.
TRA2B controls its own abundance by activating inclusion of a nonproductive poison exon in TRA2B pre-mRNA [PMID:14709600, "We investigated the mechanism that controls the cellular HTRA2-BETA1 concentration and found it utilizes a negative feedback loop to regulate the splicing of its exon 2."] [PMID:14709600, "Inclusion of exon 2 generates mRNAs that are not translated into proteins."]

Annotation decisions

Prefer GO:1990825 sequence-specific mRNA binding over generic nucleic-acid/RNA/mRNA-binding terms when the evidence is the biochemical or structural activity. GO has no single term combining sequence specificity with a pre-mRNA substrate, so the core MF emphasizes specificity while the accepted GO:0036002 pre-mRNA binding row preserves precursor-RNA context.
Use GO:0048024 regulation of mRNA splicing, via spliceosome for the core process and general regulatory evidence because TRA2A/TRA2B jointly control both constitutive and alternative target exons. Use GO:0000381 regulation of alternative mRNA splicing, via spliceosome for experiments specifically demonstrating alternative exon choice; neither term implies that TRA2B performs the constitutive splicing reaction, which PMID:9546399 explicitly excluded.
Add GO:0048025 negative regulation of mRNA splicing, via spliceosome because PMID:12761049 directly shows context-dependent repression as well as activation.
Generic GO:0005515 protein binding rows are biologically uninformative. Where the partner class is clear, replace them with GO:1990935 splicing factor binding, GO:0019901 protein kinase binding, or GO:0140297 DNA-binding transcription factor binding. The CPSF6 row supports GO:0019904 protein domain specific binding for a different reason: CFIm68 binds TRA2B through a mapped C-terminal alternating-charge domain [PMID:15169763, "CF I(m)68 interacts with SRp20, 9G8, and hTra2beta, members of the SR family of splicing factors, via its C-terminal alternating charge domain."]. Keep the mixed HuRI tuple over-annotated because its fifteen partners cannot be collapsed to one informative function.
GO:0071333 cellular response to glucose stimulus is supported for the AGER/RAGE experiment but is contextual and non-core [PMID:25689357, "Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1."]

