{"gene":"KHDRBS3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"T-STAR/ETOILE (KHDRBS3) was identified as a novel RNA-binding protein closely related to SAM68, discovered via yeast two-hybrid screen using testis cDNA as bait for RBM (Y-chromosome RNA-binding protein). T-STAR interacts with RBM and other hnRNP G family members. When fused to GFP and transfected into HeLa cells, T-STAR accumulated in a novel nuclear compartment adjacent to the nucleolus but distinct from the peri-nucleolar compartment.","method":"Yeast two-hybrid screen, GFP fusion transfection, subcellular localization imaging","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid plus GFP localization in transfected cells, single lab, two methods","pmids":["10332027"],"is_preprint":false},{"year":1999,"finding":"SLM-2 (KHDRBS3) is an RNA-binding protein that is NOT tyrosine phosphorylated by Src or p59(fyn), and does not associate with the SH3 domains of p59(fyn), Grb-2, PLCgamma-1, or p120(rasGAP), unlike its paralog SLM-1. This distinguishes SLM-2 from SLM-1 and SAM68 as a non-adapter protein for these signaling partners.","method":"In vitro kinase assay, SH2/SH3 domain binding assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro kinase and domain binding assays, single lab, two orthogonal methods; negative result is mechanistically informative","pmids":["10077576"],"is_preprint":false},{"year":2001,"finding":"Overexpression of T-STAR (KHDRBS3) in SV40-transformed immortalized cells resulted in strong reduction of colony formation; deletion of the RNA-binding domain abrogated this growth-inhibitory effect, indicating the RNA-binding domain is required for T-STAR's growth-inhibitory function.","method":"Overexpression with deletion mutants, colony formation assay","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain deletion mutagenesis with functional readout, single lab, single method","pmids":["11714634"],"is_preprint":false},{"year":2004,"finding":"The tyrosine kinase BRK/Sik phosphorylates SLM-2 (KHDRBS3), and this phosphorylation inhibits the RNA-binding ability of SLM-2. Expression of active BRK/Sik resulted in increased SLM-2 phosphorylation and increased nuclear retention of BRK/Sik.","method":"In vitro kinase assay, RNA-binding assay, phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay demonstrating phosphorylation plus functional RNA-binding inhibition assay, single lab but two orthogonal methods","pmids":["15471878"],"is_preprint":false},{"year":2004,"finding":"SIAH1 (E3 ubiquitin ligase) binds to an octapeptide sequence in human T-STAR (KHDRBS3) and targets it for proteasome-dependent degradation. Rodent T-STAR orthologues lack this SIAH1-binding site and are not degraded; a double amino acid substitution in mouse T-STAR that mimics the human SIAH1-binding site brings mouse T-STAR under SIAH1 control. Human T-STAR-dependent alternative splicing is modulated by SIAH1, demonstrating that proteasomal degradation controls T-STAR splicing activity.","method":"Yeast two-hybrid screen, co-immunoprecipitation, proteasome inhibitor assays, minigene splicing assays, site-directed mutagenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — yeast two-hybrid identification, mutagenesis defining the binding site, functional splicing assay, proteasome inhibition, multiple orthogonal methods in one study","pmids":["15163637"],"is_preprint":false},{"year":2009,"finding":"SLM-2 (KHDRBS3) binds RNA via a bipartite U(U/A)AA direct repeat motif identified by SELEX. Both halves of the bipartite motif are required for high-affinity RNA binding by SLM-2.","method":"SELEX (Systematic Evolution of Ligands by EXponential enrichment), in vitro RNA binding assays","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SELEX with in vitro binding validation, bipartite site confirmed by mutagenesis of motif halves, single lab but rigorous biochemical methods","pmids":["19457263"],"is_preprint":false},{"year":2009,"finding":"Mouse T-STAR (KHDRBS3) directly binds Fabp9 mRNA, with binding sites located in a short sequence of the coding region and 3' UTR of Fabp9 mRNA, as identified from testis extract by SNAAP (isolation of specific nucleic acids associated with proteins).","method":"SNAAP method (protein-RNA co-isolation from testis extract), direct RNA binding assay","journal":"Biochemistry. Biokhimiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (SNAAP), partial characterization of binding sites","pmids":["19916944"],"is_preprint":false},{"year":2011,"finding":"SerpinB5 physically interacts with KHDRBS3 in gastric cancer cells, confirmed by co-immunoprecipitation. KHDRBS3 interacts with FBXO32 mRNA, as shown by RNA co-immunoprecipitation. KHDRBS3 protein is primarily detected in the nucleus of normal mucosal cells.","method":"Yeast two-hybrid screening, co-immunoprecipitation, RNA co-immunoprecipitation, Western blotting, immunohistochemistry","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus RNA-CoIP, single lab, two orthogonal methods confirming protein-protein and protein-RNA interactions","pmids":["21725612"],"is_preprint":false},{"year":2013,"finding":"T-STAR (KHDRBS3) acts as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of Stxbp5l, in the mouse brain. T-STAR expression is highest in forebrain structures (hippocampus), which correlates with maximal Neurexin1-3 AS4 splicing repression. In T-STAR null mice, AS4 splicing repression dramatically decreased despite co-expression of Sam68. T-STAR controls Neurexin2 AS4 splicing through a UWAA-rich response element immediately downstream of the regulated exon. Human T-STAR represses zebrafish Nrxn3 AS4 splicing, indicating an ancient mechanism.","method":"T-STAR null mouse generation, transcriptome-wide splicing analysis, minigene transfection assays, cross-species functional assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mouse, transcriptome-wide splicing screen, minigene functional assays, cross-species validation; multiple orthogonal approaches, single lab","pmids":["23637638"],"is_preprint":false},{"year":2016,"finding":"Crystal/NMR structure of T-STAR (KHDRBS3) STAR domain revealed an unexpected dimerization mode different from other STAR family members. This unique dimerization interface is required for biological activity in splicing regulation, and increased RNA affinity through dimer formation enables functional target selection within the transcriptome.","method":"Crystal structure determination, NMR, mutagenesis of dimerization interface, splicing assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structure plus interface mutagenesis plus functional splicing validation, multiple orthogonal methods in a single rigorous study","pmids":["26758068"],"is_preprint":false},{"year":2016,"finding":"SLM2 (KHDRBS3) controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask in addition to Neurexin1-3 AS4. SLM2 levels are maintained by a homeostatic feedback control pathway (autoregulation) that predates the divergence of SLM2 and Sam68. Loss of SLM2 in null mice decreases cortical neural network activity dependent on synaptic connections between SLM2-expressing pyramidal neurons and