{"gene":"SRSF10","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2002,"finding":"SRp38 (SRSF10) is a general splicing repressor when dephosphorylated; in its phosphorylated form it is essentially inactive in splicing assays. Dephosphorylation converts it to a potent, general repressor that inhibits splicing at an early step. SRp38 is specifically dephosphorylated in mitotic cells and is required for splicing repression observed in mitotic cell extracts.","method":"In vitro splicing assays, immunodepletion, cell-cycle synchronization, phosphorylation-state analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with defined biochemical states, replicated across multiple subsequent labs","pmids":["12419250"],"is_preprint":false},{"year":2004,"finding":"SRp38 (SRSF10) is dephosphorylated upon heat shock, and dephosphorylated SRp38 is required for heat-shock-induced splicing repression. Depletion of SRp38 from heat-shocked extracts derepresses splicing; adding back dephosphorylated SRp38 restores inhibition. Dephosphorylated SRp38 interacts with U1 snRNP protein and interferes with 5'-splice-site recognition by U1 snRNP. SRp38-deficient DT40 cells show altered cell-cycle profile and are temperature sensitive.","method":"In vitro splicing assays, immunodepletion/reconstitution, co-immunoprecipitation with U1 snRNP, SRp38-knockout DT40 cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution with purified proteins, immunodepletion, snRNP interaction, KO cell phenotype; replicated by subsequent work","pmids":["14765198"],"is_preprint":false},{"year":2005,"finding":"Dephosphorylated SRp38 redistributes and colocalizes with snRNPs (but not SC35) during mitosis and after heat shock. An snRNP component fully rescues heat-shock-induced splicing repression in vitro; purified U1 snRNP does so partially. The RS domain of SRp38 contains two subdomains (RS1 and RS2): RS1 deletion mutant specifically inhibits the second step of splicing, while RS2 deletion retains dephosphorylation-dependent repression. The RBD of SRp38 is responsible for repression activity whereas the RS domain of SC35 confers activation.","method":"Immunofluorescence, in vitro splicing assays with deletion mutants, chimeric SRp38/SC35 constructs, snRNP rescue experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, domain swap, localization, in vitro assay) in a single focused study","pmids":["16135820"],"is_preprint":false},{"year":2007,"finding":"SRp38 dephosphorylation upon heat shock is carried out by the phosphatase PP1, which is activated by dissociation of its inhibitor NIPP1. PP1 is targeted to SRp38 through a direct interaction via SRp38's RS domain. The specific dephosphorylation of SRp38 (and not other SR proteins) is largely determined by the low activity of SR protein kinases toward SRp38. Under non-stress conditions, 14-3-3 proteins associate with SRp38 and protect it from dephosphorylation; upon heat shock, 14-3-3 dissociates.","method":"In vitro phosphatase assay, co-immunoprecipitation, domain mapping, kinase activity assays, immunoblotting","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution with PP1/NIPP1/14-3-3, domain-interaction mapping, multiple orthogonal methods in one study","pmids":["17936706"],"is_preprint":false},{"year":2005,"finding":"Hsp27 (but not alphaB-crystallin) enhances rephosphorylation of SRp38 after heat shock, thereby promoting recovery of splicing. This requires phosphorylatable Hsp27 and a Hsp90 client protein. Hsp27 does not prevent dephosphorylation of SRp38 during heat shock. Calyculin A (phosphatase inhibitor) prevents SRp38 dephosphorylation during heat shock, indicating cells recovering from heat shock are not kinase-deficient.","method":"Exogenous expression of Hsp27/alphaB-crystallin, immunoblotting for SRp38 phosphorylation, in vitro splicing assays, pharmacological inhibition","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional rephosphorylation assays and splicing recovery, single lab with multiple orthogonal approaches","pmids":["16339078"],"is_preprint":false},{"year":2008,"finding":"Phosphorylated SRp38 (SRSF10) functions as a sequence-specific splicing activator, unlike all other characterized SR proteins. It can induce spliceosome complex A formation without a cofactor, but requires a cofactor for progression to complexes B and C. Phosphorylated SRp38 strengthens stable recognition of pre-mRNA by U1 and U2 snRNPs. SRp38 was shown to alter alternative splicing of glutamate receptor B pre-mRNA in a sequence-specific manner.","method":"In vitro splicing assays, spliceosomal complex assembly analysis, minigene splicing, U1/U2 snRNP binding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined phosphorylation states, spliceosome assembly intermediates characterized, replicated by subsequent work","pmids":["18794844"],"is_preprint":false},{"year":2009,"finding":"SRp38 (SRSF10) null mice die mostly by E15.5 with cardiac defects. In the embryonic heart, SRp38 regulates alternative splicing of cardiac triadin pre-mRNA; absence of SRp38 reduces triadin protein and interacting protein calsequestrin 2. Purified SRp38 binds specifically to the regulated triadin exon and modulates triadin splicing in vitro. SRp38-null embryonic cardiomyocytes exhibit defective Ca2+ handling.","method":"Knockout mouse, RNA profiling, in vitro splicing assay with purified SRp38, RNA binding (direct binding to regulated exon), Ca2+ imaging in isolated cardiomyocytes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding/splicing reconstitution, KO mouse with defined molecular and physiological phenotype, multiple orthogonal methods","pmids":["19386262"],"is_preprint":false},{"year":2010,"finding":"A mild heat pretreatment (thermotolerance) protects SRSF10 from dephosphorylation during a subsequent severe heat shock, and this requires de novo protein synthesis. Hsp27 overexpression inhibits SRSF10 dephosphorylation by directly interacting with SRSF10, thereby preventing splicing repression.","method":"Immunoblotting for SRSF10 phosphorylation, overexpression of Hsp27, co-immunoprecipitation of Hsp27-SRSF10, in vitro splicing assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP demonstrating direct Hsp27-SRSF10 interaction, functional splicing assays; single lab","pmids":["21135127"],"is_preprint":false},{"year":2014,"finding":"SRSF10 stimulates inclusion of BCLAF1 alternative exon 5a in a sequence-specific manner, producing a pro-tumorigenic BCLAF1 protein isoform. SRSF10 knockdown inhibits growth of colorectal cancer cells and reduces exon 5a inclusion.","method":"Minigene splicing assays, siRNA knockdown, RT-PCR for isoform quantification, cell growth assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — minigene splicing validation plus KD functional assays, single lab","pmids":["25091051"],"is_preprint":false},{"year":2014,"finding":"SRSF10 promotes both exon inclusion and exclusion in a position-dependent manner: binding to cassette exons promotes inclusion, whereas binding within downstream constitutive exons promotes exclusion. This positional effect was validated by mutagenesis of SRSF10 binding motifs in minigene constructs. Cells depleted of SRSF10 are more susceptible to ER stress-induced apoptosis; reconstitution of SRSF10 in KO cells rescues wild-type splicing and stress resistance.","method":"RNA-seq coupled with bioinformatics, minigene mutagenesis, SRSF10 knockout and reconstitution, cell viability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — transcriptome-wide mapping plus mutagenesis plus KO rescue, multiple orthogonal methods","pmids":["24442672"],"is_preprint":false},{"year":2014,"finding":"SRSF10 controls alternative splicing of lipin1 pre-mRNA by binding a cis-element in constitutive exon 8 to promote skipping of exon 7, generating the lipin1α isoform required for early adipocyte differentiation. SRSF10-null mice display severely impaired subcutaneous white adipose tissue development. Lipin1α expression rescues adipogenic defects caused by SRSF10 loss.","method":"SRSF10 knockout mice, RNA-seq, minigene splicing assays, cis-element binding analysis, adipocyte differentiation assays, rescue experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO mouse phenotype, in vitro binding and splicing reconstitution, rescue by specific isoform; multiple orthogonal methods","pmids":["24710272"],"is_preprint":false},{"year":2015,"finding":"SRSF10 activates inclusion of alternative exons 16 and 17 of Lrrfip1 in muscle, an event essential for myoblast differentiation. SRSF10 also represses inclusion of PGC1α exon 7a in hepatocytes, facilitating production of functional PGC1α protein that regulates glucose production. SRSF10-null mice exhibit defects in striated muscle development.","method":"Conditional KO mice, RNA-seq, minigene splicing assays, siRNA knockdown, glucose production assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO mouse phenotype, in vitro minigene splicing, multiple tissue and target validations","pmids":["26586428"],"is_preprint":false},{"year":2016,"finding":"In normally growing cells SRSF10 partially relieves repression of the Bcl-xS 5' splice site and interacts with both repressor hnRNP K and stimulatory hnRNP F/H on the Bcl-x pre-mRNA. Oxaliplatin-induced DNA damage (via ATM/CHK2) causes dephosphorylation of SRSF10, abrogates the interaction of SRSF10 with hnRNP F/H, and decreases association of SRSF10 and hnRNP K with the Bcl-x pre-mRNA, shifting splicing toward pro-apoptotic Bcl-xS.","method":"RNA immunoprecipitation, co-immunoprecipitation, siRNA knockdown, minigene splicing assays, ATM/CHK2 inhibition, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RIP/co-IP, kinase pathway manipulation, genome-wide splicing analysis, multiple orthogonal methods","pmids":["27851963"],"is_preprint":false},{"year":2017,"finding":"Compound 1C8 promotes dephosphorylation of SRSF10 and increases its interaction with hTra2β. Depleting SRSF10 by RNAi reduces HIV-1 splicing and expression of Tat, Gag, and Env, mimicking 1C8's effect. 