📄 View Raw YAML

id: P62995
gene_symbol: TRA2B
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TRA2B is an SR-like nuclear splicing regulator whose central RNA-recognition motif binds
  AGAA/GAA-rich and structured CAA elements in pre-mRNAs. Through its arginine/serine-rich
  regions and interactions with other splicing factors, it couples bound exonic elements to
  spliceosomal machinery and controls exon selection, promoting or repressing inclusion
  according to RNA and partner context. Established targets include MAPT, SMN2, CHEK1, AGER, and
  the TRA2B poison exon that mediates negative autoregulation; TRA2A compensates for TRA2B at
  many endogenous targets.
alternative_products:
- name: 1 (HTRA2-beta1)
  id: P62995-1, Q15815-1
- name: 2 (HTRA2-beta2)
  id: P62995-2, Q15815-2
  sequence_note: VSP_005898, VSP_005899
- name: 3 (HTRA2-beta3)
  id: P62995-3, Q15815-3
  sequence_note: VSP_005896
existing_annotations:
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - PANTHER:PTN008729690
  - RGD:3153
  - UniProtKB:O93235
  - UniProtKB:P0DJD3
  - UniProtKB:P19338
  - UniProtKB:P38159
  - UniProtKB:P62995
  - UniProtKB:Q14011
  - UniProtKB:Q9DED4
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0000398
    label: mRNA splicing, via spliceosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - FB:FBgn0003742
  - PANTHER:PTN000391532
  - RGD:1306751
  - RGD:1565256
  - UniProtKB:P62995
  - UniProtKB:Q13595
  review:
    summary: >-
      The family-level annotation correctly places TRA2B in spliceosomal mRNA splicing, but
      describes it as core machinery rather than as a regulator of splice-site choice.
    action: MODIFY
    reason: >-
      TRA2B regulates both constitutive and alternative target exons, so the general regulatory
      parent GO:0048024 is more accurate here than the alternative-only child. It also avoids
      implying that TRA2B performs the core splicing reaction.
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      - GRANULARITY_MISMATCH
    proposed_replacement_terms:
    - id: GO:0048024
      label: regulation of mRNA splicing, via spliceosome
    supported_by:
    - reference_id: PMID:25208576
      supporting_text: >-
        Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces
        substantial shifts in splicing of endogenous Tra2β target exons, and that both
        constitutive and alternative target exons are under dual Tra2α-Tra2β control.
- term:
    id: GO:0005681
    label: spliceosomal complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  supporting_entities:
  - PANTHER:PTN000391532
  - RGD:1306751
  - UniProtKB:P38159
  - UniProtKB:P62995
  review:
    summary: >-
      Spliceosomal-complex association is consistent with phylogenetic, experimental, and
      pathway evidence and with TRA2B coupling enhancer-bound RNA to snRNP machinery.
    action: ACCEPT
    reason: >-
      TRA2B functions in dynamic pre-mRNA processing assemblies, and independent mechanistic
      evidence connects ESE-bound TRA2 proteins to U1/U2 spliceosomal machinery.
    supported_by:
    - reference_id: PMID:10339552
      supporting_text: >-
        The results suggest a model for ESE function in which the SRm160/300 splicing
        coactivator promotes critical interactions between ESE-bound "activators" and the snRNP
        machinery of the spliceosome.
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR035979
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR000504
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0191
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17332742
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q15428
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q96MU7
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22365833
  qualifier: enables
  supporting_entities:
  - UniProtKB:P38159
  - UniProtKB:Q08170
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23602568
  qualifier: enables
  supporting_entities:
  - UniProtKB:P49761
  - UniProtKB:P78362
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  supporting_entities:
  - UniProtKB:P38159
  - UniProtKB:P49759-3
  - UniProtKB:P49761
  - UniProtKB:P78362
  - UniProtKB:Q01081
  - UniProtKB:Q07955
  - UniProtKB:Q08170
  - UniProtKB:Q13242
  - UniProtKB:Q15415
  - UniProtKB:Q7L775
  - UniProtKB:Q86VE0
  - UniProtKB:Q96A72
  - UniProtKB:Q96MU7
  - UniProtKB:Q9BRL6-2
  - UniProtKB:Q9Y5E9
  review:
    summary: >-
      A proteome-scale binary-interaction map yields many partners, but bare protein binding is
      uninformative and the mixed partner set cannot be represented by one precise
      molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Four partners in this collapsed tuple recur in independent splicing-factor or kinase
      interaction datasets and can be classified in those source-specific rows. The other eleven
      span heterogeneous molecular classes, so no single informative replacement represents the
      full HuRI set. The binary interactions remain available in the source database without a
      generic GO term that overstates their functional interpretation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  qualifier: enables
  supporting_entities:
  - UniProtKB:P49761
  - UniProtKB:P78362
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  supporting_entities:
  - UniProtKB:P49761
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a protein kinase partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:0019901
      label: protein kinase binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q15428
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  supporting_entities:
  - UniProtKB:P62995
  review:
    summary: >-
      The HuRI-derived self-association is encoded by the IPI/WITH record, but the cached article
      does not expose the TRA2B-specific pair for direct verification.
    action: UNDECIDED
    reason: >-
      The interaction may be present in HuRI's underlying dataset, but the available text only
      describes the atlas globally. Keep the curated row undecided until the pair-level source
      data can be inspected rather than treating dataset-level evidence as positive support.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:10749975
  qualifier: part_of
  review:
    summary: >-
      The experimental complex association is real but the generic protein-containing complex
      term does not identify the relevant RNA-processing assembly.
    action: MODIFY
    reason: >-
      TRA2B associates with splicing regulators and enhancer-dependent spliceosomal machinery.
      Spliceosomal complex is the more informative cellular-component term.
    proposed_replacement_terms:
    - id: GO:0005681
      label: spliceosomal complex
