{"gene":"SRSF5","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1997,"finding":"Phosphorylation of the RS domain of SRp40 (SRSF5) is required for sequence-specific RNA binding; unphosphorylated SRp40 fails to select specific RNA sequences, and three copies of the selected high-affinity site (B1) function as a strong splicing enhancer activated specifically by SRp40 but not by ASF/SF2 or SC35.","method":"SELEX RNA binding selection, in vitro splicing assay in nuclear extracts and S100 extracts, SR protein-specific complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with mutagenesis (unphosphorylated vs phosphorylated protein) plus functional splicing assay demonstrating enhancer specificity","pmids":["9037021"],"is_preprint":false},{"year":1993,"finding":"HRS (SRSF5) was identified as a member of the family of regulators of alternative pre-mRNA splicing; different forms of HRS mRNA are temporally regulated during the growth response, suggesting autoregulation of its own pre-mRNA processing.","method":"cDNA cloning, sequence analysis, RT-PCR temporal expression profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — sequence-based identification with temporal mRNA analysis; mechanistic claim of autoregulation is indirect","pmids":["7686911"],"is_preprint":false},{"year":1997,"finding":"HRS/SRp40 (SRSF5) directly mediates inclusion of the fibronectin EIIIB alternative exon in vivo; this activity depends on a purine-rich splicing enhancer sequence within the EIIIB exon to which HRS specifically binds, and no other SR protein tested could substitute.","method":"In vivo splicing minigene assay, RNA binding specificity assay, comparison across SR protein family members","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vivo splicing assay with specific RNA binding demonstrated, replicated across multiple SR proteins showing unique activity of SRSF5","pmids":["9199345"],"is_preprint":false},{"year":2001,"finding":"Insulin regulates PKCbetaII exon inclusion via PI 3-kinase-dependent phosphorylation of SRp40 (SRSF5); antisense oligonucleotides targeting a putative SRp40-binding sequence in the betaII-betaI intron blocked both insulin-induced splicing and glucose uptake; overexpression of SRp40 mimicked insulin-induced exon inclusion.","method":"Antisense oligonucleotide knockdown, overexpression, PI 3-kinase inhibitor (LY294002), phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (inhibitor, antisense, overexpression) in the same study establishing PI3K pathway → SRp40 phosphorylation → PKCbetaII splicing","pmids":["11283022"],"is_preprint":false},{"year":2005,"finding":"Akt2 kinase directly phosphorylates SRp40 (SRSF5) on Ser86 in vitro and in vivo; this phosphorylation event promotes PKCbetaII exon inclusion; mutation of Ser86 blocks in vitro phosphorylation and Akt2-deficient mice show defective PKCbetaII splicing.","method":"In vitro kinase assay, site-directed mutagenesis (Ser86Ala), Akt2 knockout mouse, quantitative RT-PCR, transfection of splicing minigene","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis plus genetic validation in knockout mouse","pmids":["15684423"],"is_preprint":false},{"year":2010,"finding":"SRp40 (SRSF5), specifically through its second RNA recognition motif and RS domain, promotes translation of unspliced HIV-1 gRNA (Gag expression) from intron-containing viral RNA; this activity does not correlate with nucleocytoplasmic shuttling capacity and is abolished by codon optimization of the gag-pol region.","method":"Overexpression/knockdown in HeLa cells, domain deletion/mutation analysis, Gag protein quantification by Western blot, codon-optimized reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with functional readout; single lab but multiple mutants tested","pmids":["20427542"],"is_preprint":false},{"year":2004,"finding":"SRp40 (SRSF5) strongly activates HIV-1 splice acceptor site A3 both in vivo and in vitro, leading to dramatic accumulation of tat mRNA; its binding site on HIV-1 RNA was delineated by footprinting and shown to overlap with hnRNP A1 sites, indicating SR protein-mediated antagonism of silencer binding.","method":"Overexpression in HeLa cells, in vitro splicing, enzymatic footprinting, quantitative RT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro splicing with footprinting; single lab","pmids":["15123677"],"is_preprint":false},{"year":2006,"finding":"SC35 and SRp40 (SRSF5) bind to overlapping sites on HIV-1 SLS2/SLS3 RNA structures near splice acceptor A3 and counteract hnRNP A1 binding on ESS2 to activate site A3; NMR demonstrates direct interaction of ESS2 with hnRNP A1 RRM domains, and enzymatic/chemical footprints delineate SR protein binding sites.","method":"Enzymatic and chemical footprinting, NMR spectroscopy, in vitro splicing, competition binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — NMR structural data combined with footprinting; defines binding sites but SRSF5-specific mechanistic detail is secondary to hnRNP A1 focus","pmids":["16990281"],"is_preprint":false},{"year":2012,"finding":"SRSF5 affects alternative splicing of Mcl-1 pre-mRNA in MCF-7 breast cancer cells, shifting the ratio of Mcl-1(L) to Mcl-1(S) isoforms; siRNA-mediated knockdown of SRSF5 alters this splicing pattern.","method":"siRNA knockdown, RT-PCR splicing assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, siRNA knockdown with splicing readout; no in vitro binding or mechanistic detail beyond splicing outcome","pmids":["23284704"],"is_preprint":false},{"year":2018,"finding":"Upon