1C8 targets SRSF10-dependent splicing regulation rather than SRSF1.","method":"RNAi knockdown, immunoblotting for SRSF10 phosphorylation, co-immunoprecipitation, RT-PCR of HIV-1 splice variants","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi, co-IP interaction data, phosphorylation assays; single lab","pmids":["27928057"],"is_preprint":false},{"year":2018,"finding":"DNA damage reconfigures the assembly of splicing regulators on the Bcl-x pre-mRNA: SRSF10, 14-3-3ε, hnRNP A1/A2, and Sam68 collaborate to drive DNA-damage-induced shift toward pro-apoptotic Bcl-xS. RNA affinity assays identified 14-3-3ε and hnRNP A1 as proteins recovered with the SRSF10-binding region of Bcl-x transcript.","method":"RNA affinity pulldown, co-immunoprecipitation, siRNA knockdown, minigene splicing assays, RNA-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNA affinity pulldown plus functional KD validation; single lab","pmids":["29396485"],"is_preprint":false},{"year":2018,"finding":"SRSF10 modulates alternative terminator usage of IL1RAP exon 13 to increase production of membrane form of IL1RAP (mIL1RAP). SRSF10 is transcriptionally upregulated by HPV E6/E7 via E2F1. The resulting mIL1RAP upregulates CD47 via NF-κB activation, inhibiting macrophage phagocytosis.","method":"Minigene splicing assays, siRNA knockdown, co-immunoprecipitation, ChIP, flow cytometry, phagocytosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — minigene splicing, functional KD assays, E2F1-ChIP for upstream regulation; single lab","pmids":["29429992"],"is_preprint":false},{"year":2020,"finding":"SRSF10 binds to the SMN2 intronic splicing silencer ISS-N1 (identified by MS/MS and surface plasmon resonance imaging). The two isoforms of SRSF10 (differing in RS domain length) regulate SMN1 and SMN2 exon 7 inclusion with different strengths, correlating with RS domain length. Splice-switching oligonucleotides that shift the SRSF10 isoform ratio modulate endogenous SMN2 exon 7 inclusion.","method":"MS/MS proteomics on RNA affinity pulldown, surface plasmon resonance imaging, splice-switching oligonucleotides, RT-PCR","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding measured by SPR plus functional splice-switching; single lab","pmids":["33300159"],"is_preprint":false},{"year":2020,"finding":"SRSF10 acts as a restriction factor for HBV by regulating the level of nascent HBV RNA (not HBV RNA splicing). The dephosphorylated form of SRSF10 is likely responsible for its anti-HBV effect. SRSF10 was identified as a nuclear interactor of HBV core protein (HBc) by proteomic analysis of the HBc interactome in differentiated HepaRG cells.","method":"Affinity proteomics/mass spectrometry (HBc interactome), SRSF10 knockdown, pharmacological inhibition (1C8), quantitative RT-PCR for HBV RNA levels, nascent RNA analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomic identification, functional KD with two orthogonal approaches; single lab","pmids":["33180834"],"is_preprint":false},{"year":2020,"finding":"SRSF10 binds a splicing regulatory cis-element in chicken ANP32A intron 4 (identified by RNA affinity purification/mass spectrometry and RIP), promoting production of the shorter ch-ANP32A-29 isoform at the expense of ch-ANP32A-33. Overexpression of SRSF10 reduces avian influenza virus polymerase activity and viral replication by decreasing the ch-ANP32A-33 isoform.","method":"RNA affinity purification and mass spectrometry, RIP, overexpression/knockdown, polymerase activity assays, viral replication assays","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding confirmed by two methods, functional splicing consequence validated; single lab","pmids":["32574681"],"is_preprint":false},{"year":2021,"finding":"RNA immunoprecipitation confirmed that TTN-derived circular RNAs (cTTN1) bind SRSF10 via the back-splice junction motif. Loss of cTTN1 in iPSC-derived cardiomyocytes causes abnormal splicing of SRSF10 targets (MEF2A, CASQ2) and disrupts RBM20 localization, indicating that circRNA-mediated sequestration/presentation of SRSF10 modulates its splicing activity.","method":"RNA immunoprecipitation, shRNA-mediated selective knockdown of circRNA back-splice junction, engineered heart tissue contractility assays, splicing analysis by RT-PCR","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP confirms direct binding, functional splicing consequences in human iPSC-CM model; single lab","pmids":["33583186"],"is_preprint":false},{"year":2021,"finding":"SRSF10 downregulates the expression of IRF1 (a transcriptional activator of Act1) by being recruited to the lncRNA TRAF3IP2-AS1, thereby suppressing IL-17A signaling. Lentiviral overexpression of SRSF10 yields therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis.","method":"Lentiviral overexpression, lncRNA-RBP interaction assays, IRF1 expression analysis, IL-17A signaling readouts, murine disease models","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — in vivo rescue experiment and signaling assays but detailed molecular mechanism of IRF1 repression by SRSF10 not biochemically defined in abstracts","pmids":["33941656"],"is_preprint":false},{"year":2021,"finding":"GPS167/192 compounds inhibit CLK1 and CLK4 kinases and increase their interaction with SRSF10, leading to impaired SRSF10 phosphorylation-dependent splicing activity (e.g., reduced BCLAF1-L production). GPS167 promotes p53-dependent apoptosis in CRC cells in a manner that requires both SRSF10 and p53.","method":"Co-immunoprecipitation (GPS167-induced SRSF10-CLK interaction), minigene splicing assays, siRNA knockdown, CRC cell growth/apoptosis assays, colonoid models","journal":"NAR cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP linking CLK-SRSF10 interaction to compound, functional splicing and apoptosis data; single lab","pmids":["34316707"],"is_preprint":false},{"year":2022,"finding":"SRSF10 is essential for expansion of PLZF+ undifferentiated progenitor spermatogonia. SRSF10 directly binds thousands of spermatogonial mRNAs (iRIP-seq) and its depletion causes alternative splicing defects in genes involved in germ cell development (Nasp, Bclaf1, Rif1, Dazl, Kit, Ret, Sycp1), leading to failed spermatogonia differentiation and meiosis initiation.","method":"Germ cell-specific KO mice, bulk RNA-seq, single-cell RNA-seq, iRIP-seq (direct binding), immunostaining","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding by RIP-seq combined with KO mouse phenotype and transcriptome-wide analysis; multiple orthogonal methods","pmids":["36355419"],"is_preprint":false},{"year":2022,"finding":"SRSF10 promotes exon 6 skipping of CDC25A pre-mRNA, producing a CDC25A(ΔE6) isoform that lacks two ubiquitination sites (Lys150, Lys169) and is therefore stabilized and retained in the nucleus. SRSF10 promotes Ser178 dephosphorylation of CDC25A to cause nuclear retention. CDC25A(ΔE6) is indispensable for SRSF10-driven HCC growth in vitro and in vivo.","method":"RNA sequencing, RIP and CLIP-qPCR, co-immunoprecipitation, immunofluorescence, mutagenesis of ubiquitination sites, xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by RIP/CLIP, isoform mechanistic consequences validated by mutagenesis and in vivo; single lab","pmids":["36539837"],"is_preprint":false},{"year":2022,"finding":"SRSF10 promotes inclusion of exon 10 in SREK1 (generating SREK1L), which in turn sustains expression of BLOC1S5-TXNDC5 (B-T) by inhibiting NMD. B-T functions as a ceRNA suppressing miR-30c-5p and miR-30e-5p, which further upregulates SRSF10 and TXNDC5, forming a positive SRSF10/SREK1L/B-T signaling loop in HCC.","method":"RNA splicing assays, siRNA knockdown, co-immunoprecipitation, luciferase reporter assays, HCC cell functional assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple pathway components validated by KD and reporter assays; single lab","pmids":["35296659"],"is_preprint":false},{"year":2023,"finding":"SRSF10 depletion in neural progenitor cells impairs NPC proliferation and cortical neurogenesis through modulation of the PI3K-AKT-mTOR-CCND2 pathway and through altered alternative splicing of Nasp (a cell cycle regulator isoform gene).","method":"Conditional KO mice, in utero electroporation, RNA-seq, RT-PCR of Nasp isoforms, pathway inhibitor experiments","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular pathway plus direct splicing target; single lab","pmids":["37360696"],"is_preprint":false},{"year":2023,"finding":"SRSF10 prevents exon 6 skipping of MDM4 pre-mRNA, thereby maintaining MDM4 protein levels that suppress p53, which in turn inhibits CD8+ T cell infiltration in HCC. SRSF10 also inhibits IFNα/γ signaling and promotes HIF1α-mediated PD-L1 upregulation.","method":"Hepatocyte-specific KO and OE mouse models, RNA-seq, co-immunoprecipitation, flow cytometry, CD8+ T cell depletion experiments, xenograft/orthotopic HCC models","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO/OE plus mechanistic pathway validation with epistasis experiments; single lab","pmids":["38113691"],"is_preprint":false},{"year":2024,"finding":"SRSF10 interacts with the 3'-UTR of MYB mRNA to enhance MYB RNA stability, subsequently upregulating glycolysis-related enzymes (GLUT1, HK1, LDHA) and increasing lactate