    supported_by:
    - reference_id: PMID:10339552
      supporting_text: >-
        The results suggest a model for ESE function in which the SRm160/300 splicing
        coactivator promotes critical interactions between ESE-bound "activators" and the snRNP
        machinery of the spliceosome.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IMP
  original_reference_id: PMID:10749975
  qualifier: enables
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10749975
  qualifier: enables
  supporting_entities:
  - UniProtKB:P09651
  - UniProtKB:P38159
  - UniProtKB:Q13242
  - UniProtKB:Q16629
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a splicing factor partner. Replacing protein binding
      preserves the interaction evidence while making the annotation biologically informative;
      it remains secondary to TRA2B's RNA-binding splicing-regulatory activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10749975
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:10749975
  qualifier: enables
  supporting_entities:
  - UniProtKB:P0DJD4
  review:
    summary: >-
      Domain-specific association with an RNA-splicing regulator is experimentally supported but
      is a partner interaction rather than TRA2B's defining RNA-recognition activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      The term is informative and more specific than protein binding, but the core activity
      remains sequence-specific pre-mRNA recognition and regulation of exon selection.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:10749975
  qualifier: enables
  review:
    summary: >-
      The curated IDA self-association cannot be verified from the cached abstract, which reports
      TRA2B interactions with RBM-family proteins but does not mention TRA2B self-binding.
    action: UNDECIDED
    reason: >-
      The experimental curator may have used data in the unavailable full text, so the annotation
      is not removed or called wrong. It remains undecided until the self-association experiment
      can be inspected directly.
- term:
    id: GO:0043484
    label: regulation of RNA splicing
  evidence_type: IMP
  original_reference_id: PMID:10749975
  qualifier: involved_in
  review:
    summary: >-
      The experiment establishes regulation of enhancer-dependent pre-mRNA splicing but does not
      restrict TRA2B's regulatory program to alternative target exons.
    action: MODIFY
    reason: >-
      Perturbing the RBM interaction domain inhibited splicing of a TRA2B-bound enhancer
      substrate. The spliceosome-specific regulatory parent captures this result and remains
      compatible with later evidence that TRA2 proteins control both constitutive and alternative
      target exons.
    proposed_replacement_terms:
    - id: GO:0048024
      label: regulation of mRNA splicing, via spliceosome
    supported_by:
    - reference_id: PMID:10749975
      supporting_text: >-
        Incubation with the protein interaction domain of RBM inhibited splicing in vitro of a
        specific pre-mRNA substrate containing an essential enhancer bound by Tra2beta.
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IMP
  original_reference_id: PMID:25689357
  qualifier: involved_in
  review:
    summary: >-
      Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central
      biological process.
    action: ACCEPT
    reason: >-
      Target-specific perturbation and biochemical studies show that TRA2B changes exon
      inclusion, with activating or repressive outcomes determined by target and partner
      context.
- term:
    id: GO:0005681
    label: spliceosomal complex
  evidence_type: IMP
  original_reference_id: PMID:25689357
  qualifier: part_of
  review:
    summary: >-
      Spliceosomal-complex association is consistent with phylogenetic, experimental, and
      pathway evidence and with TRA2B coupling enhancer-bound RNA to snRNP machinery.
    action: ACCEPT
    reason: >-
      TRA2B functions in dynamic pre-mRNA processing assemblies, and independent mechanistic
      evidence connects ESE-bound TRA2 proteins to U1/U2 spliceosomal machinery.
    supported_by:
    - reference_id: PMID:10339552
      supporting_text: >-
        The results suggest a model for ESE function in which the SRm160/300 splicing
        coactivator promotes critical interactions between ESE-bound "activators" and the snRNP
        machinery of the spliceosome.
- term:
    id: GO:0036002
    label: pre-mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:25689357
  qualifier: enables
  review:
    summary: >-
      Direct pre-mRNA binding is a core TRA2B activity and is supported by target-specific
      RNA-binding and splicing assays.
    action: ACCEPT
    reason: >-
      The annotation is accurate. Structural work further resolves the activity as
      sequence-specific recognition of purine-rich pre-mRNA elements.
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0071333
    label: cellular response to glucose stimulus
  evidence_type: IMP
  original_reference_id: PMID:25689357
  qualifier: involved_in
  review:
    summary: >-
      TRA2B abundance changes during glucose deprivation in the AGER/RAGE splicing experiment,
      but this is a condition-specific response rather than its core activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      The experimental observation is supported, yet it describes one regulatory context for
      TRA2B expression and downstream isoform balance, not the molecular role that defines
      TRA2B.
    supported_by:
    - reference_id: PMID:25689357
      supporting_text: >-
        Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of
        hnRNP A1 and down-regulation of Tra2β-1.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-72103
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770119
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770129
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770131
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770132
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770141
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770142
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770145
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770236
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9770847
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9794542
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970141
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970179
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970189
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970190
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970191
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970193