glucose intake, SRSF5 is acetylated on K125 by the acetyltransferase Tip60, which antagonizes Smurf1-mediated ubiquitylation of the same lysine and prevents proteasomal degradation; upon glucose starvation, HDAC1 deacetylates SRSF5, allowing Smurf1 to ubiquitylate K125 and target SRSF5 for proteasomal degradation. Stabilized SRSF5 promotes alternative splicing of CCAR1 to produce the short CCAR1S isoform, enhancing glucose consumption and tumor growth.","method":"Co-IP, in vitro ubiquitylation/acetylation assays, mutagenesis (K125R/K125Q), HDAC1/Tip60/Smurf1 knockdown and overexpression, splicing minigene assay, xenograft tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assays with mutagenesis, multiple writer/eraser identified, functional splicing outcome and in vivo tumor validation","pmids":["29942010"],"is_preprint":false},{"year":2018,"finding":"SRSF5 is upregulated by SRSF3 in oral squamous cell carcinoma; SRSF3 impairs the autoregulation of SRSF5 (a mechanism that normally controls SRSF5 levels) and promotes SRSF5 overexpression, which drives cell proliferation and tumor formation.","method":"siRNA knockdown, overexpression, RT-PCR (autoregulation assay), soft-agar transformation assay, xenograft tumor model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional knockdown/overexpression with defined phenotypic readout; autoregulation mechanism supported by RT-PCR but not biochemically reconstituted","pmids":["29857020"],"is_preprint":false},{"year":2021,"finding":"CLK1 phosphorylates SRSF5 on Ser250, which inhibits METTL14 exon10 skipping while promoting Cyclin L2 exon6.3 skipping; SRSF5 directly binds METTL14 and Cyclin L2 pre-mRNA (confirmed by RIP, RNA pull-down, and CLIP-qPCR), and these splicing events promote growth and metastasis of pancreatic cancer cells in vitro and in vivo.","method":"Phosphorylation mass spectrometry, RNA-seq, RIP assay, RNA pull-down, CLIP-qPCR, site-directed mutagenesis, xenograft mouse model","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 1-2 — phosphorylation site identified by mass spectrometry and validated by mutagenesis; direct RNA binding confirmed by CLIP; in vivo functional validation","pmids":["33849617"],"is_preprint":false},{"year":2009,"finding":"SRp40 (SRSF5) induces a GRα-to-GRβ alternative splicing shift of glucocorticoid receptor pre-mRNA in exon 9 in HeLa cells (but not 293T cells), as confirmed by minigene transfection and siRNA knockdown; other SR proteins tested did not produce this shift.","method":"Minigene transfection assay, siRNA knockdown, RT-PCR","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — minigene and siRNA validation in two cell lines; single lab; cell-type specificity noted but not mechanistically explained","pmids":["19343537"],"is_preprint":false},{"year":2014,"finding":"SRSF5 (SRp40) associates with the lncRNA NEAT1 in 3T3-L1 cells (shown by RNA-IP); depletion of NEAT1 results in failure to phosphorylate SRp40, and siRNA knockdown of SRp40 dysregulates PPARγ2 mRNA levels; overexpression of SRp40 increases PPARγ2 but not PPARγ1, indicating SRp40 selectively promotes PPARγ2 splicing during adipogenesis.","method":"RNA immunoprecipitation (RNA-IP), siRNA knockdown, overexpression, RT-PCR","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 3 — RNA-IP and functional knockdown/overexpression; single lab; phosphorylation mechanism is indirect","pmids":["25437750"],"is_preprint":false},{"year":2022,"finding":"CPEB2 binds SRSF5 mRNA and increases its stability; in glioblastoma endothelial cells, elevated CPEB2 (through METTL3/IGF2BP3-mediated m6A methylation) stabilizes SRSF5 protein, which promotes ETS1 exon inclusion, leading to upregulation of tight junction proteins ZO-1, occludin, and claudin-5 and reduced blood-tumor barrier permeability.","method":"RNA immunoprecipitation, co-immunoprecipitation, shRNA knockdown, splicing minigene assay, in vivo glioblastoma xenograft","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding confirmed by RIP and co-IP; functional in vivo validation; splicing outcome demonstrated; single lab","pmids":["36064747"],"is_preprint":false},{"year":2024,"finding":"LINC01852 promotes TRIM72-mediated ubiquitination and proteasomal degradation of SRSF5, thereby inhibiting SRSF5-mediated alternative splicing of PKM pre-mRNA; loss of SRSF5 shifts PKM splicing from PKM2 to PKM1, inducing a metabolic switch from aerobic glycolysis to oxidative phosphorylation and attenuating chemoresistance in colorectal cancer.","method":"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation, dual-luciferase assay, siRNA/shRNA knockdown, in vivo mouse model","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1-2 — E3 ligase (TRIM72) identified with ubiquitination assay; direct RNA binding confirmed by pull-down and RIP; splicing outcome and metabolic consequence validated in vivo","pmids":["38263157"],"is_preprint":false}],"current_model":"SRSF5 (SRp40) is a phosphorylation-regulated SR splicing factor whose RS domain phosphorylation (by Akt2 via the PI3K pathway, or by CLK1) is required for sequence-specific RNA binding and splicing enhancer activity; it controls alternative splicing of multiple targets including PKCbetaII, fibronectin EIIIB, CCAR1, PKM, METTL14, Cyclin L2, GR, and Mcl-1, and its protein stability is regulated by mutually exclusive acetylation (Tip60 on K125, stabilizing) and ubiquitylation (Smurf1/TRIM72 on K125 or TRIM72, leading to proteasomal degradation) in response to glucose availability or lncRNA LINC01852."