interneurons; these mice are also anxious and show decreased novel object recognition.","method":"Slm2-null mice, RNA-seq splicing analysis, cortical network electrophysiology, behavioral assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null, transcriptome splicing profiling, electrophysiology, and behavior, multiple orthogonal methods single lab","pmids":["28009295"],"is_preprint":false},{"year":2017,"finding":"SLM2 (KHDRBS3) and Sam68 show paralog-specific activity on Neurexin2 AS4 splicing despite similar RNA binding. A protein domain-swap experiment identified a region including the STAR domain (not the RNA-contact residues) that differentiates SLM2 and Sam68 activity. The density of shared RNA binding sites flanking a target exon — rather than different paralog-specific protein-RNA contacts — controls functional target specificity: doubling the number of binding sites around Neurexin2 AS4 switched it to joint control by both paralogs.","method":"Domain-swap mutagenesis, in vitro RNA binding, in vivo splicing assays, minigene reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain-swap mutagenesis combined with in vitro binding and functional splicing assays, single lab, multiple orthogonal methods","pmids":["27994030"],"is_preprint":false},{"year":2017,"finding":"Knockdown of KHDRBS3 in human ovarian cancer CAOV-3 cells caused G0/G1 phase cell cycle arrest and inhibited cell proliferation, indicating KHDRBS3 is required for cell cycle progression in these cells.","method":"siRNA knockdown, MTT proliferation assay, flow cytometry cell cycle analysis","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with cell cycle readout, no molecular pathway placement","pmids":["28871947"],"is_preprint":false},{"year":2017,"finding":"SLM2 (KHDRBS3) expression in cerebellar neurons controls AS4 splicing of Nrxn genes; ectopic SLM2 expression caused marked skipping of exon 20 of Nrxn AS4. SLM2-dependent AS4 splicing of Nrxn3 is required for neuroligin-induced GABAergic presynaptic differentiation: lentiviral Nrxn3 containing exon 20 rescued reduced GABAergic contacts in SLM2-overexpressing co-cultures.","method":"Lentiviral overexpression, neuron-fibroblast co-culture synapse formation assay, splicing analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral gain-of-function with rescue experiment and functional synapse formation readout, single lab","pmids":["28939043"],"is_preprint":false},{"year":2018,"finding":"SALL4 transcription factor upregulates KHDRBS3 expression, and KHDRBS3 in turn modulates CD44 alternative splicing to produce a CD44 variant (CD44v) lacking exons 8 and 9. This CD44v isoform positively contributes to cancer stemness and anoikis resistance in basal-like breast cancer cells. CD44v overexpression rescued the reduction in sphere formation caused by KHDRBS3 knockdown.","method":"shRNA knockdown, overexpression, sphere formation assay, RT-PCR splicing analysis, anoikis assay","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — shRNA plus overexpression with rescue experiment defining SALL4-KHDRBS3-CD44v axis, single lab, multiple functional assays","pmids":["29356399"],"is_preprint":false},{"year":2019,"finding":"Metadherin interacts with T-STAR (KHDRBS3) as shown by yeast two-hybrid assay and immunoprecipitation. Metadherin influences splice site selection in CD44v5-luc minigene reporter assays in a dose-dependent manner.","method":"Yeast two-hybrid, immunoprecipitation, minigene splicing reporter assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus immunoprecipitation plus functional splicing assay, single lab, two orthogonal binding methods","pmids":["31450747"],"is_preprint":false},{"year":2019,"finding":"KHDRBS3 binds to circular RNA DENND4C (cDENND4C) and increases its stability in glioma endothelial cells. This KHDRBS3-cDENND4C interaction regulates blood-tumor barrier (BTB) permeability via a cDENND4C/miR-577 axis that controls tight junction proteins ZO-1, occludin, and claudin-1.","method":"RNA immunoprecipitation, knockdown, overexpression, permeability assays, Western blotting for tight junction proteins","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RNA-IP showing binding but functional mechanism relies on circRNA/miRNA sponge axis with limited mechanistic depth on KHDRBS3's direct role","pmids":["31296839"],"is_preprint":false},{"year":2020,"finding":"KHDRBS3 regulates CD44 variant expression in gastric cancer cells, contributing to acquisition of cancer stem cell-like features including multi-drug resistance and organoid formation in 5-FU-resistant gastric cancer organoids.","method":"Organoid culture, microarray analysis, RT-PCR, Western blotting, drug resistance assays","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — organoid model with gene expression correlation, limited mechanistic dissection of direct splicing mechanism by KHDRBS3","pmids":["33046798"],"is_preprint":false},{"year":2021,"finding":"SLM2/KHDRBS3 binds mRNAs of sarcomere constituents MYL2, TNNI3, TNNT2, TPM1/2, and TTN in the human heart (identified by RNA-immunoprecipitation sequencing). SLM2 mediates intron retention, prevents exon exclusion, and thereby controls alternative splicing of the PEVK domain-encoding region and another part of the I-band region of titin mRNA.","method":"RNA-immunoprecipitation sequencing (RIP-seq), RNA-seq splicing analysis, cardiac tissue from DCM patients","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq identifies binding targets, splicing analysis defines mechanistic outcome, single lab, two orthogonal methods","pmids":["34273561"],"is_preprint":false},{"year":2021,"finding":"SLM2 (KHDRBS3) expression in cortical VIP-positive GABAergic interneurons (originating from caudal ganglionic eminence) contributes to GABAergic synapse specification. SLM2 knockdown reduced NRX AS4(-) isoform expression and weakened LRRTM2-induced synapse formation; addition of NRX AS4(-) rescued synaptic formation in SLM2 knockdown neurons.","method":"In vitro knockdown, artificial synapse formation assay, splicing analysis, immunostaining for interneuron subtypes","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with molecular rescue and functional synapse formation readout, single lab","pmids":["34196888"],"is_preprint":false},{"year":2022,"finding":"KHDRBS3 interacts with lncRNA MIR17HG (RNA immunoprecipitation). KHDRBS3 knockdown reduced paclitaxel resistance and glycolysis in ovarian cancer cells; overexpression of KHDRBS3 enhanced these phenotypes, which were rescued by MIR17HG overexpression. MIR17HG targets CLDN6 3'UTR to negatively regulate CLDN6 expression, defining a KHDRBS3-MIR17HG-CLDN6 regulatory axis.","method":"RNA immunoprecipitation, MTT assay, colony formation, apoptosis assay, Seahorse glycolysis assay, xenograft model","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-IP confirms binding but downstream mechanism is primarily through lncRNA/miRNA axis; KHDRBS3's direct molecular function not deeply characterized","pmids":["35051418"],"is_preprint":false},{"year":2023,"finding":"KHDRBS3 directly binds YWHAZ mRNA (encoding 14-3-3ζ), as demonstrated by RNA pull-down and RNA immunoprecipitation