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970282
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970294
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970318
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970320
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970428
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970429
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9970431
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      The Reactome event is assigned to the nucleoplasm, matching direct microscopy showing
      nuclear TRA2B in SC35-positive speckles. The localization is a core setting for its
      RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:16791210
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12165565
  qualifier: enables
  supporting_entities:
  - UniProtKB:P0DJD3
  - UniProtKB:P38159
  review:
    summary: >-
      Direct interactions with RBMY1A1 and RBMX are more informatively represented as splicing
      factor binding than as generic protein binding.
    action: MODIFY
    reason: >-
      The WITH/FROM partners P0DJD3 and P38159 are RBMY1A1 and RBMX, and the paper directly shows
      specific binding of hnRNP-G/RBM proteins to Htra2-beta1 in an exon-inclusion mechanism.
      Splicing factor binding preserves that informative partner class.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
    supported_by:
    - reference_id: PMID:12165565
      supporting_text: >-
        hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind
        Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate
        inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7
        pre-mRNA.
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IDA
  original_reference_id: PMID:12165565
  qualifier: involved_in
  review:
    summary: >-
      Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central
      biological process.
    action: ACCEPT
    reason: >-
      Target-specific perturbation and biochemical studies show that TRA2B changes exon
      inclusion, with activating or repressive outcomes determined by target and partner
      context.
    supported_by:
    - reference_id: PMID:12165565
      supporting_text: >-
        hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind
        Htra2-beta1, an SR-like splicing factor which we have previously shown to stimulate
        inclusion of exon 7 through a direct interaction with the AG-rich ESE in SMN2 exon 7
        pre-mRNA.
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:12165565
  qualifier: enables
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0000381
    label: regulation of alternative mRNA splicing, via spliceosome
  evidence_type: IDA
  original_reference_id: PMID:12761049
  qualifier: involved_in
  review:
    summary: >-
      Regulation of alternative mRNA splicing through the spliceosome is TRA2B's central
      biological process.
    action: ACCEPT
    reason: >-
      Target-specific perturbation and biochemical studies show that TRA2B changes exon
      inclusion, with activating or repressive outcomes determined by target and partner
      context.
    supported_by:
    - reference_id: PMID:12761049
      supporting_text: >-
        We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of
        several exons, both being able to act as either an activator or a repressor.
- term:
    id: GO:0003729
    label: mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:12761049
  qualifier: enables
  review:
    summary: >-
      The annotation captures TRA2B RNA recognition but is less specific than the established
      sequence-selective activity of its RNA-recognition motif.
    action: MODIFY
    reason: >-
      Biochemical and structural studies show direct recognition of AGAA/GAA-rich and structured
      CAA elements in pre-mRNAs. Sequence-specific mRNA binding is therefore more informative
      than generic nucleic acid, RNA, or mRNA binding.
    proposed_replacement_terms:
    - id: GO:1990825
      label: sequence-specific mRNA binding
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0048026
    label: positive regulation of mRNA splicing, via spliceosome
  evidence_type: IDA
  original_reference_id: PMID:15009664
  qualifier: involved_in
  review:
    summary: >-
      Positive regulation of spliceosomal mRNA splicing is supported for MAPT exon 10 and other
      enhancer-dependent targets.
    action: ACCEPT
    reason: >-
      The cached abstract for the original paper does not name TRA2B, so the curator's full-text
      assessment is retained and independently corroborated by direct TRA2B binding and
      RNA-interference studies on the same MAPT enhancer.
    supported_by:
    - reference_id: PMID:12649279
      supporting_text: >-
        The interaction between Tra2 beta and the exonic splicing enhancer correlates with the
        activity of this enhancer element in stimulating splicing.
    - reference_id: PMID:16308321
      supporting_text: >-
        Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta
        significantly reduces exon 10 splicing.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19282290
  qualifier: enables
  supporting_entities:
  - UniProtKB:P84586
  review:
    summary: >-
      The WITH/FROM accession P84586 resolves to rat Rbmxrtl, an hnRNP G retrogene-like pre-mRNA
      splicing regulator, so the interaction is more informative than generic protein binding.
    action: MODIFY
    reason: >-
      The source paper characterizes hnRNP G-family proteins as supraspliceosomal regulators of
      alternative splice-site selection. Splicing factor binding therefore records the verified
      partner class while remaining secondary to TRA2B's RNA-binding activity.
    proposed_replacement_terms:
    - id: GO:1990935
      label: splicing factor binding
    supported_by:
    - reference_id: PMID:19282290
      supporting_text: >-
        hnRNP G is part of the supraspliceosome, where it regulates alternative splice site
        selection in a concentration-dependent manner.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17577209
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q9BQA5
  review:
    summary: >-
      The reported physical association is better described by the molecular class of the
      identified partner than by generic protein binding.
    action: MODIFY
    reason: >-
      The GOA WITH/FROM identifier records a DNA-binding transcription factor partner. Replacing
      protein binding preserves the interaction evidence while making the annotation
      biologically informative; it remains secondary to TRA2B's RNA-binding splicing-regulatory
      activity.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15169763