production. Elevated lactate promotes M2 macrophage polarization via histone H3K18 lactylation, creating an immunosuppressive tumor microenvironment. SRSF10/glycolysis/H3K18la forms a positive feedback loop.","method":"RNA immunoprecipitation (SRSF10-MYB 3'-UTR), co-culture systems, flow cytometry, ChIP for lactylation marks, tumor-bearing mouse models, patient-derived organotypic tumor spheroids","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP confirms direct 3'-UTR binding, functional pathway validated in multiple models; single lab","pmids":["39223929"],"is_preprint":false},{"year":2025,"finding":"Casein kinase 1ε (CK1ε) directly interacts with SRSF10 and phosphorylates SRSF10 at S23 and S133, which is required for SRSF10 binding to Bcl-xL mRNA to favor Bcl-xL over Bcl-xS production. Overexpression of CK1ε abrogates the effect of SRSF10 knockdown on Bcl-xS/Bcl-xL ratio.","method":"Co-immunoprecipitation (CK1ε-SRSF10), in vitro kinase assay with phosphosite mapping (S23/S133), CK1δ/ε inhibitor SR3029, SRSF10 KD + CK1ε OE epistasis, xenograft model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with phosphosite identification plus epistasis; single lab","pmids":["40701249"],"is_preprint":false},{"year":2025,"finding":"SRSF10 depletion in oligodendrocyte lineage cells (OLCs) causes hypomyelination and reduced OLC numbers during mouse CNS development by impairing early OLC differentiation (not proliferation or apoptosis). Among SRSF10-regulated AS targets, correcting the alternative splicing of Myo5a using antisense oligonucleotides reverses OLC differentiation inhibition caused by SRSF10 depletion.","method":"OLC-specific conditional KO mice, RNA-seq, RIP-seq (direct binding), antisense oligonucleotide rescue of Myo5a splicing","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO plus direct RIP-seq binding evidence plus ASO epistasis rescue; multiple orthogonal methods","pmids":["40439883"],"is_preprint":false},{"year":2026,"finding":"SRSF10 promotes inclusion of exon 2 in BCAT2 mRNA, activating mTOR signaling. SRSF10 blockade (by inhibitor 1C8) reprograms tumor-associated macrophages via CCL2, enhancing CD8+ T-cell infiltration and potentiating anti-PD-1 efficacy in gastric cancer models.","method":"Multiple mouse GC models, RNA splicing analysis, SRSF10 knockout/inhibitor experiments, flow cytometry, mTOR pathway analysis, orthotopic model with PD-1 antibody combination","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AS target validated in multiple models, mTOR pathway epistasis shown; single lab","pmids":["42020371"],"is_preprint":false},{"year":2026,"finding":"SRSF10 induces retention of BIN1 exon 12, producing a BIN1(12+) isoform that directly interacts with and activates ANXA1, contributing to cisplatin resistance in bladder cancer. This was shown by co-immunoprecipitation confirming BIN1(12+)-ANXA1 interaction and by functional rescue experiments.","method":"SRSF10 KD/OE, RNA sequencing, RIP-qPCR/CLIP, co-immunoprecipitation (BIN1(12+)-ANXA1), xenograft model, cisplatin IC50 assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and splicing validated, isoform-specific co-IP, in vivo xenograft; single lab","pmids":["41942629"],"is_preprint":false},{"year":2025,"finding":"SRSF10 preferentially binds and traffics mRNAs to the central axon of dorsal root ganglion neurons, establishing compartment-specific translational programs in sensory neurons.","method":"Translating Ribosome Affinity Purification (TRAP) with spatial compartment-specific sequencing, cross-dataset integration with scRNA-seq, RBP-mRNA binding analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, RBP-mRNA association inferred from TRAP-seq without direct binding validation","pmids":[],"is_preprint":true},{"year":2007,"finding":"TASR-1 (SRSF10), but not TASR-2, influences alternative splicing of type II and type XI collagen genes in mouse ATDC5 chondroprogenitor cells. TASR-1 can also down-regulate expression of type X collagen.","method":"Retroviral stable expression in ATDC5 cells, RT-PCR for collagen isoforms, microarray analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression system without direct binding or mechanistic follow-up; single lab","pmids":["17367759"],"is_preprint":false}],"current_model":"SRSF10 is an atypical SR protein whose activity is governed by phosphorylation state: dephosphorylated SRSF10 is a potent general splicing repressor that acts by interacting with U1 snRNP to block 5'-splice-site recognition, while phosphorylated SRSF10 is a sequence-specific splicing activator that stabilizes U1/U2 snRNP engagement with pre-mRNA. Dephosphorylation is mediated by PP1 (targeted to SRSF10's RS domain) and is triggered by heat shock or mitosis, with protection provided by 14-3-3 proteins (which dissociate under stress) and by Hsp27 (which promotes rephosphorylation during recovery). CK1ε phosphorylates SRSF10 at S23 and S133, enabling its binding to specific splice-site-containing mRNAs. Through position-dependent binding to pre-mRNA, SRSF10 controls a broad alternative splicing network critical for cardiac Ca2+ handling (triadin), adipogenesis (lipin1α), myogenesis (Lrrfip1), hepatic glucose production (PGC1α), spermatogenesis, oligodendrocyte differentiation (Myo5a), and neurogenesis; upon DNA damage or chemotherapy, SRSF10 dephosphorylation rewires its interactions with hnRNP K, hnRNP F/H, Sam68, and 14-3-3 to shift Bcl-x and other apoptosis-related transcripts toward pro-apoptotic isoforms."},"narrative":{"mechanistic_narrative":"SRSF10 is an atypical SR-family splicing regulator whose function is switched by phosphorylation state, allowing it to act either as a general splicing repressor or as a sequence-specific splicing activator that shapes broad alternative-splicing networks across development and stress [PMID:12419250, PMID:18794844]. In its dephosphorylated form it is a potent general repressor that blocks splicing at an early step, acting through its RNA-binding domain and an interaction with U1 snRNP that interferes with 5'-splice-site recognition [PMID:12419250, PMID:16135820]; this dephosphorylated, repressive state is induced specifically in mitosis and upon heat shock [PMID:12419250, PMID:14765198]. The conversion is executed by PP1, which is recruited to the SRSF10 RS domain and activated by NIPP1 dissociation, while 14-3-3 binding protects SRSF10 from dephosphorylation under non-stress conditions and Hsp27 drives rephosphorylation during recovery [PMID:17936706, PMID:21135127]. When phosphorylated, SRSF10 instead stabilizes U1/U2 snRNP engagement with pre-mRNA and functions as a sequence-specific activator, with CK1ε phosphorylating S23 and S133 to license target-mRNA binding [PMID:18794844, PMID:40701249]. Through position-dependent binding—promoting cassette-exon inclusion when bound to the exon and exclusion when bound downstream—SRSF10 controls defined splicing programs essential for cardiac Ca2+ handling via triadin, adipogenesis via lipin1α, myogenesis via Lrrfip1, hepatic glucose output via PGC1α, spermatogonial expansion, oligodendrocyte differentiation via Myo5a, and cortical neurogenesis [PMID:24442672, PMID:19386262, PMID:24710272, PMID:26586428, PMID:36355419, PMID:40439883, PMID:37360696]. Upon DNA damage, SRSF10 dephosphorylation rewires its assembly with hnRNP K, hnRNP F/H, Sam68 and 14-3-3ε on the Bcl-x pre-mRNA to shift splicing toward the pro-apoptotic Bcl-xS isoform [PMID:27851963, PMID:29396485]. SRSF10 is co-opted in multiple cancers, where it controls oncogenic isoform choices such as BCLAF1 exon 5a, CDC25A and MDM4 exons, and modulates the tumor microenvironment [PMID:25091051, PMID:36539837, PMID:38113691], and it restricts viral pathogens including HBV and HIV-1 in a phosphorylation-dependent manner [PMID:33180834, PMID:27928057].","teleology":[{"year":2002,"claim":"Established that SRSF10 is not a constitutive splicing factor but a phosphorylation-gated general repressor, defining the central regulatory logic of the protein.","evidence":"In vitro splicing assays with defined phosphorylation states, immunodepletion, and cell-cycle synchronization","pmids":["12419250"],"confidence":"High","gaps":["Did not define the snRNP target or step of repression","Phosphatase/kinase machinery unidentified"]},{"year":2004,"claim":"Identified the mechanistic basis of repression and a physiological trigger, showing dephosphorylated SRSF10 binds U1 snRNP to block 5'-splice-site recognition during heat shock.","evidence":"In vitro splicing reconstitution, U1 snRNP co-IP, and SRSF10-knockout DT40 cells","pmids":["14765198"],"confidence":"High","gaps":["Precise contact between SRSF10 and U1 components not structurally resolved","Whether other snRNPs contribute left open"]},{"year":2005,"claim":"Localized repressive activity to the RNA-binding domain and mapped RS subdomain functions, distinguishing SRSF10 from activating SR proteins like SC35.","evidence":"Immunofluorescence colocalization with snRNPs, deletion mutants, and SRSF10/SC35 chimeras in vitro","pmids":["16135820"],"confidence":"High","gaps":["Structural basis of RBD-mediated repression not determined"]},{"year":2007,"claim":"Defined the enzymatic switch controlling SRSF10, identifying PP1 as the phosphatase, NIPP1 as its regulator, and 14-3-3 as a protective binding partner.","evidence":"In vitro phosphatase assays, domain-mapped PP1 recruitment to the RS domain, and 14-3-3 co-IP","pmids":["17936706"],"confidence":"High","gaps":["Identity of the relevant SR protein kinase(s) under basal conditions not fully resolved here","How 14-3-3 dissociation is signaled unclear"]},{"year":2005,"claim":"Showed