assays. KHDRBS3 upregulates 14-3-3ζ protein expression, and 14-3-3ζ silencing reversed the promotion of proliferation and glycolysis caused by KHDRBS3 overexpression in hepatocellular carcinoma cells.","method":"RNA pull-down, RNA immunoprecipitation, lentiviral knockdown/overexpression, xenograft model, functional proliferation and glycolysis assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA pull-down plus RIP confirm direct mRNA binding, rescue experiment places 14-3-3ζ downstream, single lab, two orthogonal binding methods","pmids":["37848941"],"is_preprint":false},{"year":2023,"finding":"circHECTD1 interacts with KHDRBS3 (demonstrated by RNA pull-down and RIP), and this interaction enhanced stability of EZH2 mRNA, increasing EZH2 protein levels and promoting proliferation and migration of vascular smooth muscle cells.","method":"RNA pull-down, RNA immunoprecipitation, knockdown/overexpression, CCK8, transwell assays","journal":"Journal of inflammation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA pull-down and RIP show KHDRBS3-circRNA interaction, but KHDRBS3's direct molecular contribution (mRNA stabilization) is inferred rather than directly demonstrated","pmids":["36998321"],"is_preprint":false},{"year":2025,"finding":"In hepatocellular carcinoma, the circFOXP1-encoded protein p196 directly binds KHDRBS3 through its D2 domain, forming a complex that stabilizes ULK1 mRNA, thereby increasing ULK1 protein levels, activating autophagy and accelerating tumor progression.","method":"RNA immunoprecipitation, co-immunoprecipitation, RNA pull-down, in vitro binding assays, loss- and gain-of-function assays","journal":"International journal of nanomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and RNA pull-down show p196-KHDRBS3 interaction and KHDRBS3-ULK1 mRNA binding, single lab, mechanism of mRNA stabilization not biochemically dissected","pmids":["40292405"],"is_preprint":false},{"year":2026,"finding":"In a mouse model of endothelin-1 overexpression, Khdrbs3 was the top upregulated gene in mesenteric arteries. KHDRBS3 protein was increased in aortic endothelial cells and vascular smooth muscle cells. KHDRBS3 acted as a splicing regulator of VEGFA pre-mRNA, with ET-1 overexpression upregulating Vegfa164 (exon 7 retention) and Vegfa188 (exons 6 and 7 retention) isoforms and downregulating Vegfa120. RNA-immunoprecipitation sequencing from DCM myocardium identified VEGFA and four VSMC-specific pre-mRNAs as KHDRBS3 targets.","method":"RNA-sequencing, RT-qPCR, immunofluorescence microscopy, RNA-immunoprecipitation sequencing (RIP-seq), tamoxifen-inducible transgenic mouse model","journal":"Journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq identifies direct mRNA targets, in vivo transgenic model with splicing outcome, two orthogonal methods, single lab","pmids":["42253124"],"is_preprint":false}],"current_model":"KHDRBS3 (T-STAR/SLM2) is a STAR-family RNA-binding protein that homodimerizes through a unique STAR-domain interface to achieve high-affinity, bipartite U(U/A)AA-repeat RNA recognition, functioning primarily as a potent tissue-specific splicing repressor — most notably of Neurexin1-3 AS4 exons in a concentration- and binding-site-density-dependent manner in the brain — while also binding and regulating the stability or splicing of mRNAs encoding cardiac sarcomere proteins, VEGFA isoforms, CD44 variants, and YWHAZ/14-3-3ζ; its activity is post-translationally regulated by BRK/Sik-mediated tyrosine phosphorylation (inhibiting RNA binding) and by SIAH1-mediated ubiquitin-proteasomal degradation (human-specific), and it participates in a homeostatic autoregulatory feedback loop controlling its own expression levels in neurons."},"narrative":{"mechanistic_narrative":"KHDRBS3 (T-STAR/SLM2/ETOILE) is a STAR-family RNA-binding protein that functions as a sequence-specific, tissue-restricted regulator of alternative splicing and mRNA fate [PMID:10332027, PMID:23637638]. It recognizes RNA through a bipartite U(U/A)AA direct-repeat motif in which both half-sites are required for high-affinity binding [PMID:19457263], and it homodimerizes through a STAR-domain interface that is structurally distinct from other STAR proteins; this dimerization raises RNA affinity and is required for splicing activity, allowing functional target selection across the transcriptome [PMID:26758068]. Its best-defined role is as a potent splicing repressor of the AS4 exons of Neurexin1-3 (and additional neuronal targets such as Stxbp5l, Tomosyn2, Dgkb, Kif21a and Cask) acting through downstream UWAA-rich response elements; this is established genetically in null mice where AS4 repression collapses despite Sam68 co-expression [PMID:23637638, PMID:28009295]. Functional target specificity relative to its paralog Sam68 is set largely by the density of shared binding sites flanking a target exon rather than by distinct protein-RNA contacts [PMID:27994030]. Through control of Neurexin AS4 isoforms, KHDRBS3 governs neuroligin- and LRRTM2-induced GABAergic presynaptic differentiation and synapse specification, and loss of the protein reduces cortical network activity and produces anxiety and recognition-memory deficits [PMID:28009295, PMID:28939043, PMID:34196888]; its own levels are set by an evolutionarily ancient homeostatic autoregulatory loop [PMID:28009295]. Beyond the brain, KHDRBS3 binds and regulates the splicing or stability of mRNAs encoding cardiac sarcomere proteins (MYL2, TNNI3, TNNT2, TPM1/2, TTN), including titin I-band/PEVK splicing, and acts as a splicing regulator of VEGFA pre-mRNA in the vasculature [PMID:34273561, PMID:42253124]. It directly binds YWHAZ mRNA to upregulate 14-3-3ζ and modulates CD44 variant splicing, linking it to proliferation, glycolysis and stem-like phenotypes in several cancers [PMID:37848941, PMID:29356399]. KHDRBS3 activity is post-translationally controlled by BRK/Sik-mediated tyrosine phosphorylation, which inhibits its RNA binding [PMID:15471878], and by human-specific SIAH1-mediated ubiquitin-proteasomal degradation acting through an octapeptide absent in rodent orthologs [PMID:15163637]. Notably, unlike its paralog SLM-1, KHDRBS3 is not phosphorylated by Src/Fyn and does not engage their SH3 adapters, distinguishing it as a non-adapter STAR protein [PMID:10077576].","teleology":[{"year":1999,"claim":"Establishing KHDRBS3 as a distinct SAM68/STAR-family RNA-binding protein answered whether it is a generic Src-pathway adapter; it is not, defining it as a non-adapter RNA-binding protein with a unique nuclear localization.","evidence":"Yeast two-hybrid against RBM, GFP-fusion localization, and in vitro kinase/SH2-SH3 binding assays","pmids":["10332027","10077576"],"confidence":"Medium","gaps":["Did not define an RNA target or sequence specificity","Functional consequence of the novel peri-nucleolar compartment unknown"]},{"year":2001,"claim":"Linking KHDRBS3's RNA-binding domain to growth inhibition addressed whether its biology depends on RNA contact, showing the RNA-binding domain is required for its anti-proliferative effect.","evidence":"Overexpression with RNA-binding-domain deletion mutants and colony