{"gene":"KHDRBS3","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1999,"finding":"T-STAR/ETOILE (KHDRBS3) is an RNA-binding protein closely related to SAM68 that physically interacts with RBM (an RNA-binding protein encoded on the Y chromosome implicated in spermatogenesis), identified by yeast two-hybrid screen with testis cDNA. T-STAR/ETOILE fused with GFP accumulates in a novel nuclear compartment adjacent to the nucleolus when transfected into HeLa cells.","method":"Yeast two-hybrid screen, GFP transfection/live imaging","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid plus localization experiment, single lab, foundational discovery paper","pmids":["10332027"],"is_preprint":false},{"year":1999,"finding":"SLM-2 (KHDRBS3) is an RNA-binding protein containing a GSG/STAR domain with ~70% sequence identity to SAM68. Unlike SLM-1, SLM-2 is not tyrosine phosphorylated by Src or p59(fyn), and does not associate with SH3 domains of p59(fyn), Grb-2, PLCγ-1, or p120(rasGAP), distinguishing it functionally from SLM-1 as a signaling adapter.","method":"In vitro kinase assay, SH2/SH3 domain pulldown, RNA-binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical assays (kinase assays, domain pulldowns, RNA binding) with clear negative controls","pmids":["10077576"],"is_preprint":false},{"year":2004,"finding":"The nuclear tyrosine kinase BRK/Sik phosphorylates SLM-1 and SLM-2 (KHDRBS3), and this phosphorylation inhibits their RNA-binding activities. Active BRK/Sik expression increases nuclear retention of BRK/Sik itself.","method":"In vitro kinase assay, RNA-binding assay, mutagenesis, co-expression in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with functional RNA-binding readout, replicated with multiple methods","pmids":["15471878"],"is_preprint":false},{"year":2004,"finding":"T-STAR (KHDRBS3) is targeted for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 and SIAH2, which bind to an octapeptide sequence in human T-STAR. This SIAH-mediated degradation modulates T-STAR-dependent alternative splicing activity. Rodent T-STAR orthologues are not targeted by SIAH1 due to sequence divergence at the binding site.","method":"Yeast two-hybrid, co-immunoprecipitation, minigene splicing assay, Western blot, proteasome inhibitor treatment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including functional splicing assay plus mutagenesis rescue experiment","pmids":["15163637"],"is_preprint":false},{"year":2009,"finding":"SLM-2 (KHDRBS3) binds RNA via direct U(U/A)AA repeat bipartite motifs identified by SELEX. The bipartite nature of the consensus sequence is essential for high-affinity RNA binding by SLM-2.","method":"SELEX (Systematic Evolution of Ligands by EXponential enrichment), in vitro RNA binding assay","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro SELEX with binding validation, clear mechanistic finding","pmids":["19457263"],"is_preprint":false},{"year":2011,"finding":"SerpinB5 physically interacts with KHDRBS3 in gastric cancer cells, confirmed by co-immunoprecipitation. KHDRBS3 in turn interacts with FBXO32 mRNA, as demonstrated by RNA co-immunoprecipitation assay. KHDRBS3 is primarily detected in the nucleus of normal mucosal cells.","method":"Yeast two-hybrid, co-immunoprecipitation, RNA co-immunoprecipitation, Western blot, immunohistochemistry","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP plus RNA-Co-IP, single lab","pmids":["21725612"],"is_preprint":false},{"year":2013,"finding":"T-STAR (KHDRBS3) functions as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from Neurexin1-3 genes and exon 23 of Stxbp5l, identified by transcriptome-wide splicing analysis in T-STAR null mice. T-STAR regulates Neurexin2 AS4 through a UWAA-rich response element immediately downstream of the regulated exon. T-STAR protein concentration in forebrain-derived structures like hippocampus correlates with degree of Nrxn1-3 AS4 splicing repression. In the absence of T-STAR, Sam68 cannot compensate for Nrxn2 AS4 repression despite co-expression.","method":"T-STAR null mouse model, transcriptome-wide RNA-seq, minigene transfection splicing assay, RT-PCR, mutational analysis of response element","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 — knockout mouse with transcriptome-wide validation plus mechanistic cell assays, multiple orthogonal approaches","pmids":["23637638"],"is_preprint":false},{"year":2016,"finding":"T-STAR and Sam68 STAR proteins dimerize through an unexpected dimerization interface, and this dimerization is crucial for their biological activity in alternative splicing regulation. Crystal/NMR structure established atomic-resolution RNA binding mode; dimer formation increases RNA affinity and enables functional target selection within the transcriptome.","method":"Crystal structure, NMR, mutagenesis of dimerization interface, RNA binding assay, splicing reporter assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — structural determination plus mutagenesis with functional splicing validation, strong mechanistic study","pmids":["26758068"],"is_preprint":false},{"year":2016,"finding":"SLM2 (KHDRBS3) controls alternative splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask in addition to Neurexin1-3 AS4. SLM2 levels are maintained by a homeostatic feedback auto-regulation pathway. Loss of SLM2 decreases cortical neural network activity dependent on synaptic connections between SLM2-expressing pyramidal neurons and interneurons, and Slm2-null mice show anxiety and