},"narrative":{"teleology":[{"year":1993,"claim":"Identifying SRSF5 as a growth-regulated SR protein with autoregulatory mRNA processing established it as a potential alternative splicing regulator whose own expression is feedback-controlled.","evidence":"cDNA cloning and temporal RT-PCR profiling of HRS mRNA isoforms during cell growth response","pmids":["7686911"],"confidence":"Medium","gaps":["Autoregulation mechanism not biochemically reconstituted","No splicing targets identified at this stage"]},{"year":1997,"claim":"Demonstrating that RS domain phosphorylation is required for SRSF5 to bind specific RNA sequences and activate splicing enhancers answered how post-translational modification governs substrate selectivity among SR proteins.","evidence":"SELEX selection of high-affinity RNA targets with phosphorylated vs. unphosphorylated SRp40; in vitro splicing reconstitution; SRSF5 uniquely activates its cognate enhancer in S100 complementation","pmids":["9037021"],"confidence":"High","gaps":["Kinase(s) responsible for activating phosphorylation not identified","In vivo targets unknown"]},{"year":1997,"claim":"Showing that SRSF5 is the specific SR protein required for fibronectin EIIIB exon inclusion via a purine-rich enhancer provided the first physiological splicing target and demonstrated non-redundancy among SR proteins.","evidence":"In vivo minigene splicing assay with RNA binding specificity comparison across multiple SR proteins","pmids":["9199345"],"confidence":"High","gaps":["Structural basis of SRSF5–EIIIB enhancer recognition unknown","Physiological consequence of EIIIB inclusion not tested"]},{"year":2001,"claim":"Linking insulin/PI3K signaling to SRp40 phosphorylation and PKCβII exon inclusion revealed that SRSF5 acts as a signal-responsive splicing switch coupling extracellular cues to alternative splicing outcomes.","evidence":"PI3K inhibitor (LY294002), antisense oligonucleotides targeting SRp40-binding site, SRp40 overexpression; phosphorylation assay in insulin-stimulated cells","pmids":["11283022"],"confidence":"High","gaps":["Direct kinase phosphorylating SRp40 downstream of PI3K not identified","Phosphorylation site not mapped"]},{"year":2005,"claim":"Identifying Akt2 as the kinase that directly phosphorylates SRSF5 at Ser86 to promote PKCβII exon inclusion completed the PI3K → Akt2 → SRp40 → splicing signaling axis.","evidence":"In vitro kinase assay, Ser86Ala mutagenesis, Akt2 knockout mouse with defective PKCβII splicing, minigene assay","pmids":["15684423"],"confidence":"High","gaps":["Whether Akt2 phosphorylation affects SRSF5 targets beyond PKCβII is unknown","Contribution of other SR protein kinases at the same site not addressed"]},{"year":2004,"claim":"Mapping SRSF5 binding on HIV-1 RNA near splice acceptor A3 and showing it antagonizes hnRNP A1-mediated silencing expanded SRSF5 function to viral RNA processing and defined the SR/hnRNP competition model at this site.","evidence":"Overexpression in HeLa, in vitro splicing, enzymatic footprinting of HIV-1 RNA, NMR of hnRNP A1 interaction (2006 follow-up)","pmids":["15123677","16990281"],"confidence":"Medium","gaps":["Endogenous SRSF5 contribution to HIV-1 splicing not isolated from other SR proteins","In vivo viral replication consequence not shown"]},{"year":2010,"claim":"Showing SRSF5 promotes translation of unspliced HIV-1 gag mRNA through its second RRM and RS domain extended its function beyond splicing to translational regulation of intron-containing RNA.","evidence":"Domain deletion/mutation analysis, Gag protein quantification by Western blot, codon-optimized reporter in HeLa cells","pmids":["20427542"],"confidence":"Medium","gaps":["Whether SRSF5 promotes translation of endogenous intron-retaining cellular mRNAs is untested","Mechanism of translational enhancement (ribosome recruitment vs. RNA export) not distinguished"]},{"year":2018,"claim":"Discovering the acetylation–ubiquitylation switch at K125 (Tip60/HDAC1/Smurf1) that couples glucose availability to SRSF5 protein stability and CCAR1 splicing established a metabolic sensing mechanism for splicing factor turnover.","evidence":"In vitro ubiquitylation and acetylation assays, K125R/K125Q mutagenesis, Tip60/HDAC1/Smurf1 perturbation, splicing minigene, xenograft tumor model","pmids":["29942010"],"confidence":"High","gaps":["Whether the K125 switch operates genome-wide on all SRSF5 targets is unknown","How glucose signals are transduced to Tip60/HDAC1 is not resolved"]},{"year":2021,"claim":"Identifying CLK1 phosphorylation at Ser250 as a second regulatory phosphorylation site controlling METTL14 and Cyclin L2 splicing showed that distinct kinase inputs generate target-specific splicing programs.","evidence":"Phosphorylation mass spectrometry, Ser250 mutagenesis, CLIP-qPCR and RNA pull-down for direct binding, RNA-seq, pancreatic cancer xenograft","pmids":["33849617"],"confidence":"High","gaps":["Relationship between Akt2-Ser86 and CLK1-Ser250 phosphorylation events is unknown","Whether CLK1-mediated phosphorylation affects the K125 stability switch is untested"]},{"year":2024,"claim":"Identifying TRIM72 as a second E3 ligase for SRSF5 degradation — recruited by lncRNA LINC01852 — and linking SRSF5 loss to a PKM2-to-PKM1 splicing switch demonstrated how non-coding RNA can reprogram cancer cell metabolism via splicing factor turnover.","evidence":"RNA pull-down, RIP, co-IP, ubiquitination assay, siRNA/shRNA knockdown, in vivo colorectal cancer mouse model","pmids":["38263157"],"confidence":"High","gaps":["Whether TRIM72 and Smurf1 act on the same or different lysine residues is not clarified","Structural basis of LINC01852-mediated TRIM72 recruitment to SRSF5 is unknown"]},{"year":null,"claim":"A unified model explaining how multiple phosphorylation inputs (Akt2-Ser86, CLK1-Ser250) and stability controls (Tip60/Smurf1/TRIM72 at K125) are integrated to determine target-specific splicing programs in different tissues and metabolic states remains unestablished.