formation assay in SV40-transformed cells","pmids":["11714634"],"confidence":"Medium","gaps":["No specific RNA target identified","Mechanism connecting RNA binding to growth arrest not resolved"]},{"year":2004,"claim":"Identifying BRK/Sik phosphorylation and SIAH1-mediated degradation answered how KHDRBS3 activity is controlled post-translationally, establishing both an activity switch (phosphorylation inhibits RNA binding) and a human-specific stability switch on splicing output.","evidence":"In vitro kinase and RNA-binding assays; yeast two-hybrid, Co-IP, site-directed mutagenesis, proteasome-inhibitor and minigene splicing assays","pmids":["15471878","15163637"],"confidence":"High","gaps":["Physiological stimuli that trigger BRK or SIAH1 regulation not defined","Whether phosphorylation and degradation act on overlapping target sets unknown"]},{"year":2009,"claim":"Defining the bipartite U(U/A)AA repeat motif answered what RNA sequence KHDRBS3 recognizes, showing both half-sites are needed for high-affinity binding.","evidence":"SELEX with in vitro binding validation and mutagenesis of motif halves","pmids":["19457263"],"confidence":"High","gaps":["In vitro motif not yet tied to endogenous transcriptome targets","Did not address dimerization contribution to affinity"]},{"year":2013,"claim":"Genetic deletion in mice established KHDRBS3's principal physiological function as a brain-region-specific repressor of Neurexin1-3 AS4 splicing, demonstrating a non-redundant role despite Sam68 co-expression.","evidence":"T-STAR null mice, transcriptome-wide splicing analysis, minigene assays, cross-species (zebrafish) functional validation","pmids":["23637638"],"confidence":"High","gaps":["Downstream synaptic and behavioral consequences not yet measured","Mechanism of repression at the response element not structurally defined"]},{"year":2016,"claim":"Solving the STAR-domain structure and profiling additional targets answered how KHDRBS3 achieves functional selectivity and homeostasis, revealing a unique dimerization interface required for activity and an autoregulatory feedback loop controlling its own levels.","evidence":"Crystal/NMR structure with interface mutagenesis and splicing assays; Slm2-null RNA-seq, cortical electrophysiology, behavioral assays","pmids":["26758068","28009295"],"confidence":"High","gaps":["Molecular sensor of the autoregulatory loop not identified","How dimerization couples to specific exon repression mechanistically unresolved"]},{"year":2017,"claim":"Domain-swap and binding-site-density experiments answered why KHDRBS3 and Sam68 differ functionally despite similar RNA binding, showing specificity is set by site density flanking the exon and by a STAR-domain region rather than distinct RNA contacts; parallel work tied AS4 control to GABAergic presynaptic differentiation.","evidence":"Domain-swap mutagenesis, in vitro binding, minigene and in vivo splicing assays; lentiviral overexpression with neuron-fibroblast co-culture synapse rescue","pmids":["27994030","28939043"],"confidence":"High","gaps":["How site density is read out mechanistically not defined","Cell-cycle role observed in cancer cells lacks molecular placement (Low-confidence)"]},{"year":2021,"claim":"RIP-seq in human heart extended KHDRBS3's role beyond neurons, identifying cardiac sarcomere mRNAs as targets and defining its control of titin I-band/PEVK splicing via intron retention and exon inclusion.","evidence":"RIP-seq and RNA-seq splicing analysis in cardiac tissue from DCM patients; parallel knockdown/rescue in cortical VIP interneurons","pmids":["34273561","34196888"],"confidence":"Medium","gaps":["Causal contribution of titin missplicing to cardiomyopathy not established","Whether cardiac regulation uses the same UWAA motif unknown"]},{"year":2023,"claim":"Direct YWHAZ mRNA binding answered whether KHDRBS3 regulates message abundance as well as splicing, showing it upregulates 14-3-3ζ to drive proliferation and glycolysis in hepatocellular carcinoma.","evidence":"RNA pull-down and RIP, lentiviral knockdown/overexpression, rescue and xenograft assays","pmids":["37848941"],"confidence":"Medium","gaps":["Mechanism of mRNA stabilization vs splicing not biochemically dissected","Relationship to the U(U/A)AA motif on YWHAZ not mapped"]},{"year":2026,"claim":"An endothelin-1-driven in vivo model placed KHDRBS3 as a VEGFA pre-mRNA splicing regulator in vasculature, connecting its activity to isoform shifts (Vegfa164/188 up, Vegfa120 down) under hypertensive stress.","evidence":"Tamoxifen-inducible ET-1 transgenic mouse, RNA-seq, RT-qPCR, immunofluorescence, and RIP-seq from DCM myocardium","pmids":["42253124"],"confidence":"Medium","gaps":["Upstream pathway linking ET-1 to KHDRBS3 induction not defined","Functional consequence of VEGFA isoform shift for vascular phenotype not isolated"]},{"year":null,"claim":"How KHDRBS3's tissue-specific expression, dimerization-driven affinity, post-translational switches, and the diverse splicing-versus-stability outcomes across neurons, heart, vasculature and cancers are mechanistically unified remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of KHDRBS3 bound to an endogenous target RNA","Many cancer-associated circRNA/lncRNA interactions rest on single RIP/pull-down studies without reciprocal validation","Whether mRNA stabilization and splicing repression use distinct or shared molecular determinants is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,5,6,7,8,18,21,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,10,11,18,24]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[21,16,22,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,8,9,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,10,13,19]}],"complexes":[],"partners":["RBM","SIAH1","BRK","SERPINB5","MTDH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75525","full_name":"KH domain-containing, RNA-binding, signal transduction-associated protein 3","aliases":["RNA-binding protein T-Star","Sam68-like mammalian protein 2","SLM-2","Sam68-like phosphotyrosine protein"],"length_aa":346,"mass_kda":38.8,"function":"RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds preferentially to the 5'-[AU]UAAA-3' motif in vitro. Binds optimally to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). RNA-binding abilities are down-regulated by tyrosine kinase PTK6 (PubMed:10564820, PubMed:19561594, PubMed:26758068). Involved in splice site selection of vascular endothelial growth factor (PubMed:15901763). In vitro regulates CD44 alternative splicing by direct binding to purine-rich exonic enhancer (By similarity). Can regulate alternative splicing of neurexins NRXN1-3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners such as neuroligins and LRRTM family members (PubMed:26758068). Targeted, cell-type specific splicing regulation of NRXN1 at AS4 is involved in neuronal glutamatergic synapse function and plasticity (By similarity). May regulate expression of KHDRBS2/SLIM-1 in defined brain neuron populations by modifying its alternative splicing (By similarity). Can bind FABP9 mRNA (By similarity). May play a role as a negative regulator of cell growth. Inhibits cell proliferation (Microbial infection) Involved in post-transcriptional regulation of HIV-1 gene expression","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O75525/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KHDRBS3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KHDRBS3","total_profiled":1310},"omim":[{"mim_id":"610487","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 2; KHDRBS2","url":"https://www.omim.org/entry/610487"},{"mim_id":"610421","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 3; 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T-STAR interacts with RBM and other hnRNP G family members. When fused to GFP and transfected into HeLa cells, T-STAR accumulated in a novel nuclear compartment adjacent to the nucleolus but distinct from the peri-nucleolar compartment.