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q16630
  review:
    summary: >-
      CPSF6/CFIm68 binds TRA2B through a defined C-terminal alternating-charge domain, making
      domain-specific binding more informative than generic protein binding.
    action: MODIFY
    reason: >-
      PMID:15169763 maps the hTra2beta interaction specifically to the C-terminal
      alternating-charge domain of CFIm68. GO:0019904 captures that experimentally localized
      interface without elevating this secondary partner interaction to a core TRA2B function.
    proposed_replacement_terms:
    - id: GO:0019904
      label: protein domain specific binding
    supported_by:
    - reference_id: PMID:15169763
      supporting_text: >-
        CF I(m)68 interacts with SRp20, 9G8, and hTra2beta, members of the SR family of splicing
        factors, via its C-terminal alternating charge domain.
- term:
    id: GO:0000375
    label: RNA splicing, via transesterification reactions
  evidence_type: TAS
  original_reference_id: PMID:9546399
  qualifier: involved_in
  review:
    summary: >-
      TRA2B regulates spliceosomal exon choice rather than catalysing constitutive pre-mRNA
      splicing.
    action: MODIFY
    reason: >-
      The founding biochemical study explicitly found no constitutive-splicing activity and
      instead demonstrated sequence-specific activation of enhancer-dependent splicing. The
      regulatory alternative-splicing term captures the activity without implying that TRA2B
      performs the core transesterification reaction.
    proposed_replacement_terms:
    - id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
    supported_by:
    - reference_id: PMID:9546399
      supporting_text: >-
        Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated
        enhancer-dependent splicing in a sequence-specific manner and restored it after
        inhibition with competitor RNA.
- term:
    id: GO:0000398
    label: mRNA splicing, via spliceosome
  evidence_type: IDA
  original_reference_id: PMID:9546399
  qualifier: involved_in
  review:
    summary: >-
      TRA2B regulates spliceosomal exon choice rather than catalysing constitutive pre-mRNA
      splicing.
    action: MODIFY
    reason: >-
      The founding biochemical study explicitly found no constitutive-splicing activity and
      instead demonstrated sequence-specific activation of enhancer-dependent splicing. The
      regulatory alternative-splicing term captures the activity without implying that TRA2B
      performs the core transesterification reaction.
    proposed_replacement_terms:
    - id: GO:0000381
      label: regulation of alternative mRNA splicing, via spliceosome
    supported_by:
    - reference_id: PMID:9546399
      supporting_text: >-
        Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated
        enhancer-dependent splicing in a sequence-specific manner and restored it after
        inhibition with competitor RNA.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:9546399
  qualifier: located_in
  review:
    summary: >-
      Nuclear or nucleoplasmic localization is appropriate for a sequence-specific pre-mRNA
      splicing regulator.
    action: ACCEPT
    reason: >-
      This localization agrees with direct microscopy showing nuclear TRA2B in SC35-positive
      speckles. The localization is a core setting for its RNA-splicing activity.
    supported_by:
    - reference_id: PMID:9212162
      supporting_text: >-
        htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
- term:
    id: GO:1990825
    label: sequence-specific mRNA binding
  evidence_type: IDA
  original_reference_id: PMID:21399644
  qualifier: enables
  review:
    summary: >-
      Direct structural and mutational evidence establishes sequence-specific recognition of an
      AGAA element by the TRA2B RNA-recognition motif.
    action: NEW
    reason: >-
      GOA contains only broader RNA- and mRNA-binding terms. This term captures the
      experimentally demonstrated molecular specificity and is the best representation of
      TRA2B's core molecular function.
    supported_by:
    - reference_id: PMID:21399644
      supporting_text: >-
        The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
        the RRM and by residues from both extremities flanking the RRM.
- term:
    id: GO:0048025
    label: negative regulation of mRNA splicing, via spliceosome
  evidence_type: IDA
  original_reference_id: PMID:12761049
  qualifier: involved_in
  review:
    summary: >-
      TRA2B can repress exon incorporation as well as activate it, depending on the exon and
      cellular context.
    action: NEW
    reason: >-
      Existing GOA records the general and positive regulatory activities but omits the directly
      demonstrated repressive direction. The paper reports several exons for which hTra2beta
      acts as a repressor.
    supported_by:
    - reference_id: PMID:12761049
      supporting_text: >-
        We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of
        several exons, both being able to act as either an activator or a repressor.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:10749975
  title: RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins
    interact with Tra2beta and affect splicing.
  findings:
  - statement: >-
      TRA2B associates with hnRNP-G/RBMY-family proteins in enhancer-dependent splicing
      complexes.
    supporting_text: >-
      Endogenous hnRNP G and Tra2beta proteins are associated in HeLa nuclear extracts.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports TRA2B association with hnRNP-G-family splicing
      regulators and a functional effect on enhancer-dependent splicing.
- id: PMID:12165565
  title: hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct
    interaction with Htra2-beta1.
  findings:
  - statement: >-
      TRA2B binds the AG-rich SMN2 exon 7 enhancer and cooperates with hnRNP-G/RBM proteins to
      promote inclusion.
    supporting_text: >-
      hnRNP-G and RBM non-specifically bind RNA, but directly and specifically bind Htra2-beta1,
      an SR-like splicing factor which we have previously shown to stimulate inclusion of exon 7
      through a direct interaction with the AG-rich ESE in SMN2 exon 7 pre-mRNA.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports TRA2B binding to the SMN2 exon 7 enhancer and
      cooperation with hnRNP-G/RBM proteins.
- id: PMID:12761049
  title: 'HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism
    in RNA binding.'
  findings:
  - statement: >-
      TRA2B can activate or repress exon incorporation according to target context.
    supporting_text: >-