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide map of direct SRSF5-dependent exons under defined signaling conditions","Structural basis of SRSF5 RNA target selectivity versus other SR proteins is unresolved","Interplay between phosphorylation and acetylation/ubiquitylation switches has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,5,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,9,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,9,11,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,15]}],"complexes":[],"partners":["AKT2","CLK1","TIP60","SMURF1","TRIM72","HDAC1","SRSF3","CPEB2"],"other_free_text":[]},"mechanistic_narrative":"SRSF5 (SRp40) is a phosphorylation-regulated SR family splicing factor that controls alternative exon inclusion and skipping across diverse pre-mRNA targets including fibronectin EIIIB, PKCβII, CCAR1, PKM, METTL14, GRβ, and Mcl-1 [PMID:9199345, PMID:11283022, PMID:29942010, PMID:38263157, PMID:33849617]. Phosphorylation of its RS domain — by Akt2 at Ser86 downstream of PI3K/insulin signaling or by CLK1 at Ser250 — is required for sequence-specific RNA binding and splicing enhancer activity [PMID:9037021, PMID:15684423, PMID:33849617]. SRSF5 protein stability is controlled by a mutually exclusive acetylation–ubiquitylation switch on K125: Tip60-mediated acetylation under glucose-replete conditions stabilizes SRSF5, whereas HDAC1-mediated deacetylation permits Smurf1- or TRIM72-dependent ubiquitylation and proteasomal degradation, coupling cellular metabolic state to splicing output [PMID:29942010, PMID:38263157]. SRSF5 levels are further modulated by autoregulation of its own pre-mRNA processing, a circuit that can be overridden by SRSF3 in cancer contexts [PMID:7686911, PMID:29857020]."},"prefetch_data":{"uniprot":{"accession":"Q13243","full_name":"Serine/arginine-rich splicing factor 5","aliases":["Delayed-early protein HRS","Pre-mRNA-splicing factor SRP40","Splicing factor, arginine/serine-rich 5"],"length_aa":272,"mass_kda":31.3,"function":"Plays a role in constitutive splicing and can modulate the selection of alternative splice sites","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13243/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRSF5","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRSF5","total_profiled":1310},"omim":[{"mim_id":"614620","title":"INTRAFLAGELLAR TRANSPORT 140; IFT140","url":"https://www.omim.org/entry/614620"},{"mim_id":"604194","title":"SOLUTE CARRIER FAMILY 27 (FATTY ACID TRANSPORTER), MEMBER 4; SLC27A4","url":"https://www.omim.org/entry/604194"},{"mim_id":"600914","title":"SPLICING FACTOR, SERINE/ARGININE-RICH, 5; SRSF5","url":"https://www.omim.org/entry/600914"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRSF5"},"hgnc":{"alias_symbol":["SRP40","HRS"],"prev_symbol":["SFRS5"]},"alphafold":{"accession":"Q13243","domains":[{"cath_id":"3.30.70.330","chopping":"4-70","consensus_level":"high","plddt":82.2357,"start":4,"end":70},{"cath_id":"3.30.70.330","chopping":"108-177","consensus_level":"high","plddt":78.6923,"start":108,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13243","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13243-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13243-F1-predicted_aligned_error_v6.png","plddt_mean":64.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRSF5","jax_strain_url":"https://www.jax.org/strain/search?query=SRSF5"},"sequence":{"accession":"Q13243","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13243.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13243/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13243"}},"corpus_meta":[{"pmid":"11988743","id":"PMC_11988743","title":"Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11988743","citation_count":587,"is_preprint":false},{"pmid":"31078652","id":"PMC_31078652","title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy.","date":"2019","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/31078652","citation_count":571,"is_preprint":false},{"pmid":"11832215","id":"PMC_11832215","title":"Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11832215","citation_count":383,"is_preprint":false},{"pmid":"11988742","id":"PMC_11988742","title":"Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11988742","citation_count":373,"is_preprint":false},{"pmid":"11532964","id":"PMC_11532964","title":"Hrs recruits clathrin to early endosomes.