how cells reverse the repressive state, with Hsp27 promoting SRSF10 rephosphorylation to restore splicing after heat shock.","evidence":"Hsp27/alphaB-crystallin expression, phosphorylation immunoblotting, and pharmacological phosphatase inhibition","pmids":["16339078"],"confidence":"Medium","gaps":["The kinase enabling rephosphorylation not identified","Single-lab functional assay"]},{"year":2010,"claim":"Demonstrated that Hsp27 acts via direct binding to SRSF10 and that thermotolerance protects SRSF10 from dephosphorylation, linking stress memory to splicing control.","evidence":"Hsp27-SRSF10 co-IP, overexpression, and in vitro splicing assays requiring de novo protein synthesis","pmids":["21135127"],"confidence":"Medium","gaps":["Mechanism by which Hsp27 binding favors rephosphorylation undefined","Single lab"]},{"year":2008,"claim":"Revealed the second functional state, showing phosphorylated SRSF10 is a sequence-specific activator that stabilizes U1/U2 snRNP recognition—uniquely bifunctional among SR proteins.","evidence":"In vitro splicing with defined phospho-states, spliceosome complex assembly analysis, and U1/U2 binding assays","pmids":["18794844"],"confidence":"High","gaps":["Cofactor required for complex B/C progression not identified","Sequence determinants of specific binding not yet mapped genome-wide"]},{"year":2009,"claim":"Provided the first in vivo demonstration of a physiological splicing target, linking SRSF10 to triadin splicing and cardiac Ca2+ handling.","evidence":"SRSF10-null mice, direct binding to the regulated triadin exon, in vitro splicing, and cardiomyocyte Ca2+ imaging","pmids":["19386262"],"confidence":"High","gaps":["Phosphorylation state of SRSF10 governing this target not specified","Other cardiac targets not catalogued"]},{"year":2014,"claim":"Defined the position-dependent splicing code of SRSF10 transcriptome-wide and tied its activity to stress-induced apoptosis resistance.","evidence":"RNA-seq, minigene mutagenesis of binding motifs, and SRSF10 knockout/reconstitution viability assays","pmids":["24442672"],"confidence":"High","gaps":["Did not resolve how the same binding event yields opposite outcomes mechanistically"]},{"year":2014,"claim":"Extended the in vivo target network to metabolic and growth programs, establishing lipin1α (adipogenesis) and a pro-tumorigenic BCLAF1 isoform as SRSF10 outputs.","evidence":"SRSF10-null mice with rescue, minigene splicing, cis-element binding, and colorectal cancer knockdown/growth assays","pmids":["24710272","25091051"],"confidence":"High","gaps":["Tissue-specific determinants of target selection unclear","BCLAF1 study is Medium confidence single-lab"]},{"year":2015,"claim":"Broadened the physiological splicing program to muscle and liver, with Lrrfip1 driving myogenesis and PGC1α regulation controlling hepatic glucose output.","evidence":"Conditional KO mice, RNA-seq, minigene assays, and glucose production assays","pmids":["26586428"],"confidence":"High","gaps":["Upstream signals selecting these tissue-specific targets undefined"]},{"year":2016,"claim":"Connected the DNA-damage response to apoptotic splicing decisions, showing damage-induced SRSF10 dephosphorylation rewires hnRNP K and hnRNP F/H interactions on Bcl-x toward Bcl-xS.","evidence":"Reciprocal RIP/co-IP, ATM/CHK2 inhibition, minigene assays, and RNA-seq","pmids":["27851963"],"confidence":"High","gaps":["Direct phosphatase acting on SRSF10 after damage not identified here"]},{"year":2018,"claim":"Resolved the multi-protein assembly underlying damage-induced Bcl-x switching, adding 14-3-3ε, hnRNP A1/A2 and Sam68 to the regulatory complex.","evidence":"RNA affinity pulldown and co-IP with siRNA functional validation","pmids":["29396485"],"confidence":"Medium","gaps":["Order of assembly and direct vs. bridged contacts not fully resolved","Single lab"]},{"year":2017,"claim":"Established SRSF10 as a druggable host splicing factor for viral infection, with compound 1C8 promoting its dephosphorylation to reduce HIV-1 splicing.","evidence":"RNAi, phosphorylation immunoblotting, hTra2β co-IP, and RT-PCR of HIV-1 splice variants","pmids":["27928057"],"confidence":"Medium","gaps":["Direct SRSF10 binding sites on HIV-1 RNA not mapped","Single lab"]},{"year":2020,"claim":"Expanded SRSF10's antiviral and clinically relevant target repertoire, including HBV restriction, SMN2 exon 7 inclusion, and avian ANP32A isoform control of influenza polymerase.","evidence":"HBc interactome proteomics with KD, SPR/MS direct-binding to ISS-N1 with splice-switching oligos, and RNA affinity/RIP for ANP32A","pmids":["33180834","33300159","32574681"],"confidence":"Medium","gaps":["HBV effect is on nascent RNA level rather than splicing and mechanism unresolved","Isoform-length dependence of SMN regulation not fully explained"]},{"year":2021,"claim":"Identified non-coding RNA control of SRSF10 activity and a kinase upstream of its activating phosphorylation, with circRNA cTTN1 binding SRSF10 and CLK1/4 inhibition impairing its splicing function.","evidence":"RIP in iPSC-cardiomyocytes, GPS167/192 CLK inhibition with co-IP, and minigene/apoptosis assays","pmids":["33583186","34316707"],"confidence":"Medium","gaps":["Whether circRNA acts by sequestration or presentation not definitively distinguished","CLK phosphosite specificity not mapped in these studies"]},{"year":2022,"claim":"Demonstrated essential roles in spermatogonial expansion and consolidated SRSF10 as an oncogenic splicing driver acting through CDC25A and SREK1/B-T circuits.","evidence":"Germ-cell KO mice with iRIP-seq, plus RIP/CLIP and isoform mutagenesis in HCC models","pmids":["36355419","36539837","35296659"],"confidence":"High","gaps":["Phospho-state dependence of germline targeting not addressed","HCC mechanisms are Medium-confidence single-lab"]},{"year":2025,"claim":"Defined CK1ε as a direct kinase phosphorylating SRSF10 at S23/S133 to enable target-mRNA binding, and extended developmental roles to oligodendrocyte differentiation via Myo5a splicing.","evidence":"In vitro kinase assay with phosphosite mapping and epistasis; OLC-specific conditional KO with RIP-seq and ASO rescue","pmids":["40701249","40439883"],"confidence":"High","gaps":["Relationship between CK1ε and previously implicated SR kinases unclear","Whether S23/S133 phosphorylation governs all activating functions not tested broadly"]},{"year":null,"claim":"How a single phosphorylation switch and position-dependent binding code are integrated to select among hundreds of tissue- and stress-specific targets remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the SRSF10–U1/U2 or SRSF10–pre-mRNA complexes","Upstream signaling that directs target choice in each tissue not defined","Kinase/phosphatase partners not unified into a single quantitative model"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,6,9,10,22,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,17]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,5,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,10,11,22,29]}],"complexes":[],"partners":["U1 SNRNP","PP1","14-3-3","HSP27","HNRNP K","HNRNP F/H","SAM68","CK1Ε"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75494","full_name":"Serine/arginine-rich splicing factor 10","aliases":["40 kDa SR-repressor protein","SRrp40","FUS-interacting serine-arginine-rich protein 1","Splicing factor SRp38","Splicing factor, arginine/serine-rich 13A","TLS-associated protein with Ser-Arg repeats","TASR","TLS-associated protein with SR repeats","TLS-associated serine-arginine protein","TLS-associated SR protein"],"length_aa":262,"mass_kda":31.3,"function":"Splicing factor that in its dephosphorylated form acts as a general repressor of pre-mRNA splicing (PubMed:11684676, PubMed:12419250, PubMed:14765198). Seems to interfere with the U1 snRNP 5'-splice recognition of SNRNP70 (PubMed:14765198). Required for splicing repression in M-phase cells and after heat shock (PubMed:14765198). Also acts as a splicing factor that specifically promotes exon skipping during alternative splicing (PubMed:26876937). Interaction with YTHDC1, a RNA-binding protein that recognizes and binds N6-methyladenosine (m6A)-containing RNAs, prevents SRSF10 from binding to its mRNA-binding sites close to m6A-containing regions, leading to inhibit exon skipping during alternative splicing (PubMed:26876937). May be involved in regulation of alternative splicing in neurons, with isoform 1 acting as a positive and isoform 3 as a negative regulator (PubMed:12419250)","subcellular_location":"Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O75494/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF10","classification":"Common Essential","n_dependent_lines":974,"n_total_lines":1208,"dependency_fraction":0.8062913907284768},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SRSF10","total_profiled":1310},"omim":[{"mim_id":"605221","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 10; SRSF10","url":"https://www.omim.org/entry/605221"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF10"},"hgnc":{"alias_symbol":["TASR1","TASR2","SRp38","SRrp40","SFRS13","PPP1R149"],"prev_symbol":["FUSIP2","FUSIP1","SFRS13A"]},"alphafold":{"accession":"O75494","domains":[{"cath_id":"3.30.70.330","chopping":"10-100","consensus_level":"high","plddt":84.2449,"start":10,"end":100}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75494","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75494-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75494-F1-predicted_aligned_error_v6.png","plddt_mean":61.