      We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of
      several exons, both being able to act as either an activator or a repressor.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly establishes context-dependent activating and repressive
      effects of hTra2beta on exon incorporation.
- id: PMID:15009664
  title: Tau exon 10, whose missplicing causes frontotemporal dementia, is regulated
    by an intricate interplay of cis elements and trans factors.
  findings:
  - statement: >-
      The abstract reports a broad survey of MAPT exon 10 regulators but does not identify
      TRA2B.
    supporting_text: >-
      We also carried out a comprehensive survey of the influence of splicing regulators on exon
      10 inclusion
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: >-
      The identifier and title are correct, but the cached abstract does not name TRA2B. The
      curator's experimental annotation is retained; independent MAPT studies provide direct
      corroboration.
- id: PMID:15169763
  title: Distinct sequence motifs within the 68-kDa subunit of cleavage factor Im
    mediate RNA binding, protein-protein interactions, and subcellular localization.
  findings:
  - statement: >-
      CFIm68/CPSF6 interacts with TRA2B through its C-terminal alternating-charge domain.
    supporting_text: >-
      CF I(m)68 interacts with SRp20, 9G8, and hTra2beta, members of the SR family of splicing
      factors, via its C-terminal alternating charge domain.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports a domain-localized CPSF6-TRA2B interaction; this is
      informative for the interaction annotation but secondary to TRA2B's core RNA-binding role.
- id: PMID:16791210
  title: Dynamic proteomics in individual human cells uncovers widespread cell-cycle
    dependence of nuclear proteins.
  findings: []
- id: PMID:17332742
  title: Composition and three-dimensional EM structure of double affinity-purified,
    human prespliceosomal A complexes.
  findings: []
- id: PMID:17577209
  title: The interactome of the histone gene regulatory factor HiNF-P suggests novel
    cell cycle related roles in transcriptional control and RNA processing.
  findings: []
- id: PMID:19282290
  title: Heterogeneous nuclear ribonucleoprotein G regulates splice site selection
    by binding to CC(A/C)-rich regions in pre-mRNA.
  findings:
  - statement: >-
      hnRNP G-family proteins are supraspliceosomal regulators of alternative splice-site choice.
    supporting_text: >-
      hnRNP G is part of the supraspliceosome, where it regulates alternative splice site
      selection in a concentration-dependent manner.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract verifies the splicing-factor class used to refine the P84586
      interaction; the pair itself remains based on the curated IPI/WITH record.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:22365833
  title: Dynamic protein-protein interaction wiring of the human spliceosome.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding
    transcripts.
  findings: []
- id: PMID:23602568
  title: The protein interaction landscape of the human CMGC kinase group.
  findings: []
- id: PMID:25689357
  title: Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its potential role
    in AD pathogenesis.
  findings:
  - statement: >-
      TRA2B and hnRNP A1 antagonistically regulate alternative AGER/RAGE isoform splicing.
    supporting_text: >-
      hnRNP A1 and Transformer2β-1 (Tra2β-1) were involved in the alternative splicing of mRAGE
      and esRAGE. Functionally, two factors had an antagonistic effect
    reference_section_type: ABSTRACT
  - statement: >-
      Glucose deprivation reduces TRA2B abundance and changes the AGER/RAGE isoform ratio.
    supporting_text: >-
      Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP
      A1 and down-regulation of Tra2β-1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports TRA2B-dependent AGER/RAGE alternative splicing
      and the glucose-deprivation context.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      HuRI is a proteome-scale map of human binary protein interactions.
    supporting_text: >-
      Here we present a human 'all-by-all' reference interactome map of human binary protein
      interactions, or 'HuRI'.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      The source is a valid binary-interaction atlas, but its collapsed heterogeneous TRA2B
      partner set does not establish one coherent molecular function.
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human
    Kinases.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:9546399
  title: Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing.
  findings:
  - statement: >-
      Human TRA2 proteins bind GAA-repeat enhancers and activate enhancer-dependent rather than
      constitutive splicing.
    supporting_text: >-
      Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated
      enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition
      with competitor RNA.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly establishes sequence-specific enhancer binding and
      enhancer-dependent splicing activation by the human TRA2 proteins.
- id: PMID:10339552
  title: >-
    The SRm160/300 splicing coactivator is required for exon-enhancer function.
  full_text_unavailable: true
  findings:
  - statement: >-
      ESE-bound TRA2 proteins are coupled to U1/U2 snRNP machinery through the SRm160/300
      coactivator.
    supporting_text: >-
      The results suggest a model for ESE function in which the SRm160/300 splicing coactivator
      promotes critical interactions between ESE-bound "activators" and the snRNP machinery of
      the spliceosome.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports the mechanistic link between ESE-bound TRA2 and
      spliceosomal snRNP machinery.
- id: PMID:12649279
  title: >-
    Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic
    splicing enhancer to interact with Tra2 beta.
  findings:
  - statement: >-
      TRA2B directly binds the MAPT exon 10 enhancer and its binding tracks enhancer-dependent
      splicing.
    supporting_text: >-
      The interaction between Tra2 beta and the exonic splicing enhancer correlates with the
      activity of this enhancer element in stimulating splicing.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC record directly supports TRA2B binding to and regulation through the MAPT exon
      10 enhancer.
- id: PMID:14709600
  title: >-
    Human tra2-beta1 autoregulates its protein concentration by influencing alternative splicing
    of its pre-mRNA.
  full_text_unavailable: true
  findings:
  - statement: >-