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11532964","citation_count":323,"is_preprint":false},{"pmid":"12802020","id":"PMC_12802020","title":"TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12802020","citation_count":274,"is_preprint":false},{"pmid":"12551915","id":"PMC_12551915","title":"STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12551915","citation_count":260,"is_preprint":false},{"pmid":"11493665","id":"PMC_11493665","title":"FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11493665","citation_count":254,"is_preprint":false},{"pmid":"12900394","id":"PMC_12900394","title":"HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12900394","citation_count":214,"is_preprint":false},{"pmid":"20673754","id":"PMC_20673754","title":"Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20673754","citation_count":210,"is_preprint":false},{"pmid":"16707569","id":"PMC_16707569","title":"Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16707569","citation_count":207,"is_preprint":false},{"pmid":"10364163","id":"PMC_10364163","title":"Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10364163","citation_count":207,"is_preprint":false},{"pmid":"10982817","id":"PMC_10982817","title":"A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10982817","citation_count":193,"is_preprint":false},{"pmid":"9037021","id":"PMC_9037021","title":"Sequence-specific RNA binding by an SR protein requires RS domain phosphorylation: creation of an SRp40-specific splicing enhancer.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9037021","citation_count":177,"is_preprint":false},{"pmid":"7400758","id":"PMC_7400758","title":"Expression of leukemogenic recombinant viruses associated with a recessive gene in HRS/J mice.","date":"1980","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7400758","citation_count":174,"is_preprint":false},{"pmid":"11110793","id":"PMC_11110793","title":"Hrs interacts with sorting nexin 1 and regulates degradation of epidermal growth factor receptor.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11110793","citation_count":170,"is_preprint":false},{"pmid":"9407053","id":"PMC_9407053","title":"Hrs is associated with STAM, a signal-transducing adaptor molecule. Its suppressive effect on cytokine-induced cell growth.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9407053","citation_count":169,"is_preprint":false},{"pmid":"16227611","id":"PMC_16227611","title":"Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16227611","citation_count":166,"is_preprint":false},{"pmid":"11390366","id":"PMC_11390366","title":"Golgi-localizing, gamma-adaptin ear homology domain, ADP-ribosylation factor-binding (GGA) proteins interact with acidic dileucine sequences within the cytoplasmic domains of sorting receptors through their Vps27p/Hrs/STAM (VHS) domains.","date":"2001","source":"The Journal of biological 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unphosphorylated SRp40 fails to select specific RNA sequences, and three copies of the selected high-affinity site (B1) function as a strong splicing enhancer activated specifically by SRp40 but not by ASF/SF2 or SC35.\",\n      \"method\": \"SELEX RNA binding selection, in vitro splicing assay in nuclear extracts and S100 extracts, SR protein-specific complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with mutagenesis (unphosphorylated vs phosphorylated protein) plus functional splicing assay demonstrating enhancer specificity\",\n      \"pmids\": [\"9037021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HRS (SRSF5) was identified as a member of the family of regulators of alternative pre-mRNA splicing; different forms of HRS mRNA are temporally regulated during the growth response, suggesting autoregulation of its own pre-mRNA processing.\",\n      \"method\": \"cDNA cloning, sequence analysis, RT-PCR temporal expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — sequence-based identification with temporal mRNA analysis; mechanistic claim of autoregulation is indirect\",\n      \"pmids\": [\"7686911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HRS/SRp40 (SRSF5) directly mediates inclusion of the fibronectin EIIIB alternative exon in vivo; this activity depends on a purine-rich splicing enhancer sequence within the EIIIB exon to which HRS specifically binds, and no other SR protein tested could substitute.\",\n      \"method\": \"In vivo splicing minigene assay, RNA binding specificity assay, comparison across SR protein family members\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vivo splicing assay with specific RNA binding demonstrated, replicated across multiple SR proteins showing unique activity of SRSF5\",\n      \"pmids\": [\"9199345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Insulin regulates PKCbetaII exon inclusion via PI 3-kinase-dependent phosphorylation of SRp40 (SRSF5); antisense oligonucleotides targeting a putative SRp40-binding sequence in the betaII-betaI intron blocked both insulin-induced splicing and glucose uptake; overexpression of SRp40 mimicked insulin-induced exon inclusion.\",\n      \"method\": \"Antisense oligonucleotide knockdown, overexpression, PI 3-kinase inhibitor (LY294002), phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (inhibitor, antisense, overexpression) in the same study establishing PI3K pathway → SRp40 phosphorylation → PKCbetaII splicing\",\n      \"pmids\": [\"11283022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Akt2 kinase directly phosphorylates SRp40 (SRSF5) on Ser86 in vitro and in vivo; this phosphorylation event promotes PKCbetaII exon inclusion; mutation of Ser86 blocks in vitro phosphorylation and Akt2-deficient mice show defective PKCbetaII splicing.