\",\n      \"method\": \"Yeast two-hybrid screen, GFP fusion transfection, subcellular localization imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid plus GFP localization in transfected cells, single lab, two methods\",\n      \"pmids\": [\"10332027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SLM-2 (KHDRBS3) is an RNA-binding protein that is NOT tyrosine phosphorylated by Src or p59(fyn), and does not associate with the SH3 domains of p59(fyn), Grb-2, PLCgamma-1, or p120(rasGAP), unlike its paralog SLM-1. This distinguishes SLM-2 from SLM-1 and SAM68 as a non-adapter protein for these signaling partners.\",\n      \"method\": \"In vitro kinase assay, SH2/SH3 domain binding assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro kinase and domain binding assays, single lab, two orthogonal methods; negative result is mechanistically informative\",\n      \"pmids\": [\"10077576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Overexpression of T-STAR (KHDRBS3) in SV40-transformed immortalized cells resulted in strong reduction of colony formation; deletion of the RNA-binding domain abrogated this growth-inhibitory effect, indicating the RNA-binding domain is required for T-STAR's growth-inhibitory function.\",\n      \"method\": \"Overexpression with deletion mutants, colony formation assay\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain deletion mutagenesis with functional readout, single lab, single method\",\n      \"pmids\": [\"11714634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The tyrosine kinase BRK/Sik phosphorylates SLM-2 (KHDRBS3), and this phosphorylation inhibits the RNA-binding ability of SLM-2. Expression of active BRK/Sik resulted in increased SLM-2 phosphorylation and increased nuclear retention of BRK/Sik.\",\n      \"method\": \"In vitro kinase assay, RNA-binding assay, phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay demonstrating phosphorylation plus functional RNA-binding inhibition assay, single lab but two orthogonal methods\",\n      \"pmids\": [\"15471878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SIAH1 (E3 ubiquitin ligase) binds to an octapeptide sequence in human T-STAR (KHDRBS3) and targets it for proteasome-dependent degradation. Rodent T-STAR orthologues lack this SIAH1-binding site and are not degraded; a double amino acid substitution in mouse T-STAR that mimics the human SIAH1-binding site brings mouse T-STAR under SIAH1 control. Human T-STAR-dependent alternative splicing is modulated by SIAH1, demonstrating that proteasomal degradation controls T-STAR splicing activity.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, proteasome inhibitor assays, minigene splicing assays, site-directed mutagenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — yeast two-hybrid identification, mutagenesis defining the binding site, functional splicing assay, proteasome inhibition, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15163637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLM-2 (KHDRBS3) binds RNA via a bipartite U(U/A)AA direct repeat motif identified by SELEX. Both halves of the bipartite motif are required for high-affinity RNA binding by SLM-2.\",\n      \"method\": \"SELEX (Systematic Evolution of Ligands by EXponential enrichment), in vitro RNA binding assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SELEX with in vitro binding validation, bipartite site confirmed by mutagenesis of motif halves, single lab but rigorous biochemical methods\",\n      \"pmids\": [\"19457263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse T-STAR (KHDRBS3) directly binds Fabp9 mRNA, with binding sites located in a short sequence of the coding region and 3' UTR of Fabp9 mRNA, as identified from testis extract by SNAAP (isolation of specific nucleic acids associated with proteins).\",\n      \"method\": \"SNAAP method (protein-RNA co-isolation from testis extract), direct RNA binding assay\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (SNAAP), partial characterization of binding sites\",\n      \"pmids\": [\"19916944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SerpinB5 physically interacts with KHDRBS3 in gastric cancer cells, confirmed by co-immunoprecipitation. KHDRBS3 interacts with FBXO32 mRNA, as shown by RNA co-immunoprecipitation. KHDRBS3 protein is primarily detected in the nucleus of normal mucosal cells.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, RNA co-immunoprecipitation, Western blotting, immunohistochemistry\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus RNA-CoIP, single lab, two orthogonal methods confirming protein-protein and protein-RNA interactions\",\n      \"pmids\": [\"21725612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T-STAR (KHDRBS3) acts as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from each of the Neurexin1-3 genes, and exon 23 of Stxbp5l, in the mouse brain. T-STAR expression is highest in forebrain structures (hippocampus), which correlates with maximal Neurexin1-3 AS4 splicing repression. In T-STAR null mice, AS4 splicing repression dramatically decreased despite co-expression of Sam68. T-STAR controls Neurexin2 AS4 splicing through a UWAA-rich response element immediately downstream of the regulated exon. Human T-STAR represses zebrafish Nrxn3 AS4 splicing, indicating an ancient mechanism.\",\n      \"method\": \"T-STAR null mouse generation, transcriptome-wide splicing analysis, minigene transfection assays, cross-species functional assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mouse, transcriptome-wide splicing screen, minigene functional assays, cross-species validation; multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"23637638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal/NMR structure of T-STAR (KHDRBS3) STAR domain revealed an unexpected dimerization mode different from other STAR family members. This unique dimerization interface is required for biological activity in splicing regulation, and increased RNA affinity through dimer formation enables functional target selection within the transcriptome.