      TRA2B binds four enhancers in its poison exon and promotes nonproductive exon inclusion in
      a negative-feedback loop.
    supporting_text: >-
      TRA2-BETA1 binds to four enhancers present in exon 2, which activates its inclusion.
      Inclusion of exon 2 generates mRNAs that are not translated into proteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports TRA2B poison-exon binding and negative
      autoregulation.
- id: PMID:16308321
  title: >-
    Arginine/serine-rich protein interaction domain-dependent modulation of a tau exon 10
    splicing enhancer: altered interactions and mechanisms for functionally antagonistic FTDP-17
    mutations Delta280K AND N279K.
  full_text_unavailable: true
  findings:
  - statement: >-
      Reducing endogenous TRA2B decreases MAPT exon 10 splicing.
    supporting_text: >-
      Small interfering RNA-mediated suppression of endogenous SF2/ASF and Tra2beta
      significantly reduces exon 10 splicing.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract independently corroborates the positive MAPT exon 10 annotation
      with direct TRA2B perturbation.
- id: PMID:20190275
  title: >-
    Deficiency of the splicing factor Sfrs10 results in early embryonic lethality in mice and
    has no impact on full-length SMN/Smn splicing.
  full_text_unavailable: true
  findings:
  - statement: >-
      Mouse Sfrs10/Tra2b loss did not alter full-length SMN2 splicing, demonstrating target and
      redundancy context.
    supporting_text: >-
      Surprisingly, deletion of Sfrs10 by recombinant Cre showed no impact on SMN2 splicing but
      increased SMN levels.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract provides a useful in-vivo caveat to biochemical SMN2 reporter
      evidence.
- id: PMID:20926394
  title: >-
    Structural basis for the dual RNA-recognition modes of human Tra2-β RRM.
  findings:
  - statement: >-
      The TRA2B RRM recognizes CAA and GAA-rich RNA through distinct structural modes.
    supporting_text: >-
      This study indicates that the hTra2-β RRM recognizes two types of RNA sequences in
      different RNA binding modes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC full text directly establishes the structural basis and dual sequence modes of
      TRA2B RNA recognition.
- id: PMID:21399644
  title: >-
    Molecular basis of purine-rich RNA recognition by the human SR-like protein Tra2-β1.
  full_text_unavailable: true
  findings:
  - statement: >-
      The TRA2B RRM specifically recognizes an AGAA motif, with RNA contacts validated in an
      SMN2 splicing assay.
    supporting_text: >-
      The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
      the RRM and by residues from both extremities flanking the RRM.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports the proposed sequence-specific mRNA-binding
      molecular function.
- id: PMID:25208576
  title: >-
    Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and
    constitutive target exons.
  findings:
  - statement: >-
      Endogenous TRA2A and TRA2B target exons show paralog compensation, with strong shifts
      after joint depletion.
    supporting_text: >-
      Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces
      substantial shifts in splicing of endogenous Tra2β target exons, and that both
      constitutive and alternative target exons are under dual Tra2α-Tra2β control.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed/PMC full text directly supports endogenous target regulation and TRA2A/TRA2B
      compensation.
- id: PMID:9212162
  title: >-
    Molecular cloning of htra2-beta-1 and htra2-beta-2, two human homologs of tra-2 generated by
    alternative splicing.
  full_text_unavailable: true
  findings:
  - statement: >-
      TRA2B is nuclear, colocalizes with SC35-positive speckles, and interacts with SR proteins.
    supporting_text: >-
      htra2-beta1 is a nuclear protein that colocalizes with SC35 in a speckled pattern.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      PubMed-cached abstract directly supports nuclear-speckle localization and the existence of
      alternatively spliced TRA2B forms.
- id: Reactome:R-HSA-72103
  title: Formation of pre-mRNPs
  findings: []
- id: Reactome:R-HSA-9770119
  title: Formation of the Spliceosomal E complex
  findings: []
- id: Reactome:R-HSA-9770129
  title: Formation of the Spliceosomal A complex
  findings: []
- id: Reactome:R-HSA-9770131
  title: Formation of the Spliceosomal B* complex
  findings: []
- id: Reactome:R-HSA-9770132
  title: Formation of the Spliceosomal Pre-B complex
  findings: []
- id: Reactome:R-HSA-9770141
  title: Formation of the Spliceosomal C* complex
  findings: []
- id: Reactome:R-HSA-9770142
  title: Formation of the Spliceosomal B complex
  findings: []
- id: Reactome:R-HSA-9770145
  title: Formation of the Spliceosomal Bact complex
  findings: []
- id: Reactome:R-HSA-9770236
  title: Formation of the Spliceosomal P complex and exon ligation
  findings: []
- id: Reactome:R-HSA-9770847
  title: Spliceosomal P complex dissociates yielding the intron-containing complex
    (ILS) and the spliced mRNP (new)
  findings: []
- id: Reactome:R-HSA-9794542
  title: Formation of the Spliceosomal C complex containing intron lariat
  findings: []
- id: Reactome:R-HSA-9970141
  title: Core CPA complex binds capped pre-mRNA
  findings: []
- id: Reactome:R-HSA-9970179
  title: Recruitment of other CPA components to pre-mRNA-bound CPA core
  findings: []
- id: Reactome:R-HSA-9970189
  title: PABPN1-stimulated PAPOL synthesizes polyA tail at distal 3'UTR PAS
  findings: []
- id: Reactome:R-HSA-9970190
  title: PP1 dephosphorylates RNA Pol II
  findings: []
- id: Reactome:R-HSA-9970191
  title: RBBP6 activates CPSF complex
  findings: []
- id: Reactome:R-HSA-9970193
  title: CPSF3 cleaves pre-mRNA at distal 3'UTR PAS
  findings: []
- id: Reactome:R-HSA-9970282
  title: U1 snRNP suppresses CPSF3-mediated pre-mRNA cleavage at intronic PAS
  findings: []
- id: Reactome:R-HSA-9970294
  title: CPSF3 cleaves pre-mRNA at proximal 3'UTR PAS
  findings: []
- id: Reactome:R-HSA-9970318
  title: PABPN1-stimulated PAPOL synthesizes polyA tail at proximal 3'UTR PAS
  findings: []
- id: Reactome:R-HSA-9970320
  title: PABPN1-stimulated PAPOL synthesizes polyA tail at intronic PAS
  findings: []
- id: Reactome:R-HSA-9970428
  title: CPA complex components dissociate from polyadenylated pre-mRNA (distal 3'UTR
    PAS)
  findings: []
- id: Reactome:R-HSA-9970429
  title: CPA complex components dissociate from polyadenylated pre-mRNA (intronic
    PAS)
  findings: []
- id: Reactome:R-HSA-9970431
  title: CPA complex components dissociate from polyadenylated pre-mRNA (proximal
    3'UTR PAS)
  findings: []

