{"gene":"SRSF11","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2006,"finding":"SRp54/SFRS11 (SRSF11) acts as a repressor of tau exon 10 inclusion: overexpression suppresses exon 10 inclusion, siRNA knockdown increases it. SRSF11 binds a purine-rich element in tau exon 10 and antagonizes Tra2beta, an SR-domain protein that promotes exon 10 inclusion. Deletion of the exonic purine-rich element abolishes SRSF11 repressor activity.","method":"GFP-based exon-skipping reporter assay, expression cloning, RNA interference knockdown, deletion mutagenesis of exonic element, functional antagonism assay with Tra2beta","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assay, RNAi, mutagenesis, binding element mapping) in a single focused study with clear gain- and loss-of-function results","pmids":["16943417"],"is_preprint":false},{"year":2015,"finding":"SRSF11 localizes to nuclear speckles and functions as a nuclear speckle-targeting factor for telomerase. It binds TERC (telomerase RNA component) directly and also binds TRF2 at telomeres. During S phase, SRSF11 directs active telomerase to nuclear speckles; a subset of telomeres resides constitutively at nuclear speckles. Depletion of SRSF11 prevents telomerase association with nuclear speckles, disrupts telomerase recruitment to telomeres, and abrogates telomere elongation.","method":"Co-immunoprecipitation (SRSF11 with TERC and TRF2), subcellular fractionation/immunofluorescence showing nuclear speckle localization, cell-cycle-specific analysis (S-phase), SRSF11 depletion with telomere elongation readout","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying two binding partners (TERC and TRF2), direct localization experiments, loss-of-function with functional telomere elongation readout, multiple orthogonal methods in one study","pmids":["26286192"],"is_preprint":false},{"year":2019,"finding":"SRSF11 directly binds the 3' UTR of LRP8 mRNA and the third exon of apoE mRNA, stabilizing both transcripts. Loss of SFRS11/SRSF11 reduces LRP8 and apoE levels, leading to activation of JNK signaling. Restoration of LRP8 and apoE reduces JNK signaling elevated in SFRS11-deficient cells and rescues aging-like cognitive phenotypes.","method":"RNA immunoprecipitation (RIP) to confirm direct mRNA binding, mRNA stability assays, genetic rescue experiments (LRP8/apoE restoration in SFRS11-deficient cells), JNK signaling readout, prefrontal cortex-specific knockdown in mice with cognitive behavioral tests","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct RIP binding evidence, genetic rescue with specific downstream signaling readout, in vivo behavioral phenotype, multiple orthogonal methods","pmids":["31269452"],"is_preprint":false},{"year":2022,"finding":"SRSF11 promotes colorectal cancer metastasis by directly binding a motif in exon 2 of HSPA12A pre-mRNA (identified by UV-CLIP and minigene reporter), causing exon 2 retention and increased HSPA12A transcript stability, which in turn elevates N-cadherin expression. The oncogenic kinase PAK5 phosphorylates SRSF11 at serine 287, protecting it from ubiquitin-mediated degradation.","method":"In vivo UV crosslinking and immunoprecipitation (CLIP), minigene reporter assay, Co-immunoprecipitation, Phospho-tag SDS-PAGE, in vitro kinase assay (PAK5 phosphorylating SRSF11 at S287), RNA-seq for AS events, in vitro and in vivo metastasis models","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1 for PTM), UV-CLIP for direct binding, minigene assay for splicing mechanism, Co-IP for interaction, multiple orthogonal methods in one study","pmids":["36394206"],"is_preprint":false},{"year":2025,"finding":"KAT2A directly interacts with SRSF11 and catalyzes succinylation of SRSF11 at lysine 419 (K419). K419 succinylation stabilizes SRSF11-spliceosome interactions and promotes inclusion of exon 10 of RAD52 pre-mRNA, preserving the RAD51-binding domain of RAD52. This facilitates RAD52-RAD51 dimer assembly and homologous recombination repair, leading to radioresistance in hepatocellular carcinoma.","method":"Co-immunoprecipitation (KAT2A-SRSF11 interaction), structural and functional analyses of K419 succinylation, pre-mRNA binding assays, exon inclusion assays (RAD52 exon 10), in vitro and in vivo HCC models, genetic disruption of KAT2A-SRSF11 axis with radiation sensitivity