\",\n      \"method\": \"Crystal structure determination, NMR, mutagenesis of dimerization interface, splicing assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structure plus interface mutagenesis plus functional splicing validation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26758068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLM2 (KHDRBS3) controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask in addition to Neurexin1-3 AS4. SLM2 levels are maintained by a homeostatic feedback control pathway (autoregulation) that predates the divergence of SLM2 and Sam68. Loss of SLM2 in null mice decreases cortical neural network activity dependent on synaptic connections between SLM2-expressing pyramidal neurons and interneurons; these mice are also anxious and show decreased novel object recognition.\",\n      \"method\": \"Slm2-null mice, RNA-seq splicing analysis, cortical network electrophysiology, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null, transcriptome splicing profiling, electrophysiology, and behavior, multiple orthogonal methods single lab\",\n      \"pmids\": [\"28009295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLM2 (KHDRBS3) and Sam68 show paralog-specific activity on Neurexin2 AS4 splicing despite similar RNA binding. A protein domain-swap experiment identified a region including the STAR domain (not the RNA-contact residues) that differentiates SLM2 and Sam68 activity. The density of shared RNA binding sites flanking a target exon — rather than different paralog-specific protein-RNA contacts — controls functional target specificity: doubling the number of binding sites around Neurexin2 AS4 switched it to joint control by both paralogs.\",\n      \"method\": \"Domain-swap mutagenesis, in vitro RNA binding, in vivo splicing assays, minigene reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain-swap mutagenesis combined with in vitro binding and functional splicing assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27994030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of KHDRBS3 in human ovarian cancer CAOV-3 cells caused G0/G1 phase cell cycle arrest and inhibited cell proliferation, indicating KHDRBS3 is required for cell cycle progression in these cells.\",\n      \"method\": \"siRNA knockdown, MTT proliferation assay, flow cytometry cell cycle analysis\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with cell cycle readout, no molecular pathway placement\",\n      \"pmids\": [\"28871947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLM2 (KHDRBS3) expression in cerebellar neurons controls AS4 splicing of Nrxn genes; ectopic SLM2 expression caused marked skipping of exon 20 of Nrxn AS4. SLM2-dependent AS4 splicing of Nrxn3 is required for neuroligin-induced GABAergic presynaptic differentiation: lentiviral Nrxn3 containing exon 20 rescued reduced GABAergic contacts in SLM2-overexpressing co-cultures.\",\n      \"method\": \"Lentiviral overexpression, neuron-fibroblast co-culture synapse formation assay, splicing analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral gain-of-function with rescue experiment and functional synapse formation readout, single lab\",\n      \"pmids\": [\"28939043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SALL4 transcription factor upregulates KHDRBS3 expression, and KHDRBS3 in turn modulates CD44 alternative splicing to produce a CD44 variant (CD44v) lacking exons 8 and 9. This CD44v isoform positively contributes to cancer stemness and anoikis resistance in basal-like breast cancer cells. CD44v overexpression rescued the reduction in sphere formation caused by KHDRBS3 knockdown.\",\n      \"method\": \"shRNA knockdown, overexpression, sphere formation assay, RT-PCR splicing analysis, anoikis assay\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — shRNA plus overexpression with rescue experiment defining SALL4-KHDRBS3-CD44v axis, single lab, multiple functional assays\",\n      \"pmids\": [\"29356399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Metadherin interacts with T-STAR (KHDRBS3) as shown by yeast two-hybrid assay and immunoprecipitation. Metadherin influences splice site selection in CD44v5-luc minigene reporter assays in a dose-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, immunoprecipitation, minigene splicing reporter assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus immunoprecipitation plus functional splicing assay, single lab, two orthogonal binding methods\",\n      \"pmids\": [\"31450747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KHDRBS3 binds to circular RNA DENND4C (cDENND4C) and increases its stability in glioma endothelial cells. This KHDRBS3-cDENND4C interaction regulates blood-tumor barrier (BTB) permeability via a cDENND4C/miR-577 axis that controls tight junction proteins ZO-1, occludin, and claudin-1.\",\n      \"method\": \"RNA immunoprecipitation, knockdown, overexpression, permeability assays, Western blotting for tight junction proteins\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RNA-IP showing binding but functional mechanism relies on circRNA/miRNA sponge axis with limited mechanistic depth on KHDRBS3's direct role\",\n      \"pmids\": [\"31296839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KHDRBS3 regulates CD44 variant expression in gastric cancer cells, contributing to acquisition of cancer stem cell-like features including multi-drug resistance and organoid formation in 5-FU-resistant gastric cancer organoids.\",\n      \"method\": \"Organoid culture, microarray analysis, RT-PCR, Western blotting, drug resistance assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — organoid model with gene expression correlation, limited mechanistic dissection of direct splicing mechanism by KHDRBS3\",\n      \"pmids\": [\"33046798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLM2/KHDRBS3 binds mRNAs of sarcomere constituents MYL2, TNNI3, TNNT2, TPM1/2, and TTN in the human heart (identified by RNA-immunoprecipitation sequencing). SLM2 mediates intron retention, prevents exon exclusion, and thereby controls alternative splicing of the PEVK domain-encoding region and another part of the I-band region of titin mRNA.\",\n      \"method\": \"RNA-immunoprecipitation sequencing (RIP-seq), RNA-seq splicing analysis, cardiac tissue from DCM patients\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq identifies binding targets, splicing analysis defines mechanistic outcome, single lab, two orthogonal methods\",\n      \"pmids\": [\"34273561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLM2 (KHDRBS3) expression in cortical VIP-positive GABAergic interneurons (originating from caudal ganglionic eminence) contributes to GABAergic synapse specification. SLM2 knockdown reduced NRX AS4(-) isoform expression and weakened LRRTM2-induced synapse formation; addition of NRX AS4(-) rescued synaptic formation in SLM2 knockdown neurons.\",\n      \"method\": \"In vitro knockdown, artificial synapse formation assay, splicing analysis, immunostaining for interneuron subtypes\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with molecular rescue and functional synapse formation readout, single lab\",\n      \"pmids\": [\"34196888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KHDRBS3 interacts with lncRNA MIR17HG (RNA immunoprecipitation). KHDRBS3 knockdown reduced paclitaxel resistance and glycolysis in ovarian cancer cells; overexpression of KHDRBS3 enhanced these phenotypes, which were rescued by MIR17HG overexpression. MIR17HG targets CLDN6 3'UTR to negatively regulate CLDN6 expression, defining a KHDRBS3-MIR17HG-CLDN6 regulatory axis.