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (Ser86Ala), Akt2 knockout mouse, quantitative RT-PCR, transfection of splicing minigene\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis plus genetic validation in knockout mouse\",\n      \"pmids\": [\"15684423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRp40 (SRSF5), specifically through its second RNA recognition motif and RS domain, promotes translation of unspliced HIV-1 gRNA (Gag expression) from intron-containing viral RNA; this activity does not correlate with nucleocytoplasmic shuttling capacity and is abolished by codon optimization of the gag-pol region.\",\n      \"method\": \"Overexpression/knockdown in HeLa cells, domain deletion/mutation analysis, Gag protein quantification by Western blot, codon-optimized reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional readout; single lab but multiple mutants tested\",\n      \"pmids\": [\"20427542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SRp40 (SRSF5) strongly activates HIV-1 splice acceptor site A3 both in vivo and in vitro, leading to dramatic accumulation of tat mRNA; its binding site on HIV-1 RNA was delineated by footprinting and shown to overlap with hnRNP A1 sites, indicating SR protein-mediated antagonism of silencer binding.\",\n      \"method\": \"Overexpression in HeLa cells, in vitro splicing, enzymatic footprinting, quantitative RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro splicing with footprinting; single lab\",\n      \"pmids\": [\"15123677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SC35 and SRp40 (SRSF5) bind to overlapping sites on HIV-1 SLS2/SLS3 RNA structures near splice acceptor A3 and counteract hnRNP A1 binding on ESS2 to activate site A3; NMR demonstrates direct interaction of ESS2 with hnRNP A1 RRM domains, and enzymatic/chemical footprints delineate SR protein binding sites.\",\n      \"method\": \"Enzymatic and chemical footprinting, NMR spectroscopy, in vitro splicing, competition binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — NMR structural data combined with footprinting; defines binding sites but SRSF5-specific mechanistic detail is secondary to hnRNP A1 focus\",\n      \"pmids\": [\"16990281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRSF5 affects alternative splicing of Mcl-1 pre-mRNA in MCF-7 breast cancer cells, shifting the ratio of Mcl-1(L) to Mcl-1(S) isoforms; siRNA-mediated knockdown of SRSF5 alters this splicing pattern.\",\n      \"method\": \"siRNA knockdown, RT-PCR splicing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, siRNA knockdown with splicing readout; no in vitro binding or mechanistic detail beyond splicing outcome\",\n      \"pmids\": [\"23284704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon glucose intake, SRSF5 is acetylated on K125 by the acetyltransferase Tip60, which antagonizes Smurf1-mediated ubiquitylation of the same lysine and prevents proteasomal degradation; upon glucose starvation, HDAC1 deacetylates SRSF5, allowing Smurf1 to ubiquitylate K125 and target SRSF5 for proteasomal degradation. Stabilized SRSF5 promotes alternative splicing of CCAR1 to produce the short CCAR1S isoform, enhancing glucose consumption and tumor growth.\",\n      \"method\": \"Co-IP, in vitro ubiquitylation/acetylation assays, mutagenesis (K125R/K125Q), HDAC1/Tip60/Smurf1 knockdown and overexpression, splicing minigene assay, xenograft tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays with mutagenesis, multiple writer/eraser identified, functional splicing outcome and in vivo tumor validation\",\n      \"pmids\": [\"29942010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRSF5 is upregulated by SRSF3 in oral squamous cell carcinoma; SRSF3 impairs the autoregulation of SRSF5 (a mechanism that normally controls SRSF5 levels) and promotes SRSF5 overexpression, which drives cell proliferation and tumor formation.\",\n      \"method\": \"siRNA knockdown, overexpression, RT-PCR (autoregulation assay), soft-agar transformation assay, xenograft tumor model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional knockdown/overexpression with defined phenotypic readout; autoregulation mechanism supported by RT-PCR but not biochemically reconstituted\",\n      \"pmids\": [\"29857020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CLK1 phosphorylates SRSF5 on Ser250, which inhibits METTL14 exon10 skipping while promoting Cyclin L2 exon6.3 skipping; SRSF5 directly binds METTL14 and Cyclin L2 pre-mRNA (confirmed by RIP, RNA pull-down, and CLIP-qPCR), and these splicing events promote growth and metastasis of pancreatic cancer cells in vitro and in vivo.\",\n      \"method\": \"Phosphorylation mass spectrometry, RNA-seq, RIP assay, RNA pull-down, CLIP-qPCR, site-directed mutagenesis, xenograft mouse model\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphorylation site identified by mass spectrometry and validated by mutagenesis; direct RNA binding confirmed by CLIP; in vivo functional validation\",\n      \"pmids\": [\"33849617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRp40 (SRSF5) induces a GRα-to-GRβ alternative splicing shift of glucocorticoid receptor pre-mRNA in exon 9 in HeLa cells (but not 293T cells), as confirmed by minigene transfection and siRNA knockdown; other SR proteins tested did not produce this shift.\",\n      \"method\": \"Minigene transfection assay, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — minigene and siRNA validation in two cell lines; single lab; cell-type specificity noted but not mechanistically explained\",\n      \"pmids\": [\"19343537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRSF5 (SRp40) associates with the lncRNA NEAT1 in 3T3-L1 cells (shown by RNA-IP); depletion of NEAT1 results in failure to phosphorylate SRp40, and siRNA knockdown of SRp40 dysregulates PPARγ2 mRNA levels; overexpression of SRp40 increases PPARγ2 but not PPARγ1, indicating SRp40 selectively promotes PPARγ2 splicing during adipogenesis.