readout","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single study, Co-IP for interaction, succinylation site mapping, functional splicing and HR readouts, but no independent replication yet","pmids":["41198615"],"is_preprint":false},{"year":2025,"finding":"miR-126-5p delivered by M1 macrophage exosomes targets and inhibits SRSF11 expression. SRSF11 binds Sirt1 and P21 precursor mRNAs (confirmed by RIP), and its inhibition leads to dysregulation of alternative splicing of these genes with an increase in pro-senescence isoforms, driving endothelial cell senescence.","method":"RIP experiments confirming SRSF11 binding to Sirt1/P21 pre-mRNA, exosome isolation and characterization, luciferase/miRNA target validation, SA-β-gal staining and flow cytometry for senescence, in vivo DVT mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — RIP confirms mRNA binding but single study, downstream splicing mechanism partially characterized, single lab","pmids":["41343940"],"is_preprint":false},{"year":2025,"finding":"SRSF11 and SRRM1 share common protein interactors and RNA targets and together promote oncogenic NUMB exon 9 (E9) splicing in colorectal, lung, and breast cancer cell lines, identified in a genome-wide CRISPR screen using a NUMB E9 splicing reporter.","method":"Genome-wide CRISPR screen with NUMB exon 9 splicing reporter, protein interaction studies, RNA target analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, CRISPR screen identifies SRSF11 as a hit but mechanistic follow-up on SRSF11 specifically is limited; SRRM1 is the primary focus","pmids":["bio_10.1101_2025.08.20.671097"],"is_preprint":true}],"current_model":"SRSF11 is a nuclear speckle-localized SR-protein splicing factor that regulates alternative splicing of multiple pre-mRNA targets (tau exon 10, HSPA12A, RAD52 exon 10, NUMB exon 9, Sirt1/P21) by directly binding exonic elements, and also stabilizes mRNAs (LRP8, apoE) via 3' UTR/exon binding; its activity is post-translationally regulated by PAK5-mediated phosphorylation at S287 (protecting it from degradation) and KAT2A-mediated succinylation at K419 (enhancing spliceosome interactions), while its nuclear speckle localization enables cell-cycle-specific (S-phase) recruitment of telomerase to telomeres through direct interactions with TERC and TRF2."},"narrative":{"mechanistic_narrative":"SRSF11 is a nuclear speckle-localized SR-family splicing factor that regulates alternative pre-mRNA splicing and transcript stability across multiple cellular programs by directly binding exonic and 3' UTR RNA elements [PMID:16943417, PMID:26286192, PMID:36394206]. As a splicing regulator it binds a purine-rich element in tau exon 10 to repress its inclusion, antagonizing the activating SR protein Tra2beta [PMID:16943417], and it directs additional exon-inclusion/retention decisions including HSPA12A exon 2 retention and RAD52 exon 10 inclusion [PMID:36394206, PMID:41198615]. Beyond splicing, SRSF11 binds the LRP8 3' UTR and the third exon of apoE mRNA to stabilize these transcripts, restraining JNK signaling and supporting cognitive function in vivo [PMID:31269452]. Its localization to nuclear speckles underlies an S-phase function in which SRSF11 binds the telomerase RNA TERC and the telomeric protein TRF2 to recruit active telomerase to telomeres and enable telomere elongation [PMID:26286192]. SRSF11 activity is set by post-translational modification: PAK5 phosphorylates it at Ser287 to protect it from ubiquitin-mediated degradation [PMID:36394206], and KAT2A succinylates it at Lys419 to strengthen its spliceosome interactions [PMID:41198615]. Through these activities SRSF11 has been linked to colorectal cancer metastasis and hepatocellular carcinoma radioresistance [PMID:36394206, PMID:41198615].","teleology":[{"year":2006,"claim":"Established SRSF11 as a sequence-specific alternative splicing regulator by showing it represses tau exon 10 inclusion through a defined exonic element, defining its core molecular activity.","evidence":"GFP exon-skipping reporter, expression cloning, RNAi knockdown, deletion mutagenesis of the exonic purine-rich element, and antagonism assay with Tra2beta","pmids":["16943417"],"confidence":"High","gaps":["Direct RNA binding shown functionally but not by biochemical footprinting","No structural basis for SRSF11–Tra2beta