\",\n      \"method\": \"RNA immunoprecipitation, MTT assay, colony formation, apoptosis assay, Seahorse glycolysis assay, xenograft model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-IP confirms binding but downstream mechanism is primarily through lncRNA/miRNA axis; KHDRBS3's direct molecular function not deeply characterized\",\n      \"pmids\": [\"35051418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KHDRBS3 directly binds YWHAZ mRNA (encoding 14-3-3ζ), as demonstrated by RNA pull-down and RNA immunoprecipitation assays. KHDRBS3 upregulates 14-3-3ζ protein expression, and 14-3-3ζ silencing reversed the promotion of proliferation and glycolysis caused by KHDRBS3 overexpression in hepatocellular carcinoma cells.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, lentiviral knockdown/overexpression, xenograft model, functional proliferation and glycolysis assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA pull-down plus RIP confirm direct mRNA binding, rescue experiment places 14-3-3ζ downstream, single lab, two orthogonal binding methods\",\n      \"pmids\": [\"37848941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circHECTD1 interacts with KHDRBS3 (demonstrated by RNA pull-down and RIP), and this interaction enhanced stability of EZH2 mRNA, increasing EZH2 protein levels and promoting proliferation and migration of vascular smooth muscle cells.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, knockdown/overexpression, CCK8, transwell assays\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA pull-down and RIP show KHDRBS3-circRNA interaction, but KHDRBS3's direct molecular contribution (mRNA stabilization) is inferred rather than directly demonstrated\",\n      \"pmids\": [\"36998321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hepatocellular carcinoma, the circFOXP1-encoded protein p196 directly binds KHDRBS3 through its D2 domain, forming a complex that stabilizes ULK1 mRNA, thereby increasing ULK1 protein levels, activating autophagy and accelerating tumor progression.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, RNA pull-down, in vitro binding assays, loss- and gain-of-function assays\",\n      \"journal\": \"International journal of nanomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and RNA pull-down show p196-KHDRBS3 interaction and KHDRBS3-ULK1 mRNA binding, single lab, mechanism of mRNA stabilization not biochemically dissected\",\n      \"pmids\": [\"40292405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a mouse model of endothelin-1 overexpression, Khdrbs3 was the top upregulated gene in mesenteric arteries. KHDRBS3 protein was increased in aortic endothelial cells and vascular smooth muscle cells. KHDRBS3 acted as a splicing regulator of VEGFA pre-mRNA, with ET-1 overexpression upregulating Vegfa164 (exon 7 retention) and Vegfa188 (exons 6 and 7 retention) isoforms and downregulating Vegfa120. RNA-immunoprecipitation sequencing from DCM myocardium identified VEGFA and four VSMC-specific pre-mRNAs as KHDRBS3 targets.\",\n      \"method\": \"RNA-sequencing, RT-qPCR, immunofluorescence microscopy, RNA-immunoprecipitation sequencing (RIP-seq), tamoxifen-inducible transgenic mouse model\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq identifies direct mRNA targets, in vivo transgenic model with splicing outcome, two orthogonal methods, single lab\",\n      \"pmids\": [\"42253124\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KHDRBS3 (T-STAR/SLM2) is a STAR-family RNA-binding protein that homodimerizes through a unique STAR-domain interface to achieve high-affinity, bipartite U(U/A)AA-repeat RNA recognition, functioning primarily as a potent tissue-specific splicing repressor — most notably of Neurexin1-3 AS4 exons in a concentration- and binding-site-density-dependent manner in the brain — while also binding and regulating the stability or splicing of mRNAs encoding cardiac sarcomere proteins, VEGFA isoforms, CD44 variants, and YWHAZ/14-3-3ζ; its activity is post-translationally regulated by BRK/Sik-mediated tyrosine phosphorylation (inhibiting RNA binding) and by SIAH1-mediated ubiquitin-proteasomal degradation (human-specific), and it participates in a homeostatic autoregulatory feedback loop controlling its own expression levels in neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KHDRBS3 (T-STAR/SLM2/ETOILE) is a STAR-family RNA-binding protein that functions as a sequence-specific, tissue-restricted regulator of alternative splicing and mRNA fate [#0, #8]. It recognizes RNA through a bipartite U(U/A)AA direct-repeat motif in which both half-sites are required for high-affinity binding [#5], and it homodimerizes through a STAR-domain interface that is structurally distinct from other STAR proteins; this dimerization raises RNA affinity and is required for splicing activity, allowing functional target selection across the transcriptome [#9]. Its best-defined role is as a potent splicing repressor of the AS4 exons of Neurexin1-3 (and additional neuronal targets such as Stxbp5l, Tomosyn2, Dgkb, Kif21a and Cask) acting through downstream UWAA-rich response elements; this is established genetically in null mice where AS4 repression collapses despite Sam68 co-expression [#8, #10]. Functional target specificity relative to its paralog Sam68 is set largely by the density of shared binding sites flanking a target exon rather than by distinct protein-RNA contacts [#11]. Through control of Neurexin AS4 isoforms, KHDRBS3 governs neuroligin- and LRRTM2-induced GABAergic presynaptic differentiation and synapse specification, and loss of the protein reduces cortical network activity and produces anxiety and recognition-memory deficits [#10, #13, #19]; its own levels are set by an evolutionarily ancient homeostatic autoregulatory loop [#10]. Beyond the brain, KHDRBS3 binds and regulates the splicing or stability of mRNAs encoding cardiac sarcomere proteins (MYL2, TNNI3, TNNT2, TPM1/2, TTN), including titin I-band/PEVK splicing, and acts as a splicing regulator of VEGFA pre-mRNA in the vasculature [#18, #24]. It directly binds YWHAZ mRNA to upregulate 14-3-3\\u03b6 and modulates CD44 variant splicing, linking it to proliferation, glycolysis and stem-like phenotypes in several cancers [#21, #14]. KHDRBS3 activity is post-translationally controlled by BRK/Sik-mediated tyrosine phosphorylation, which inhibits its RNA binding [#3], and by human-specific SIAH1-mediated ubiquitin-proteasomal degradation acting through an octapeptide absent in rodent orthologs [#4]. Notably, unlike its paralog SLM-1, KHDRBS3 is not phosphorylated by Src/Fyn and does not engage their SH3 adapters, distinguishing it as a non-adapter STAR protein [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing KHDRBS3 as a distinct SAM68/STAR-family RNA-binding protein answered whether it is a generic Src-pathway adapter; it is not, defining it as a non-adapter RNA-binding protein with a unique nuclear localization.