\",\n      \"method\": \"RNA immunoprecipitation (RNA-IP), siRNA knockdown, overexpression, RT-PCR\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RNA-IP and functional knockdown/overexpression; single lab; phosphorylation mechanism is indirect\",\n      \"pmids\": [\"25437750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CPEB2 binds SRSF5 mRNA and increases its stability; in glioblastoma endothelial cells, elevated CPEB2 (through METTL3/IGF2BP3-mediated m6A methylation) stabilizes SRSF5 protein, which promotes ETS1 exon inclusion, leading to upregulation of tight junction proteins ZO-1, occludin, and claudin-5 and reduced blood-tumor barrier permeability.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, shRNA knockdown, splicing minigene assay, in vivo glioblastoma xenograft\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding confirmed by RIP and co-IP; functional in vivo validation; splicing outcome demonstrated; single lab\",\n      \"pmids\": [\"36064747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LINC01852 promotes TRIM72-mediated ubiquitination and proteasomal degradation of SRSF5, thereby inhibiting SRSF5-mediated alternative splicing of PKM pre-mRNA; loss of SRSF5 shifts PKM splicing from PKM2 to PKM1, inducing a metabolic switch from aerobic glycolysis to oxidative phosphorylation and attenuating chemoresistance in colorectal cancer.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assay, chromatin immunoprecipitation, dual-luciferase assay, siRNA/shRNA knockdown, in vivo mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — E3 ligase (TRIM72) identified with ubiquitination assay; direct RNA binding confirmed by pull-down and RIP; splicing outcome and metabolic consequence validated in vivo\",\n      \"pmids\": [\"38263157\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRSF5 (SRp40) is a phosphorylation-regulated SR splicing factor whose RS domain phosphorylation (by Akt2 via the PI3K pathway, or by CLK1) is required for sequence-specific RNA binding and splicing enhancer activity; it controls alternative splicing of multiple targets including PKCbetaII, fibronectin EIIIB, CCAR1, PKM, METTL14, Cyclin L2, GR, and Mcl-1, and its protein stability is regulated by mutually exclusive acetylation (Tip60 on K125, stabilizing) and ubiquitylation (Smurf1/TRIM72 on K125 or TRIM72, leading to proteasomal degradation) in response to glucose availability or lncRNA LINC01852.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SRSF5 (SRp40) is a phosphorylation-regulated SR family splicing factor that controls alternative exon inclusion and skipping across diverse pre-mRNA targets including fibronectin EIIIB, PKCβII, CCAR1, PKM, METTL14, GRβ, and Mcl-1 [PMID:9199345, PMID:11283022, PMID:29942010, PMID:38263157, PMID:33849617]. Phosphorylation of its RS domain — by Akt2 at Ser86 downstream of PI3K/insulin signaling or by CLK1 at Ser250 — is required for sequence-specific RNA binding and splicing enhancer activity [PMID:9037021, PMID:15684423, PMID:33849617]. SRSF5 protein stability is controlled by a mutually exclusive acetylation–ubiquitylation switch on K125: Tip60-mediated acetylation under glucose-replete conditions stabilizes SRSF5, whereas HDAC1-mediated deacetylation permits Smurf1- or TRIM72-dependent ubiquitylation and proteasomal degradation, coupling cellular metabolic state to splicing output [PMID:29942010, PMID:38263157]. SRSF5 levels are further modulated by autoregulation of its own pre-mRNA processing, a circuit that can be overridden by SRSF3 in cancer contexts [PMID:7686911, PMID:29857020].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying SRSF5 as a growth-regulated SR protein with autoregulatory mRNA processing established it as a potential alternative splicing regulator whose own expression is feedback-controlled.\",\n      \"evidence\": \"cDNA cloning and temporal RT-PCR profiling of HRS mRNA isoforms during cell growth response\",\n      \"pmids\": [\"7686911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autoregulation mechanism not biochemically reconstituted\", \"No splicing targets identified at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that RS domain phosphorylation is required for SRSF5 to bind specific RNA sequences and activate splicing enhancers answered how post-translational modification governs substrate selectivity among SR proteins.\",\n      \"evidence\": \"SELEX selection of high-affinity RNA targets with phosphorylated vs. unphosphorylated SRp40; in vitro splicing reconstitution; SRSF5 uniquely activates its cognate enhancer in S100 complementation\",\n      \"pmids\": [\"9037021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for activating phosphorylation not identified\", \"In vivo targets unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that SRSF5 is the specific SR protein required for fibronectin EIIIB exon inclusion via a purine-rich enhancer provided the first physiological splicing target and demonstrated non-redundancy among SR proteins.