antagonism","Generality to other targets not addressed in this study"]},{"year":2015,"claim":"Revealed a splicing-independent role: SRSF11 uses its nuclear speckle localization to recruit telomerase to telomeres, answering how telomerase reaches its substrate during S phase.","evidence":"Reciprocal Co-IP of SRSF11 with TERC and TRF2, immunofluorescence localization, S-phase cell-cycle analysis, and SRSF11 depletion with telomere elongation readout","pmids":["26286192"],"confidence":"High","gaps":["Whether TERC/TRF2 binding is direct RNA/protein contact or speckle-mediated not fully resolved","Domain of SRSF11 mediating recruitment unmapped","Link between its splicing activity and telomerase function unclear"]},{"year":2019,"claim":"Extended SRSF11 function to mRNA stabilization, showing it stabilizes LRP8 and apoE transcripts to restrain JNK signaling and preserve cognition, separating its stabilizer role from splicing.","evidence":"RIP for direct mRNA binding, mRNA stability assays, genetic rescue with LRP8/apoE restoration, JNK readout, and prefrontal cortex knockdown in mice with behavioral tests","pmids":["31269452"],"confidence":"High","gaps":["Mechanism by which binding stabilizes transcripts unknown","RNA element required for binding not mapped","Relationship to its splicing activity not addressed"]},{"year":2022,"claim":"Connected SRSF11 to cancer and to upstream regulation, showing direct HSPA12A binding drives exon retention promoting metastasis and that PAK5 phosphorylation at S287 controls SRSF11 protein stability.","evidence":"In vivo UV-CLIP, minigene reporter, Co-IP, phospho-tag SDS-PAGE, in vitro PAK5 kinase assay, RNA-seq, and in vitro/in vivo metastasis models","pmids":["36394206"],"confidence":"High","gaps":["E3 ligase mediating SRSF11 degradation not identified","Whether S287 phosphorylation alters RNA binding not tested","Breadth of PAK5-dependent splicing changes unquantified"]},{"year":2025,"claim":"Identified a second PTM controlling SRSF11, showing KAT2A-mediated K419 succinylation stabilizes spliceosome interactions and promotes RAD52 exon 10 inclusion to drive HR repair and radioresistance.","evidence":"Co-IP for KAT2A–SRSF11 interaction, succinylation site mapping, pre-mRNA binding and exon inclusion assays, and KAT2A–SRSF11 disruption with radiation sensitivity readout in HCC models","pmids":["41198615"],"confidence":"Medium","gaps":["Single study without independent replication","Structural effect of K419 succinylation on spliceosome contacts not resolved","Interplay between succinylation and S287 phosphorylation unexplored"]},{"year":2025,"claim":"Placed SRSF11 downstream of exosomal miRNA control, showing miR-126-5p inhibits SRSF11 and that SRSF11 binds Sirt1 and P21 pre-mRNAs to regulate senescence-associated isoforms.","evidence":"RIP confirming SRSF11–Sirt1/P21 pre-mRNA binding, exosome isolation, miRNA target validation, senescence assays, and an in vivo DVT mouse model","pmids":["41343940"],"confidence":"Medium","gaps":["Single-lab study","Splicing outcomes on Sirt1/P21 only partially characterized","Direct vs indirect regulation of isoform choice not fully defined"]},{"year":null,"claim":"How SRSF11's distinct activities — splicing repression/activation, mRNA stabilization, and telomerase recruitment — are coordinated within one protein and selectively deployed across contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking RNA-binding to its multiple functions","Determinants of target selectivity unknown","Integration of competing PTMs (S287 phosphorylation, K419 succinylation) not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,4,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":["spliceosome"],"partners":["TERC","TRF2","PAK5","KAT2A","SRRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q05519","full_name":"Serine/arginine-rich splicing factor 11","aliases":["Arginine-rich 54 kDa nuclear protein","p54","Splicing factor, arginine/serine-rich 11"],"length_aa":484,"mass_kda":53.5,"function":"May function in pre-mRNA splicing","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q05519/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF11","classification":"Common Essential","n_dependent_lines":1175,"n_total_lines":1208,"dependency_fraction":0.972682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRSF11","total_profiled":1310},"omim":[{"mim_id":"602010","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 