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF10","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF10"},"sequence":{"accession":"O75494","fasta_url":"https://rest.uniprot.org/uniprotkb/O75494.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75494/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75494"}},"corpus_meta":[{"pmid":"14765198","id":"PMC_14765198","title":"Dephosphorylated 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Axons","date":"2025-03-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.640799","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25558,"output_tokens":9266,"usd":0.107832,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19115,"output_tokens":5445,"usd":0.11585,"stage2_stop_reason":"end_turn"},"total_usd":0.223682,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"SRp38 (SRSF10) is a general splicing repressor when dephosphorylated; in its phosphorylated form it is essentially inactive in splicing assays. Dephosphorylation converts it to a potent, general repressor that inhibits splicing at an early step. SRp38 is specifically dephosphorylated in mitotic cells and is required for splicing repression observed in mitotic cell extracts.\",\n      \"method\": \"In vitro splicing assays, immunodepletion, cell-cycle synchronization, phosphorylation-state analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with defined biochemical states, replicated across multiple subsequent labs\",\n      \"pmids\": [\"12419250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRp38 (SRSF10) is dephosphorylated upon heat shock, and dephosphorylated SRp38 is required for heat-shock-induced splicing repression. Depletion of SRp38 from heat-shocked extracts derepresses splicing; adding back dephosphorylated SRp38 restores inhibition. Dephosphorylated SRp38 interacts with U1 snRNP protein and interferes with 5'-splice-site recognition by U1 snRNP. SRp38-deficient DT40 cells show altered cell-cycle profile and are temperature sensitive.\",\n      \"method\": \"In vitro splicing assays, immunodepletion/reconstitution, co-immunoprecipitation with U1 snRNP, SRp38-knockout DT40 cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution with purified proteins, immunodepletion, snRNP interaction, KO cell phenotype; replicated by subsequent work\",\n      \"pmids\": [\"14765198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dephosphorylated SRp38 redistributes and colocalizes with snRNPs (but not SC35) during mitosis and after heat shock. An snRNP component fully rescues heat-shock-induced splicing repression in vitro; purified U1 snRNP does so partially. The RS domain of SRp38 contains two subdomains (RS1 and RS2): RS1 deletion mutant specifically inhibits the second step of splicing, while RS2 deletion retains dephosphorylation-dependent repression. The RBD of SRp38 is responsible for repression activity whereas the RS domain of SC35 confers activation.\",\n      \"method\": \"Immunofluorescence, in vitro splicing assays with deletion mutants, chimeric SRp38/SC35 constructs, snRNP rescue experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, domain swap, localization, in vitro assay) in a single focused study\",\n      \"pmids\": [\"16135820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SRp38 dephosphorylation upon heat shock is carried out by the phosphatase PP1, which is activated by dissociation of its inhibitor NIPP1. PP1 is targeted to SRp38 through a direct interaction via SRp38's RS domain. The specific dephosphorylation of SRp38 (and not other SR proteins) is largely determined by the low activity of SR protein kinases toward SRp38. Under non-stress conditions, 14-3-3 proteins associate with SRp38 and protect it from dephosphorylation; upon heat shock, 14-3-3 dissociates.\",\n      \"method\": \"In vitro phosphatase assay, co-immunoprecipitation, domain mapping, kinase activity assays, immunoblotting\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution with PP1/NIPP1/14-3-3, domain-interaction mapping, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17936706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Hsp27 (but not alphaB-crystallin) enhances rephosphorylation of SRp38 after heat shock, thereby promoting recovery of splicing. This requires phosphorylatable Hsp27 and a Hsp90 client protein. Hsp27 does not prevent dephosphorylation of SRp38 during heat shock. Calyculin A (phosphatase inhibitor) prevents SRp38 dephosphorylation during heat shock, indicating cells recovering from heat shock are not kinase-deficient.\",\n      \"method\": \"Exogenous expression of Hsp27/alphaB-crystallin, immunoblotting for SRp38 phosphorylation, in vitro splicing assays, pharmacological inhibition\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional rephosphorylation assays and splicing recovery, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"16339078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Phosphorylated SRp38 (SRSF10) functions as a sequence-specific splicing activator, unlike all other characterized SR proteins. It can induce spliceosome complex A formation without a cofactor, but requires a cofactor for progression to complexes B and C. Phosphorylated SRp38 strengthens stable recognition of pre-mRNA by U1 and U2 snRNPs. SRp38 was shown to alter alternative splicing of glutamate receptor B pre-mRNA in a sequence-specific manner.\",\n      \"method\": \"In vitro splicing assays, spliceosomal complex assembly analysis, minigene splicing, U1/U2 snRNP binding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined phosphorylation states, spliceosome assembly intermediates characterized, replicated by subsequent work\",\n      \"pmids\": [\"18794844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRp38 (SRSF10) null mice die mostly by E15.5 with cardiac defects. In the embryonic heart, SRp38 regulates alternative splicing of cardiac triadin pre-mRNA; absence of SRp38 reduces triadin protein and interacting protein calsequestrin 2. Purified SRp38 binds specifically to the regulated triadin exon and modulates triadin splicing in vitro. SRp38-null embryonic cardiomyocytes exhibit defective Ca2+ handling.\",\n      \"method\": \"Knockout mouse, RNA profiling, in vitro splicing assay with purified SRp38, RNA binding (direct binding to regulated exon), Ca2+ imaging in isolated cardiomyocytes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding/splicing reconstitution, KO mouse with defined molecular and physiological phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19386262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A mild heat pretreatment (thermotolerance) protects SRSF10 from dephosphorylation during a subsequent severe heat shock, and this requires de novo protein synthesis. Hsp27 overexpression inhibits SRSF10 dephosphorylation by directly interacting with SRSF10, thereby preventing splicing repression.\",\n      \"method\": \"Immunoblotting for SRSF10 phosphorylation, overexpression of Hsp27, co-immunoprecipitation of Hsp27-SRSF10, in vitro splicing assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP demonstrating direct Hsp27-SRSF10 interaction, functional splicing assays; single lab\",\n      \"pmids\": [\"21135127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRSF10 stimulates inclusion of BCLAF1 alternative exon 5a in a sequence-specific manner, producing a pro-tumorigenic BCLAF1 protein isoform. SRSF10 knockdown inhibits growth of colorectal cancer cells and reduces exon 5a inclusion.\",\n      \"method\": \"Minigene splicing assays, siRNA knockdown, RT-PCR for isoform quantification, cell growth assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — minigene splicing validation plus KD functional assays, single lab\",\n      \"pmids\": [\"25091051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRSF10 promotes both exon inclusion and exclusion in a position-dependent manner: binding to cassette exons promotes inclusion, whereas binding within downstream constitutive exons promotes exclusion. This positional effect was validated by mutagenesis of SRSF10 binding motifs in minigene constructs. Cells depleted of SRSF10 are more susceptible to ER stress-induced apoptosis; reconstitution of SRSF10 in KO cells rescues wild-type splicing and stress resistance.\",\n      \"method\": \"RNA-seq coupled with bioinformatics, minigene mutagenesis, SRSF10 knockout and reconstitution, cell viability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — transcriptome-wide mapping plus mutagenesis plus KO rescue, multiple orthogonal methods\",\n      \"pmids\": [\"24442672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRSF10 controls alternative splicing of lipin1 pre-mRNA by binding a cis-element in constitutive exon 8 to promote skipping of exon 7, generating the lipin1α isoform required for early adipocyte differentiation. SRSF10-null mice display severely impaired subcutaneous white adipose tissue development. Lipin1α expression rescues adipogenic defects caused by SRSF10 loss.\",\n      \"method\": \"SRSF10 knockout mice, RNA-seq, minigene splicing assays, cis-element binding analysis, adipocyte differentiation assays, rescue experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO mouse phenotype, in vitro binding and splicing reconstitution, rescue by specific isoform; multiple orthogonal methods\",\n      \"pmids\": [\"24710272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF10 activates inclusion of alternative exons 16 and 17 of Lrrfip1 in muscle, an event essential for myoblast differentiation. SRSF10 also represses inclusion of PGC1α exon 7a in hepatocytes, facilitating production of functional PGC1α protein that regulates glucose production. SRSF10-null mice exhibit defects in striated muscle development.