\",\n      \"evidence\": \"In vivo minigene splicing assay with RNA binding specificity comparison across multiple SR proteins\",\n      \"pmids\": [\"9199345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SRSF5–EIIIB enhancer recognition unknown\", \"Physiological consequence of EIIIB inclusion not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linking insulin/PI3K signaling to SRp40 phosphorylation and PKCβII exon inclusion revealed that SRSF5 acts as a signal-responsive splicing switch coupling extracellular cues to alternative splicing outcomes.\",\n      \"evidence\": \"PI3K inhibitor (LY294002), antisense oligonucleotides targeting SRp40-binding site, SRp40 overexpression; phosphorylation assay in insulin-stimulated cells\",\n      \"pmids\": [\"11283022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase phosphorylating SRp40 downstream of PI3K not identified\", \"Phosphorylation site not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying Akt2 as the kinase that directly phosphorylates SRSF5 at Ser86 to promote PKCβII exon inclusion completed the PI3K → Akt2 → SRp40 → splicing signaling axis.\",\n      \"evidence\": \"In vitro kinase assay, Ser86Ala mutagenesis, Akt2 knockout mouse with defective PKCβII splicing, minigene assay\",\n      \"pmids\": [\"15684423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Akt2 phosphorylation affects SRSF5 targets beyond PKCβII is unknown\", \"Contribution of other SR protein kinases at the same site not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping SRSF5 binding on HIV-1 RNA near splice acceptor A3 and showing it antagonizes hnRNP A1-mediated silencing expanded SRSF5 function to viral RNA processing and defined the SR/hnRNP competition model at this site.\",\n      \"evidence\": \"Overexpression in HeLa, in vitro splicing, enzymatic footprinting of HIV-1 RNA, NMR of hnRNP A1 interaction (2006 follow-up)\",\n      \"pmids\": [\"15123677\", \"16990281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous SRSF5 contribution to HIV-1 splicing not isolated from other SR proteins\", \"In vivo viral replication consequence not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing SRSF5 promotes translation of unspliced HIV-1 gag mRNA through its second RRM and RS domain extended its function beyond splicing to translational regulation of intron-containing RNA.\",\n      \"evidence\": \"Domain deletion/mutation analysis, Gag protein quantification by Western blot, codon-optimized reporter in HeLa cells\",\n      \"pmids\": [\"20427542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRSF5 promotes translation of endogenous intron-retaining cellular mRNAs is untested\", \"Mechanism of translational enhancement (ribosome recruitment vs. RNA export) not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovering the acetylation–ubiquitylation switch at K125 (Tip60/HDAC1/Smurf1) that couples glucose availability to SRSF5 protein stability and CCAR1 splicing established a metabolic sensing mechanism for splicing factor turnover.\",\n      \"evidence\": \"In vitro ubiquitylation and acetylation assays, K125R/K125Q mutagenesis, Tip60/HDAC1/Smurf1 perturbation, splicing minigene, xenograft tumor model\",\n      \"pmids\": [\"29942010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the K125 switch operates genome-wide on all SRSF5 targets is unknown\", \"How glucose signals are transduced to Tip60/HDAC1 is not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying CLK1 phosphorylation at Ser250 as a second regulatory phosphorylation site controlling METTL14 and Cyclin L2 splicing showed that distinct kinase inputs generate target-specific splicing programs.\",\n      \"evidence\": \"Phosphorylation mass spectrometry, Ser250 mutagenesis, CLIP-qPCR and RNA pull-down for direct binding, RNA-seq, pancreatic cancer xenograft\",\n      \"pmids\": [\"33849617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between Akt2-Ser86 and CLK1-Ser250 phosphorylation events is unknown\", \"Whether CLK1-mediated phosphorylation affects the K125 stability switch is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying TRIM72 as a second E3 ligase for SRSF5 degradation — recruited by lncRNA LINC01852 — and linking SRSF5 loss to a PKM2-to-PKM1 splicing switch demonstrated how non-coding RNA can reprogram cancer cell metabolism via splicing factor turnover.\",\n      \"evidence\": \"RNA pull-down, RIP, co-IP, ubiquitination assay, siRNA/shRNA knockdown, in vivo colorectal cancer mouse model\",\n      \"pmids\": [\"38263157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM72 and Smurf1 act on the same or different lysine residues is not clarified\", \"Structural basis of LINC01852-mediated TRIM72 recruitment to SRSF5 is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model explaining how multiple phosphorylation inputs (Akt2-Ser86, CLK1-Ser250) and stability controls (Tip60/Smurf1/TRIM72 at K125) are integrated to determine target-specific splicing programs in different tissues and metabolic states remains unestablished.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide map of direct SRSF5-dependent exons under defined signaling conditions\", \"Structural basis of SRSF5 RNA target selectivity versus other SR proteins is unresolved\", \"Interplay between phosphorylation and acetylation/ubiquitylation switches has not been tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 5, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 9, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 9, 11, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AKT2\",\n      \"CLK1\",\n      \"TIP60\",\n      \"SMURF1\",\n      \"TRIM72\",\n      \"HDAC1\",\n      \"SRSF3\",\n      \"CPEB2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}