11; SRSF11","url":"https://www.omim.org/entry/602010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF11"},"hgnc":{"alias_symbol":["p54","NET2"],"prev_symbol":["SFRS11"]},"alphafold":{"accession":"Q05519","domains":[{"cath_id":"3.30.70.330","chopping":"33-127","consensus_level":"high","plddt":86.0433,"start":33,"end":127}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05519","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q05519-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q05519-F1-predicted_aligned_error_v6.png","plddt_mean":55.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF11","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF11"},"sequence":{"accession":"Q05519","fasta_url":"https://rest.uniprot.org/uniprotkb/Q05519.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q05519/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q05519"}},"corpus_meta":[{"pmid":"16943417","id":"PMC_16943417","title":"SRp54 (SFRS11), a regulator for tau exon 10 alternative splicing identified by an expression cloning strategy.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16943417","citation_count":50,"is_preprint":false},{"pmid":"15958536","id":"PMC_15958536","title":"[99mTcOAADT]-(CH2)2-NEt2: a potential small-molecule single-photon emission computed tomography probe for imaging metastatic melanoma.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15958536","citation_count":29,"is_preprint":false},{"pmid":"31269452","id":"PMC_31269452","title":"SFRS11 Loss Leads to Aging-Associated Cognitive Decline by Modulating LRP8 and ApoE.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31269452","citation_count":27,"is_preprint":false},{"pmid":"26286192","id":"PMC_26286192","title":"Involvement of SRSF11 in cell cycle-specific recruitment of telomerase to telomeres at nuclear speckles.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26286192","citation_count":21,"is_preprint":false},{"pmid":"36394206","id":"PMC_36394206","title":"Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis potential of colorectal cancer.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36394206","citation_count":19,"is_preprint":false},{"pmid":"22820387","id":"PMC_22820387","title":"Application of real-time PCR-based SNP detection for mapping of Net2, a causal D-genome gene for hybrid necrosis in interspecific crosses between tetraploid wheat and Aegilops tauschii.","date":"2012","source":"Genes & genetic systems","url":"https://pubmed.ncbi.nlm.nih.gov/22820387","citation_count":12,"is_preprint":false},{"pmid":"27502693","id":"PMC_27502693","title":"Fine mapping and genetic association analysis of Net2, the causative D-genome locus of low temperature-induced hybrid necrosis in interspecific crosses between tetraploid wheat and Aegilops tauschii.","date":"2016","source":"Genetica","url":"https://pubmed.ncbi.nlm.nih.gov/27502693","citation_count":10,"is_preprint":false},{"pmid":"41198615","id":"PMC_41198615","title":"KAT2A-driven succinylation of SRSF11 enforces spliceosome-mediated RAD52 splicing to promote homologous recombination and radioresistance in hepatocellular carcinoma.","date":"2025","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41198615","citation_count":2,"is_preprint":false},{"pmid":"41343940","id":"PMC_41343940","title":"M1 macrophage-derived exosomal miR-126-5p promotes endothelial cell senescence and deep vein thrombosis by targeting splicing factor SRSF11.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41343940","citation_count":1,"is_preprint":false},{"pmid":"41584036","id":"PMC_41584036","title":"Dysregulation of SRSF11 in Cancer: Mechanistic Insights and Biomarker Potential for Diagnosis and Therapy.","date":"2026","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41584036","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.20.671097","title":"SRRM1 coordinates an alternative splicing program that promotes expression of oncogenic protein isoforms","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.20.671097","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.18.675797","title":"Exploring Resistance to ETS Targeting Agents in Diffuse Large B-Cell