\",\n      \"method\": \"Conditional KO mice, RNA-seq, minigene splicing assays, siRNA knockdown, glucose production assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO mouse phenotype, in vitro minigene splicing, multiple tissue and target validations\",\n      \"pmids\": [\"26586428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In normally growing cells SRSF10 partially relieves repression of the Bcl-xS 5' splice site and interacts with both repressor hnRNP K and stimulatory hnRNP F/H on the Bcl-x pre-mRNA. Oxaliplatin-induced DNA damage (via ATM/CHK2) causes dephosphorylation of SRSF10, abrogates the interaction of SRSF10 with hnRNP F/H, and decreases association of SRSF10 and hnRNP K with the Bcl-x pre-mRNA, shifting splicing toward pro-apoptotic Bcl-xS.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, siRNA knockdown, minigene splicing assays, ATM/CHK2 inhibition, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RIP/co-IP, kinase pathway manipulation, genome-wide splicing analysis, multiple orthogonal methods\",\n      \"pmids\": [\"27851963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Compound 1C8 promotes dephosphorylation of SRSF10 and increases its interaction with hTra2β. Depleting SRSF10 by RNAi reduces HIV-1 splicing and expression of Tat, Gag, and Env, mimicking 1C8's effect. 1C8 targets SRSF10-dependent splicing regulation rather than SRSF1.\",\n      \"method\": \"RNAi knockdown, immunoblotting for SRSF10 phosphorylation, co-immunoprecipitation, RT-PCR of HIV-1 splice variants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi, co-IP interaction data, phosphorylation assays; single lab\",\n      \"pmids\": [\"27928057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNA damage reconfigures the assembly of splicing regulators on the Bcl-x pre-mRNA: SRSF10, 14-3-3ε, hnRNP A1/A2, and Sam68 collaborate to drive DNA-damage-induced shift toward pro-apoptotic Bcl-xS. RNA affinity assays identified 14-3-3ε and hnRNP A1 as proteins recovered with the SRSF10-binding region of Bcl-x transcript.\",\n      \"method\": \"RNA affinity pulldown, co-immunoprecipitation, siRNA knockdown, minigene splicing assays, RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNA affinity pulldown plus functional KD validation; single lab\",\n      \"pmids\": [\"29396485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF10 modulates alternative terminator usage of IL1RAP exon 13 to increase production of membrane form of IL1RAP (mIL1RAP). SRSF10 is transcriptionally upregulated by HPV E6/E7 via E2F1. The resulting mIL1RAP upregulates CD47 via NF-κB activation, inhibiting macrophage phagocytosis.\",\n      \"method\": \"Minigene splicing assays, siRNA knockdown, co-immunoprecipitation, ChIP, flow cytometry, phagocytosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — minigene splicing, functional KD assays, E2F1-ChIP for upstream regulation; single lab\",\n      \"pmids\": [\"29429992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF10 binds to the SMN2 intronic splicing silencer ISS-N1 (identified by MS/MS and surface plasmon resonance imaging). The two isoforms of SRSF10 (differing in RS domain length) regulate SMN1 and SMN2 exon 7 inclusion with different strengths, correlating with RS domain length. Splice-switching oligonucleotides that shift the SRSF10 isoform ratio modulate endogenous SMN2 exon 7 inclusion.\",\n      \"method\": \"MS/MS proteomics on RNA affinity pulldown, surface plasmon resonance imaging, splice-switching oligonucleotides, RT-PCR\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding measured by SPR plus functional splice-switching; single lab\",\n      \"pmids\": [\"33300159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF10 acts as a restriction factor for HBV by regulating the level of nascent HBV RNA (not HBV RNA splicing). The dephosphorylated form of SRSF10 is likely responsible for its anti-HBV effect. SRSF10 was identified as a nuclear interactor of HBV core protein (HBc) by proteomic analysis of the HBc interactome in differentiated HepaRG cells.\",\n      \"method\": \"Affinity proteomics/mass spectrometry (HBc interactome), SRSF10 knockdown, pharmacological inhibition (1C8), quantitative RT-PCR for HBV RNA levels, nascent RNA analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomic identification, functional KD with two orthogonal approaches; single lab\",\n      \"pmids\": [\"33180834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF10 binds a splicing regulatory cis-element in chicken ANP32A intron 4 (identified by RNA affinity purification/mass spectrometry and RIP), promoting production of the shorter ch-ANP32A-29 isoform at the expense of ch-ANP32A-33. Overexpression of SRSF10 reduces avian influenza virus polymerase activity and viral replication by decreasing the ch-ANP32A-33 isoform.\",\n      \"method\": \"RNA affinity purification and mass spectrometry, RIP, overexpression/knockdown, polymerase activity assays, viral replication assays\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding confirmed by two methods, functional splicing consequence validated; single lab\",\n      \"pmids\": [\"32574681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNA immunoprecipitation confirmed that TTN-derived circular RNAs (cTTN1) bind SRSF10 via the back-splice junction motif. Loss of cTTN1 in iPSC-derived cardiomyocytes causes abnormal splicing of SRSF10 targets (MEF2A, CASQ2) and disrupts RBM20 localization, indicating that circRNA-mediated sequestration/presentation of SRSF10 modulates its splicing activity.\",\n      \"method\": \"RNA immunoprecipitation, shRNA-mediated selective knockdown of circRNA back-splice junction, engineered heart tissue contractility assays, splicing analysis by RT-PCR\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP confirms direct binding, functional splicing consequences in human iPSC-CM model; single lab\",\n      \"pmids\": [\"33583186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF10 downregulates the expression of IRF1 (a transcriptional activator of Act1) by being recruited to the lncRNA TRAF3IP2-AS1, thereby suppressing IL-17A signaling. Lentiviral overexpression of SRSF10 yields therapeutic effects in mouse models of psoriasis and experimental autoimmune encephalomyelitis.\",\n      \"method\": \"Lentiviral overexpression, lncRNA-RBP interaction assays, IRF1 expression analysis, IL-17A signaling readouts, murine disease models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo rescue experiment and signaling assays but detailed molecular mechanism of IRF1 repression by SRSF10 not biochemically defined in abstracts\",\n      \"pmids\": [\"33941656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPS167/192 compounds inhibit CLK1 and CLK4 kinases and increase their interaction with SRSF10, leading to impaired SRSF10 phosphorylation-dependent splicing activity (e.g., reduced BCLAF1-L production). GPS167 promotes p53-dependent apoptosis in CRC cells in a manner that requires both SRSF10 and p53.\",\n      \"method\": \"Co-immunoprecipitation (GPS167-induced SRSF10-CLK interaction), minigene splicing assays, siRNA knockdown, CRC cell growth/apoptosis assays, colonoid models\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP linking CLK-SRSF10 interaction to compound, functional splicing and apoptosis data; single lab\",\n      \"pmids\": [\"34316707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF10 is essential for expansion of PLZF+ undifferentiated progenitor spermatogonia. SRSF10 directly binds thousands of spermatogonial mRNAs (iRIP-seq) and its depletion causes alternative splicing defects in genes involved in germ cell development (Nasp, Bclaf1, Rif1, Dazl, Kit, Ret, Sycp1), leading to failed spermatogonia differentiation and meiosis initiation.\",\n      \"method\": \"Germ cell-specific KO mice, bulk RNA-seq, single-cell RNA-seq, iRIP-seq (direct binding), immunostaining\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding by RIP-seq combined with KO mouse phenotype and transcriptome-wide analysis; multiple orthogonal methods\",\n      \"pmids\": [\"36355419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF10 promotes exon 6 skipping of CDC25A pre-mRNA, producing a CDC25A(ΔE6) isoform that lacks two ubiquitination sites (Lys150, Lys169) and is therefore stabilized and retained in the nucleus. SRSF10 promotes Ser178 dephosphorylation of CDC25A to cause nuclear retention. CDC25A(ΔE6) is indispensable for SRSF10-driven HCC growth in vitro and in vivo.\",\n      \"method\": \"RNA sequencing, RIP and CLIP-qPCR, co-immunoprecipitation, immunofluorescence, mutagenesis of ubiquitination sites, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by RIP/CLIP, isoform mechanistic consequences validated by mutagenesis and in vivo; single lab\",\n      \"pmids\": [\"36539837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF10 promotes inclusion of exon 10 in SREK1 (generating SREK1L), which in turn sustains expression of BLOC1S5-TXNDC5 (B-T) by inhibiting NMD. B-T functions as a ceRNA suppressing miR-30c-5p and miR-30e-5p, which further upregulates SRSF10 and TXNDC5, forming a positive SRSF10/SREK1L/B-T signaling loop in HCC.\",\n      \"method\": \"RNA splicing assays, siRNA knockdown, co-immunoprecipitation, luciferase reporter assays, HCC cell functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple pathway components validated by KD and reporter assays; single lab\",\n      \"pmids\": [\"35296659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF10 depletion in neural progenitor cells impairs NPC proliferation and cortical neurogenesis through modulation of the PI3K-AKT-mTOR-CCND2 pathway and through altered alternative splicing of Nasp (a cell cycle regulator isoform gene).