\",\n      \"evidence\": \"Yeast two-hybrid against RBM, GFP-fusion localization, and in vitro kinase/SH2-SH3 binding assays\",\n      \"pmids\": [\"10332027\", \"10077576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define an RNA target or sequence specificity\", \"Functional consequence of the novel peri-nucleolar compartment unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linking KHDRBS3's RNA-binding domain to growth inhibition addressed whether its biology depends on RNA contact, showing the RNA-binding domain is required for its anti-proliferative effect.\",\n      \"evidence\": \"Overexpression with RNA-binding-domain deletion mutants and colony formation assay in SV40-transformed cells\",\n      \"pmids\": [\"11714634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No specific RNA target identified\", \"Mechanism connecting RNA binding to growth arrest not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying BRK/Sik phosphorylation and SIAH1-mediated degradation answered how KHDRBS3 activity is controlled post-translationally, establishing both an activity switch (phosphorylation inhibits RNA binding) and a human-specific stability switch on splicing output.\",\n      \"evidence\": \"In vitro kinase and RNA-binding assays; yeast two-hybrid, Co-IP, site-directed mutagenesis, proteasome-inhibitor and minigene splicing assays\",\n      \"pmids\": [\"15471878\", \"15163637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli that trigger BRK or SIAH1 regulation not defined\", \"Whether phosphorylation and degradation act on overlapping target sets unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining the bipartite U(U/A)AA repeat motif answered what RNA sequence KHDRBS3 recognizes, showing both half-sites are needed for high-affinity binding.\",\n      \"evidence\": \"SELEX with in vitro binding validation and mutagenesis of motif halves\",\n      \"pmids\": [\"19457263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro motif not yet tied to endogenous transcriptome targets\", \"Did not address dimerization contribution to affinity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic deletion in mice established KHDRBS3's principal physiological function as a brain-region-specific repressor of Neurexin1-3 AS4 splicing, demonstrating a non-redundant role despite Sam68 co-expression.\",\n      \"evidence\": \"T-STAR null mice, transcriptome-wide splicing analysis, minigene assays, cross-species (zebrafish) functional validation\",\n      \"pmids\": [\"23637638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream synaptic and behavioral consequences not yet measured\", \"Mechanism of repression at the response element not structurally defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solving the STAR-domain structure and profiling additional targets answered how KHDRBS3 achieves functional selectivity and homeostasis, revealing a unique dimerization interface required for activity and an autoregulatory feedback loop controlling its own levels.\",\n      \"evidence\": \"Crystal/NMR structure with interface mutagenesis and splicing assays; Slm2-null RNA-seq, cortical electrophysiology, behavioral assays\",\n      \"pmids\": [\"26758068\", \"28009295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor of the autoregulatory loop not identified\", \"How dimerization couples to specific exon repression mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Domain-swap and binding-site-density experiments answered why KHDRBS3 and Sam68 differ functionally despite similar RNA binding, showing specificity is set by site density flanking the exon and by a STAR-domain region rather than distinct RNA contacts; parallel work tied AS4 control to GABAergic presynaptic differentiation.\",\n      \"evidence\": \"Domain-swap mutagenesis, in vitro binding, minigene and in vivo splicing assays; lentiviral overexpression with neuron-fibroblast co-culture synapse rescue\",\n      \"pmids\": [\"27994030\", \"28939043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How site density is read out mechanistically not defined\", \"Cell-cycle role observed in cancer cells lacks molecular placement (Low-confidence)\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"RIP-seq in human heart extended KHDRBS3's role beyond neurons, identifying cardiac sarcomere mRNAs as targets and defining its control of titin I-band/PEVK splicing via intron retention and exon inclusion.\",\n      \"evidence\": \"RIP-seq and RNA-seq splicing analysis in cardiac tissue from DCM patients; parallel knockdown/rescue in cortical VIP interneurons\",\n      \"pmids\": [\"34273561\", \"34196888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of titin missplicing to cardiomyopathy not established\", \"Whether cardiac regulation uses the same UWAA motif unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Direct YWHAZ mRNA binding answered whether KHDRBS3 regulates message abundance as well as splicing, showing it upregulates 14-3-3\\u03b6 to drive proliferation and glycolysis in hepatocellular carcinoma.\",\n      \"evidence\": \"RNA pull-down and RIP, lentiviral knockdown/overexpression, rescue and xenograft assays\",\n      \"pmids\": [\"37848941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA stabilization vs splicing not biochemically dissected\", \"Relationship to the U(U/A)AA motif on YWHAZ not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"An endothelin-1-driven in vivo model placed KHDRBS3 as a VEGFA pre-mRNA splicing regulator in vasculature, connecting its activity to isoform shifts (Vegfa164/188 up, Vegfa120 down) under hypertensive stress.\",\n      \"evidence\": \"Tamoxifen-inducible ET-1 transgenic mouse, RNA-seq, RT-qPCR, immunofluorescence, and RIP-seq from DCM myocardium\",\n      \"pmids\": [\"42253124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream pathway linking ET-1 to KHDRBS3 induction not defined\", \"Functional consequence of VEGFA isoform shift for vascular phenotype not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KHDRBS3's tissue-specific expression, dimerization-driven affinity, post-translational switches, and the diverse splicing-versus-stability outcomes across neurons, heart, vasculature and cancers are mechanistically unified remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of KHDRBS3 bound to an endogenous target RNA\", \"Many cancer-associated circRNA/lncRNA interactions rest on single RIP/pull-down studies without reciprocal validation\", \"Whether mRNA stabilization and splicing repression use distinct or shared molecular determinants is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5, 6, 7, 8, 18, 21, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 10, 11, 18, 24]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [21, 16, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 8, 9, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 10, 13, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RBM\", \"SIAH1\", \"BRK\", \"SERPINB5\", \"MTDH\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}