core_functions:
- description: >-
    Binds purine-rich sequences in pre-mRNA exonic splicing enhancers through its RRM and
    cooperates with splicing factors and snRNP machinery to regulate exon selection. Sequence
    specificity is the defining molecular feature represented here; the accepted pre-mRNA
    binding annotation independently captures the precursor-RNA substrate. Depending on RNA and
    partner context, TRA2B promotes or represses exon inclusion, while TRA2A can compensate at
    many endogenous targets.
  molecular_function:
    id: GO:1990825
    label: sequence-specific mRNA binding
  directly_involved_in:
  - id: GO:0048024
    label: regulation of mRNA splicing, via spliceosome
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0005681
    label: spliceosomal complex
  supported_by:
  - reference_id: PMID:21399644
    supporting_text: >-
      The central 5'-AGAA-3' motif is specifically recognized by residues from the β-sheet of
      the RRM and by residues from both extremities flanking the RRM.
  - reference_id: PMID:9546399
    supporting_text: >-
      Neither Tra2 protein functioned in constitutive splicing in vitro, but both activated
      enhancer-dependent splicing in a sequence-specific manner and restored it after inhibition
      with competitor RNA.
  - reference_id: PMID:10339552
    supporting_text: >-
      The results suggest a model for ESE function in which the SRm160/300 splicing coactivator
      promotes critical interactions between ESE-bound "activators" and the snRNP machinery of
      the spliceosome.
  - reference_id: PMID:12761049
    supporting_text: >-
      We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of
      several exons, both being able to act as either an activator or a repressor.
  - reference_id: PMID:25208576
    supporting_text: >-
      Here we find simultaneous--but not individual--depletion of Tra2α and Tra2β induces
      substantial shifts in splicing of endogenous Tra2β target exons, and that both
      constitutive and alternative target exons are under dual Tra2α-Tra2β control.
proposed_new_terms: []
suggested_questions:
- question: >-
    Which endogenous exons require TRA2B specifically, rather than redundant TRA2A/TRA2B
    activity, across human cell types and physiological expression ranges?
- question: >-
    Which positional RNA-binding, local sequence, partner, and phosphorylation features
    determine whether TRA2B promotes or represses exon inclusion?
- question: >-
    Are the short TRA2B isoform 2 and N-terminally truncated isoform 3 stable endogenous
    products with distinct RNA targets or regulatory activities?
suggested_experiments:
- hypothesis: >-
    TRA2B has both paralog-redundant and cell-type-specific direct splicing targets that are
    masked by TRA2A compensation.
  description: >-
    Introduce rapid endogenous degrons for TRA2B and TRA2A in several differentiated human cell
    types and compare acute single and joint depletion by TRA2B/TRA2A eCLIP and short- plus
    long-read RNA sequencing. Rescue from a matched locus with wild-type TRA2B or an RRM
    RNA-contact-defective mutant, and classify as direct targets only events with nearby binding
    and wild-type-specific rescue.
  experiment_type: Acute degron perturbation, eCLIP, and RNA sequencing
- hypothesis: >-
    Motif position, local RNA architecture, partner abundance, and RS-domain phosphorylation
    determine whether TRA2B activates or represses exon inclusion.
  description: >-
    Test a massively parallel minigene library varying AGAA/GAA and structured CAA elements,
    their position relative to splice sites, and adjacent regulator motifs under titrated TRA2B
    expression and perturbation of TRA2A, RBMX, SR proteins, CLK kinases, and SRPK kinases.
    Validate predictive sequence features by base editing representative endogenous exons.
  experiment_type: Massively parallel splicing reporter and endogenous base editing
- hypothesis: >-
    TRA2B isoform 3 retains RNA binding but has altered partner recruitment, whereas isoform 2
    is unstable or lacks splicing-regulatory activity.
  description: >-
    Establish endogenous expression of each isoform by long-read RNA sequencing and targeted
    proteomics, then perform matched single-copy isoform rescue in an acute TRA2B-depletion
    background. Compare nuclear localization, eCLIP profiles, protein interactomes, and rescue
    of direct splicing events.
  experiment_type: Isoform-resolved proteomics, eCLIP, and functional rescue

TRA2B

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: TRA2B (Transformer-2 Protein Homolog Beta)

1. Gene and Protein Identity

2. Protein Structure and Domain Architecture

3. RNA Binding Specificity and Mechanism

4. Primary Function: Splicing Activation

5. Subcellular Localization

6. Autoregulation via Poison Exon and Paralog Compensation

7. Key Splicing Targets and Biological Pathways

7.1 DNA Damage Response: CHEK1

7.2 Hepatic Lipogenesis and Metabolic Regulation: LPIN1

7.3 Neurodevelopment and Neuronal Survival

7.4 Spinal Muscular Atrophy: SMN2 Exon 7

7.5 Alzheimer's Disease: RAGE Splicing

7.6 Male Fertility and Meiosis: Poison Exon Function

8. Role in Cancer

9. Summary of Signaling and Biochemical Context

Artifacts

Citations

📚 Additional Documentation

Notes

TRA2B review notes

Core molecular activity

Direction and mechanism of splicing regulation

Localization and regulation

Annotation decisions

📄 View Raw YAML