\",\n      \"method\": \"Conditional KO mice, in utero electroporation, RNA-seq, RT-PCR of Nasp isoforms, pathway inhibitor experiments\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular pathway plus direct splicing target; single lab\",\n      \"pmids\": [\"37360696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF10 prevents exon 6 skipping of MDM4 pre-mRNA, thereby maintaining MDM4 protein levels that suppress p53, which in turn inhibits CD8+ T cell infiltration in HCC. SRSF10 also inhibits IFNα/γ signaling and promotes HIF1α-mediated PD-L1 upregulation.\",\n      \"method\": \"Hepatocyte-specific KO and OE mouse models, RNA-seq, co-immunoprecipitation, flow cytometry, CD8+ T cell depletion experiments, xenograft/orthotopic HCC models\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO/OE plus mechanistic pathway validation with epistasis experiments; single lab\",\n      \"pmids\": [\"38113691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRSF10 interacts with the 3'-UTR of MYB mRNA to enhance MYB RNA stability, subsequently upregulating glycolysis-related enzymes (GLUT1, HK1, LDHA) and increasing lactate production. Elevated lactate promotes M2 macrophage polarization via histone H3K18 lactylation, creating an immunosuppressive tumor microenvironment. SRSF10/glycolysis/H3K18la forms a positive feedback loop.\",\n      \"method\": \"RNA immunoprecipitation (SRSF10-MYB 3'-UTR), co-culture systems, flow cytometry, ChIP for lactylation marks, tumor-bearing mouse models, patient-derived organotypic tumor spheroids\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP confirms direct 3'-UTR binding, functional pathway validated in multiple models; single lab\",\n      \"pmids\": [\"39223929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Casein kinase 1ε (CK1ε) directly interacts with SRSF10 and phosphorylates SRSF10 at S23 and S133, which is required for SRSF10 binding to Bcl-xL mRNA to favor Bcl-xL over Bcl-xS production. Overexpression of CK1ε abrogates the effect of SRSF10 knockdown on Bcl-xS/Bcl-xL ratio.\",\n      \"method\": \"Co-immunoprecipitation (CK1ε-SRSF10), in vitro kinase assay with phosphosite mapping (S23/S133), CK1δ/ε inhibitor SR3029, SRSF10 KD + CK1ε OE epistasis, xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with phosphosite identification plus epistasis; single lab\",\n      \"pmids\": [\"40701249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRSF10 depletion in oligodendrocyte lineage cells (OLCs) causes hypomyelination and reduced OLC numbers during mouse CNS development by impairing early OLC differentiation (not proliferation or apoptosis). Among SRSF10-regulated AS targets, correcting the alternative splicing of Myo5a using antisense oligonucleotides reverses OLC differentiation inhibition caused by SRSF10 depletion.\",\n      \"method\": \"OLC-specific conditional KO mice, RNA-seq, RIP-seq (direct binding), antisense oligonucleotide rescue of Myo5a splicing\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO plus direct RIP-seq binding evidence plus ASO epistasis rescue; multiple orthogonal methods\",\n      \"pmids\": [\"40439883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SRSF10 promotes inclusion of exon 2 in BCAT2 mRNA, activating mTOR signaling. SRSF10 blockade (by inhibitor 1C8) reprograms tumor-associated macrophages via CCL2, enhancing CD8+ T-cell infiltration and potentiating anti-PD-1 efficacy in gastric cancer models.\",\n      \"method\": \"Multiple mouse GC models, RNA splicing analysis, SRSF10 knockout/inhibitor experiments, flow cytometry, mTOR pathway analysis, orthotopic model with PD-1 antibody combination\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AS target validated in multiple models, mTOR pathway epistasis shown; single lab\",\n      \"pmids\": [\"42020371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SRSF10 induces retention of BIN1 exon 12, producing a BIN1(12+) isoform that directly interacts with and activates ANXA1, contributing to cisplatin resistance in bladder cancer. This was shown by co-immunoprecipitation confirming BIN1(12+)-ANXA1 interaction and by functional rescue experiments.\",\n      \"method\": \"SRSF10 KD/OE, RNA sequencing, RIP-qPCR/CLIP, co-immunoprecipitation (BIN1(12+)-ANXA1), xenograft model, cisplatin IC50 assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and splicing validated, isoform-specific co-IP, in vivo xenograft; single lab\",\n      \"pmids\": [\"41942629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRSF10 preferentially binds and traffics mRNAs to the central axon of dorsal root ganglion neurons, establishing compartment-specific translational programs in sensory neurons.\",\n      \"method\": \"Translating Ribosome Affinity Purification (TRAP) with spatial compartment-specific sequencing, cross-dataset integration with scRNA-seq, RBP-mRNA binding analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, RBP-mRNA association inferred from TRAP-seq without direct binding validation\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TASR-1 (SRSF10), but not TASR-2, influences alternative splicing of type II and type XI collagen genes in mouse ATDC5 chondroprogenitor cells. TASR-1 can also down-regulate expression of type X collagen.\",\n      \"method\": \"Retroviral stable expression in ATDC5 cells, RT-PCR for collagen isoforms, microarray analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression system without direct binding or mechanistic follow-up; single lab\",\n      \"pmids\": [\"17367759\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF10 is an atypical SR protein whose activity is governed by phosphorylation state: dephosphorylated SRSF10 is a potent general splicing repressor that acts by interacting with U1 snRNP to block 5'-splice-site recognition, while phosphorylated SRSF10 is a sequence-specific splicing activator that stabilizes U1/U2 snRNP engagement with pre-mRNA. Dephosphorylation is mediated by PP1 (targeted to SRSF10's RS domain) and is triggered by heat shock or mitosis, with protection provided by 14-3-3 proteins (which dissociate under stress) and by Hsp27 (which promotes rephosphorylation during recovery). CK1ε phosphorylates SRSF10 at S23 and S133, enabling its binding to specific splice-site-containing mRNAs. Through position-dependent binding to pre-mRNA, SRSF10 controls a broad alternative splicing network critical for cardiac Ca2+ handling (triadin), adipogenesis (lipin1α), myogenesis (Lrrfip1), hepatic glucose production (PGC1α), spermatogenesis, oligodendrocyte differentiation (Myo5a), and neurogenesis; upon DNA damage or chemotherapy, SRSF10 dephosphorylation rewires its interactions with hnRNP K, hnRNP F/H, Sam68, and 14-3-3 to shift Bcl-x and other apoptosis-related transcripts toward pro-apoptotic isoforms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF10 is an atypical SR-family splicing regulator whose function is switched by phosphorylation state, allowing it to act either as a general splicing repressor or as a sequence-specific splicing activator that shapes broad alternative-splicing networks across development and stress [#0, #5]. In its dephosphorylated form it is a potent general repressor that blocks splicing at an early step, acting through its RNA-binding domain and an interaction with U1 snRNP that interferes with 5'-splice-site recognition [#0, #2]; this dephosphorylated, repressive state is induced specifically in mitosis and upon heat shock [#0, #1]. The conversion is executed by PP1, which is recruited to the SRSF10 RS domain and activated by NIPP1 dissociation, while 14-3-3 binding protects SRSF10 from dephosphorylation under non-stress conditions and Hsp27 drives rephosphorylation during recovery [#3, #7]. When phosphorylated, SRSF10 instead stabilizes U1/U2 snRNP engagement with pre-mRNA and functions as a sequence-specific activator, with CK1\\u03b5 phosphorylating S23 and S133 to license target-mRNA binding [#5, #28]. Through position-dependent binding\\u2014promoting cassette-exon inclusion when bound to the exon and exclusion when bound downstream\\u2014SRSF10 controls defined splicing programs essential for cardiac Ca2+ handling via triadin, adipogenesis via lipin1\\u03b1, myogenesis via Lrrfip1, hepatic glucose output via PGC1\\u03b1, spermatogonial expansion, oligodendrocyte differentiation via Myo5a, and cortical neurogenesis [#9, #6, #10, #11, #22, #29, #25]. Upon DNA damage, SRSF10 dephosphorylation rewires its assembly with hnRNP K, hnRNP F/H, Sam68 and 14-3-3\\u03b5 on the Bcl-x pre-mRNA to shift splicing toward the pro-apoptotic Bcl-xS isoform [#12, #14]. SRSF10 is co-opted in multiple cancers, where it controls oncogenic isoform choices such as BCLAF1 exon 5a, CDC25A and MDM4 exons, and modulates the tumor microenvironment [#8, #23, #26], and it restricts viral pathogens including HBV and HIV-1 in a phosphorylation-dependent manner [#17, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that SRSF10 is not a constitutive splicing factor but a phosphorylation-gated general repressor, defining the central regulatory logic of the protein.\",\n      \"evidence\": \"In vitro splicing assays with defined phosphorylation states, immunodepletion, and cell-cycle synchronization\",\n      \"pmids\": [\"12419250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the snRNP target or step of repression\", \"Phosphatase/kinase machinery unidentified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the mechanistic basis of repression and a physiological trigger, showing dephosphorylated SRSF10 binds U1 snRNP to block 5'-splice-site recognition during heat shock.