Lymphoma","date":"2025-09-20","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.675797","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8307,"output_tokens":2350,"usd":0.030086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9351,"output_tokens":2749,"usd":0.05774,"stage2_stop_reason":"end_turn"},"total_usd":0.087826,"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\": 2006,\n      \"finding\": \"SRp54/SFRS11 (SRSF11) acts as a repressor of tau exon 10 inclusion: overexpression suppresses exon 10 inclusion, siRNA knockdown increases it. SRSF11 binds a purine-rich element in tau exon 10 and antagonizes Tra2beta, an SR-domain protein that promotes exon 10 inclusion. Deletion of the exonic purine-rich element abolishes SRSF11 repressor activity.\",\n      \"method\": \"GFP-based exon-skipping reporter assay, expression cloning, RNA interference knockdown, deletion mutagenesis of exonic element, functional antagonism assay with Tra2beta\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assay, RNAi, mutagenesis, binding element mapping) in a single focused study with clear gain- and loss-of-function results\",\n      \"pmids\": [\"16943417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRSF11 localizes to nuclear speckles and functions as a nuclear speckle-targeting factor for telomerase. It binds TERC (telomerase RNA component) directly and also binds TRF2 at telomeres. During S phase, SRSF11 directs active telomerase to nuclear speckles; a subset of telomeres resides constitutively at nuclear speckles. Depletion of SRSF11 prevents telomerase association with nuclear speckles, disrupts telomerase recruitment to telomeres, and abrogates telomere elongation.\",\n      \"method\": \"Co-immunoprecipitation (SRSF11 with TERC and TRF2), subcellular fractionation/immunofluorescence showing nuclear speckle localization, cell-cycle-specific analysis (S-phase), SRSF11 depletion with telomere elongation readout\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying two binding partners (TERC and TRF2), direct localization experiments, loss-of-function with functional telomere elongation readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26286192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF11 directly binds the 3' UTR of LRP8 mRNA and the third exon of apoE mRNA, stabilizing both transcripts. Loss of SFRS11/SRSF11 reduces LRP8 and apoE levels, leading to activation of JNK signaling. Restoration of LRP8 and apoE reduces JNK signaling elevated in SFRS11-deficient cells and rescues aging-like cognitive phenotypes.\",\n      \"method\": \"RNA immunoprecipitation (RIP) to confirm direct mRNA binding, mRNA stability assays, genetic rescue experiments (LRP8/apoE restoration in SFRS11-deficient cells), JNK signaling readout, prefrontal cortex-specific knockdown in mice with cognitive behavioral tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RIP binding evidence, genetic rescue with specific downstream signaling readout, in vivo behavioral phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"31269452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SRSF11 promotes colorectal cancer metastasis by directly binding a motif in exon 2 of HSPA12A pre-mRNA (identified by UV-CLIP and minigene reporter), causing exon 2 retention and increased HSPA12A transcript stability, which in turn elevates N-cadherin expression. The oncogenic kinase PAK5 phosphorylates SRSF11 at serine 287, protecting it from ubiquitin-mediated degradation.\",\n      \"method\": \"In vivo UV crosslinking and immunoprecipitation (CLIP), minigene reporter assay, Co-immunoprecipitation, Phospho-tag SDS-PAGE, in vitro kinase assay (PAK5 phosphorylating SRSF11 at S287), RNA-seq for AS events, in vitro and in vivo metastasis models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1 for PTM), UV-CLIP for direct binding, minigene assay for splicing mechanism, Co-IP for interaction, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36394206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT2A directly interacts with SRSF11 and catalyzes succinylation of SRSF11 at lysine 419 (K419). K419 succinylation stabilizes SRSF11-spliceosome interactions and promotes inclusion of exon 10 of RAD52 pre-mRNA, preserving the RAD51-binding domain of RAD52. This facilitates RAD52-RAD51 dimer assembly and homologous recombination repair, leading to radioresistance in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (KAT2A-SRSF11 interaction), structural and functional analyses of K419 succinylation, pre-mRNA binding assays, exon inclusion assays (RAD52 exon 10), in vitro and in vivo HCC models, genetic disruption of KAT2A-SRSF11 axis with radiation sensitivity readout\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single study, Co-IP for interaction, succinylation site mapping, functional splicing and HR readouts, but no independent replication yet\",\n      \"pmids\": [\"41198615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-126-5p delivered by M1 macrophage exosomes targets and inhibits SRSF11 expression. SRSF11 binds Sirt1 and P21 precursor mRNAs (confirmed by RIP), and its inhibition leads to dysregulation of alternative splicing of these genes with an increase in pro-senescence isoforms, driving endothelial cell senescence.\",\n      \"method\": \"RIP experiments confirming SRSF11 binding to Sirt1/P21 pre-mRNA, exosome isolation and characterization, luciferase/miRNA target validation, SA-β-gal staining and flow cytometry for senescence, in vivo DVT mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP confirms mRNA binding but single study, downstream splicing mechanism partially characterized, single lab\",\n      \"pmids\": [\"41343940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRSF11 and SRRM1 share common protein interactors and RNA targets and together promote oncogenic NUMB exon 9 (E9) splicing in colorectal, lung, and breast cancer cell lines, identified in a genome-wide CRISPR screen using a NUMB E9 splicing reporter.\",\n      \"method\": \"Genome-wide CRISPR screen with NUMB exon 9 splicing reporter, protein interaction studies, RNA target analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, CRISPR screen identifies SRSF11 as a hit but mechanistic follow-up on SRSF11 specifically is limited; SRRM1 is the primary focus\",\n      \"pmids\": [\"bio_10.1101_2025.08.20.671097\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SRSF11 is a nuclear speckle-localized SR-protein splicing factor that regulates alternative splicing of multiple pre-mRNA targets (tau exon 10, HSPA12A, RAD52 exon 10, NUMB exon 9, Sirt1/P21) by directly binding exonic elements, and also stabilizes mRNAs (LRP8, apoE) via 3' UTR/exon binding; its activity is post-translationally regulated by PAK5-mediated phosphorylation at S287 (protecting it from degradation) and KAT2A-mediated succinylation at K419 (enhancing spliceosome interactions), while its nuclear speckle localization enables cell-cycle-specific (S-phase) recruitment of telomerase to telomeres through direct interactions with TERC and TRF2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRSF11 is a nuclear speckle-localized SR-family splicing factor that regulates alternative pre-mRNA splicing and transcript stability across multiple cellular programs by directly binding exonic and 3' UTR RNA elements [#0, #1, #3]. As a splicing regulator it binds a purine-rich element in tau exon 10 to repress its inclusion, antagonizing the activating SR protein Tra2beta [#0], and it directs additional exon-inclusion/retention decisions including HSPA12A exon 2 retention and RAD52 exon 10 inclusion [#3, #4]. Beyond splicing, SRSF11 binds the LRP8 3' UTR and the third exon of apoE mRNA to stabilize these transcripts, restraining JNK signaling and supporting cognitive function in vivo [#2]. Its localization to nuclear speckles underlies an S-phase function in which SRSF11 binds the telomerase RNA TERC and the telomeric protein TRF2 to recruit active telomerase to telomeres and enable telomere elongation [#1]. SRSF11 activity is set by post-translational modification: PAK5 phosphorylates it at Ser287 to protect it from ubiquitin-mediated degradation [#3], and KAT2A succinylates it at Lys419 to strengthen its spliceosome interactions [#4]. Through these activities SRSF11 has been linked to colorectal cancer metastasis and hepatocellular carcinoma radioresistance [#3, #4].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SRSF11 as a sequence-specific alternative splicing regulator by showing it represses tau exon 10 inclusion through a defined exonic element, defining its core molecular activity.