\",\n      \"evidence\": \"In vitro splicing reconstitution, U1 snRNP co-IP, and SRSF10-knockout DT40 cells\",\n      \"pmids\": [\"14765198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise contact between SRSF10 and U1 components not structurally resolved\", \"Whether other snRNPs contribute left open\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Localized repressive activity to the RNA-binding domain and mapped RS subdomain functions, distinguishing SRSF10 from activating SR proteins like SC35.\",\n      \"evidence\": \"Immunofluorescence colocalization with snRNPs, deletion mutants, and SRSF10/SC35 chimeras in vitro\",\n      \"pmids\": [\"16135820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RBD-mediated repression not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the enzymatic switch controlling SRSF10, identifying PP1 as the phosphatase, NIPP1 as its regulator, and 14-3-3 as a protective binding partner.\",\n      \"evidence\": \"In vitro phosphatase assays, domain-mapped PP1 recruitment to the RS domain, and 14-3-3 co-IP\",\n      \"pmids\": [\"17936706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the relevant SR protein kinase(s) under basal conditions not fully resolved here\", \"How 14-3-3 dissociation is signaled unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed how cells reverse the repressive state, with Hsp27 promoting SRSF10 rephosphorylation to restore splicing after heat shock.\",\n      \"evidence\": \"Hsp27/alphaB-crystallin expression, phosphorylation immunoblotting, and pharmacological phosphatase inhibition\",\n      \"pmids\": [\"16339078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The kinase enabling rephosphorylation not identified\", \"Single-lab functional assay\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that Hsp27 acts via direct binding to SRSF10 and that thermotolerance protects SRSF10 from dephosphorylation, linking stress memory to splicing control.\",\n      \"evidence\": \"Hsp27-SRSF10 co-IP, overexpression, and in vitro splicing assays requiring de novo protein synthesis\",\n      \"pmids\": [\"21135127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Hsp27 binding favors rephosphorylation undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed the second functional state, showing phosphorylated SRSF10 is a sequence-specific activator that stabilizes U1/U2 snRNP recognition\\u2014uniquely bifunctional among SR proteins.\",\n      \"evidence\": \"In vitro splicing with defined phospho-states, spliceosome complex assembly analysis, and U1/U2 binding assays\",\n      \"pmids\": [\"18794844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor required for complex B/C progression not identified\", \"Sequence determinants of specific binding not yet mapped genome-wide\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided the first in vivo demonstration of a physiological splicing target, linking SRSF10 to triadin splicing and cardiac Ca2+ handling.\",\n      \"evidence\": \"SRSF10-null mice, direct binding to the regulated triadin exon, in vitro splicing, and cardiomyocyte Ca2+ imaging\",\n      \"pmids\": [\"19386262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation state of SRSF10 governing this target not specified\", \"Other cardiac targets not catalogued\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the position-dependent splicing code of SRSF10 transcriptome-wide and tied its activity to stress-induced apoptosis resistance.\",\n      \"evidence\": \"RNA-seq, minigene mutagenesis of binding motifs, and SRSF10 knockout/reconstitution viability assays\",\n      \"pmids\": [\"24442672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the same binding event yields opposite outcomes mechanistically\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the in vivo target network to metabolic and growth programs, establishing lipin1\\u03b1 (adipogenesis) and a pro-tumorigenic BCLAF1 isoform as SRSF10 outputs.\",\n      \"evidence\": \"SRSF10-null mice with rescue, minigene splicing, cis-element binding, and colorectal cancer knockdown/growth assays\",\n      \"pmids\": [\"24710272\", \"25091051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific determinants of target selection unclear\", \"BCLAF1 study is Medium confidence single-lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Broadened the physiological splicing program to muscle and liver, with Lrrfip1 driving myogenesis and PGC1\\u03b1 regulation controlling hepatic glucose output.\",\n      \"evidence\": \"Conditional KO mice, RNA-seq, minigene assays, and glucose production assays\",\n      \"pmids\": [\"26586428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals selecting these tissue-specific targets undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected the DNA-damage response to apoptotic splicing decisions, showing damage-induced SRSF10 dephosphorylation rewires hnRNP K and hnRNP F/H interactions on Bcl-x toward Bcl-xS.\",\n      \"evidence\": \"Reciprocal RIP/co-IP, ATM/CHK2 inhibition, minigene assays, and RNA-seq\",\n      \"pmids\": [\"27851963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphatase acting on SRSF10 after damage not identified here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the multi-protein assembly underlying damage-induced Bcl-x switching, adding 14-3-3\\u03b5, hnRNP A1/A2 and Sam68 to the regulatory complex.\",\n      \"evidence\": \"RNA affinity pulldown and co-IP with siRNA functional validation\",\n      \"pmids\": [\"29396485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of assembly and direct vs. bridged contacts not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established SRSF10 as a druggable host splicing factor for viral infection, with compound 1C8 promoting its dephosphorylation to reduce HIV-1 splicing.\",\n      \"evidence\": \"RNAi, phosphorylation immunoblotting, hTra2\\u03b2 co-IP, and RT-PCR of HIV-1 splice variants\",\n      \"pmids\": [\"27928057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRSF10 binding sites on HIV-1 RNA not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded SRSF10's antiviral and clinically relevant target repertoire, including HBV restriction, SMN2 exon 7 inclusion, and avian ANP32A isoform control of influenza polymerase.\",\n      \"evidence\": \"HBc interactome proteomics with KD, SPR/MS direct-binding to ISS-N1 with splice-switching oligos, and RNA affinity/RIP for ANP32A\",\n      \"pmids\": [\"33180834\", \"33300159\", \"32574681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HBV effect is on nascent RNA level rather than splicing and mechanism unresolved\", \"Isoform-length dependence of SMN regulation not fully explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified non-coding RNA control of SRSF10 activity and a kinase upstream of its activating phosphorylation, with circRNA cTTN1 binding SRSF10 and CLK1/4 inhibition impairing its splicing function.\",\n      \"evidence\": \"RIP in iPSC-cardiomyocytes, GPS167/192 CLK inhibition with co-IP, and minigene/apoptosis assays\",\n      \"pmids\": [\"33583186\", \"34316707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether circRNA acts by sequestration or presentation not definitively distinguished\", \"CLK phosphosite specificity not mapped in these studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated essential roles in spermatogonial expansion and consolidated SRSF10 as an oncogenic splicing driver acting through CDC25A and SREK1/B-T circuits.\",\n      \"evidence\": \"Germ-cell KO mice with iRIP-seq, plus RIP/CLIP and isoform mutagenesis in HCC models\",\n      \"pmids\": [\"36355419\", \"36539837\", \"35296659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-state dependence of germline targeting not addressed\", \"HCC mechanisms are Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined CK1\\u03b5 as a direct kinase phosphorylating SRSF10 at S23/S133 to enable target-mRNA binding, and extended developmental roles to oligodendrocyte differentiation via Myo5a splicing.\",\n      \"evidence\": \"In vitro kinase assay with phosphosite mapping and epistasis; OLC-specific conditional KO with RIP-seq and ASO rescue\",\n      \"pmids\": [\"40701249\", \"40439883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between CK1\\u03b5 and previously implicated SR kinases unclear\", \"Whether S23/S133 phosphorylation governs all activating functions not tested broadly\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single phosphorylation switch and position-dependent binding code are integrated to select among hundreds of tissue- and stress-specific targets remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the SRSF10\\u2013U1/U2 or SRSF10\\u2013pre-mRNA complexes\", \"Upstream signaling that directs target choice in each tissue not defined\", \"Kinase/phosphatase partners not unified into a single quantitative model\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 6, 9, 10, 22, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 17]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 5, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 10, 11, 22, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"U1 snRNP\", \"PP1\", \"14-3-3\", \"Hsp27\", \"hnRNP K\", \"hnRNP F/H\", \"Sam68\", \"CK1\\u03b5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}