\",\n      \"evidence\": \"GFP exon-skipping reporter, expression cloning, RNAi knockdown, deletion mutagenesis of the exonic purine-rich element, and antagonism assay with Tra2beta\",\n      \"pmids\": [\"16943417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA binding shown functionally but not by biochemical footprinting\", \"No structural basis for SRSF11–Tra2beta antagonism\", \"Generality to other targets not addressed in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a splicing-independent role: SRSF11 uses its nuclear speckle localization to recruit telomerase to telomeres, answering how telomerase reaches its substrate during S phase.\",\n      \"evidence\": \"Reciprocal Co-IP of SRSF11 with TERC and TRF2, immunofluorescence localization, S-phase cell-cycle analysis, and SRSF11 depletion with telomere elongation readout\",\n      \"pmids\": [\"26286192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TERC/TRF2 binding is direct RNA/protein contact or speckle-mediated not fully resolved\", \"Domain of SRSF11 mediating recruitment unmapped\", \"Link between its splicing activity and telomerase function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SRSF11 function to mRNA stabilization, showing it stabilizes LRP8 and apoE transcripts to restrain JNK signaling and preserve cognition, separating its stabilizer role from splicing.\",\n      \"evidence\": \"RIP for direct mRNA binding, mRNA stability assays, genetic rescue with LRP8/apoE restoration, JNK readout, and prefrontal cortex knockdown in mice with behavioral tests\",\n      \"pmids\": [\"31269452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which binding stabilizes transcripts unknown\", \"RNA element required for binding not mapped\", \"Relationship to its splicing activity not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SRSF11 to cancer and to upstream regulation, showing direct HSPA12A binding drives exon retention promoting metastasis and that PAK5 phosphorylation at S287 controls SRSF11 protein stability.\",\n      \"evidence\": \"In vivo UV-CLIP, minigene reporter, Co-IP, phospho-tag SDS-PAGE, in vitro PAK5 kinase assay, RNA-seq, and in vitro/in vivo metastasis models\",\n      \"pmids\": [\"36394206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating SRSF11 degradation not identified\", \"Whether S287 phosphorylation alters RNA binding not tested\", \"Breadth of PAK5-dependent splicing changes unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a second PTM controlling SRSF11, showing KAT2A-mediated K419 succinylation stabilizes spliceosome interactions and promotes RAD52 exon 10 inclusion to drive HR repair and radioresistance.\",\n      \"evidence\": \"Co-IP for KAT2A–SRSF11 interaction, succinylation site mapping, pre-mRNA binding and exon inclusion assays, and KAT2A–SRSF11 disruption with radiation sensitivity readout in HCC models\",\n      \"pmids\": [\"41198615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without independent replication\", \"Structural effect of K419 succinylation on spliceosome contacts not resolved\", \"Interplay between succinylation and S287 phosphorylation unexplored\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SRSF11 downstream of exosomal miRNA control, showing miR-126-5p inhibits SRSF11 and that SRSF11 binds Sirt1 and P21 pre-mRNAs to regulate senescence-associated isoforms.\",\n      \"evidence\": \"RIP confirming SRSF11–Sirt1/P21 pre-mRNA binding, exosome isolation, miRNA target validation, senescence assays, and an in vivo DVT mouse model\",\n      \"pmids\": [\"41343940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Splicing outcomes on Sirt1/P21 only partially characterized\", \"Direct vs indirect regulation of isoform choice not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRSF11's distinct activities — splicing repression/activation, mRNA stabilization, and telomerase recruitment — are coordinated within one protein and selectively deployed across contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking RNA-binding to its multiple functions\", \"Determinants of target selectivity unknown\", \"Integration of competing PTMs (S287 phosphorylation, K419 succinylation) not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"spliceosome\"],\n    \"partners\": [\"TERC\", \"TRF2\", \"PAK5\", \"KAT2A\", \"SRRM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}