impaired novel object recognition.","method":"Slm2-null mouse, RNA-seq splicing analysis, multi-electrode array cortical network activity recording, behavioral testing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — knockout mouse with transcriptome-wide splicing analysis plus electrophysiology and behavior, multiple orthogonal methods","pmids":["28009295"],"is_preprint":false},{"year":2017,"finding":"The density of shared RNA binding sites (UWAA repeats) around a target exon, rather than different paralog-specific protein-RNA contacts, determines functional specificity between SLM2 (KHDRBS3) and Sam68 on the Neurexin2 AS4 exon. Doubling binding site numbers switched paralog sensitivity. Protein domain-swap experiments identified a region including the STAR domain that differentiates SLM2 and Sam68 splicing activity.","method":"Domain-swap mutagenesis, binding site mutagenesis/addition, splicing reporter assay, in vivo cortex RNA binding analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple mutagenesis experiments with functional splicing readouts, mechanistic model validated by domain swaps and site number manipulation","pmids":["27994030"],"is_preprint":false},{"year":2018,"finding":"SALL4 upregulates KHDRBS3 expression, and KHDRBS3 in turn modulates CD44 alternative splicing, producing a CD44 variant (CD44v) lacking exons 8 and 9 that promotes cancer stemness (sphere formation, anoikis resistance) in basal-like breast cancer cells.","method":"shRNA knockdown, gene overexpression, sphere formation assay, splicing analysis, anoikis resistance assay","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD/OE with defined splicing and stemness phenotypes, single lab","pmids":["29356399"],"is_preprint":false},{"year":2019,"finding":"Metadherin interacts with T-STAR (KHDRBS3) and Sam68, demonstrated by yeast two-hybrid and immunoprecipitation. Metadherin influences splice site selection in a dose-dependent manner in CD44v5-luc minigene reporter assays, and T-STAR is significantly overexpressed in prostate cancer tissue compared to benign prostate.","method":"Yeast two-hybrid, co-immunoprecipitation, CD44v5-luc minigene splicing reporter assay, immunohistochemistry","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal interaction assays plus functional splicing reporter, single lab","pmids":["31450747"],"is_preprint":false},{"year":2019,"finding":"KHDRBS3 binds to circular RNA cDENND4C and increases its stability in glioma endothelial cells (GECs). The KHDRBS3/cDENND4C/miR-577 regulatory axis controls blood-tumor barrier permeability by modulating tight junction proteins ZO-1, occludin, and claudin-1.","method":"RNA immunoprecipitation, RNA stability assay, knockdown/overexpression, tight junction protein Western blot, BTB permeability assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-protein interaction validated by RIP plus functional permeability readout, single lab","pmids":["31296839"],"is_preprint":false},{"year":2020,"finding":"KHDRBS3 promotes cancer stem cell-like features in gastric cancer organoids by regulating CD44 variant expression, contributing to 5-FU resistance and multi-drug resistance. KHDRBS3 was identified as a splicing regulator of CD44 variants in this cancer context.","method":"Organoid culture, 5-FU resistance induction, microarray, siRNA knockdown, CD44 variant splicing analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional organoid system with defined molecular mechanism (CD44 splicing), single lab","pmids":["33046798"],"is_preprint":false},{"year":2021,"finding":"SLM2 (KHDRBS3) binds to mRNAs encoding sarcomere constituents (MYL2, TNNI3, TNNT2, TPM1/2, TTN) in the human heart. Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and promotes alternative splicing of mRNA regions encoding the PEVK domain and I-band region of titin in dilated cardiomyopathy.","method":"RNA-seq in human heart, CLIP-seq/RNA immunoprecipitation, alternative splicing analysis, tissue-enrichment analysis","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq plus binding analysis in human tissue, mechanistic splicing mechanism defined, single lab","pmids":["34273561"],"is_preprint":false},{"year":2021,"finding":"KHDRBS3 promotes drug resistance and anchorage-independent growth in colorectal cancer by regulating CD44 variant expression and the Wnt signaling pathway. KHDRBS3-positive cells show efficient tumor formation and lung metastasis in immunodeficient mice.","method":"siRNA knockdown, organoid formation, spheroid assay, xenograft mouse model, CD44 splicing analysis, Wnt pathway analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD with in vivo xenograft validation plus defined molecular mechanism, single lab","pmids":["33423358"],"is_preprint":false},{"year":2021,"finding":"SLM2 (KHDRBS3) knockdown in neurons reduces NRX AS4(-) isoform expression and weakens LRRTM2-induced synapse formation in cerebellar cultures. SLM2 modifies network formation in VIP-positive GABAergic interneurons through regulation of Nrxn splicing.","method":"shRNA knockdown in neurons, artificial synapse formation assay, immunostaining, RT-PCR for AS4 isoforms","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with defined synaptic phenotype and splicing readout in neurons","pmids":["34196888"],"is_preprint":false},{"year":2022,"finding":"KHDRBS3 interacts with lncRNA MIR17HG in epithelial ovarian cancer cells. Overexpression of KHDRBS3 promotes glycolysis and paclitaxel resistance, effects rescued by MIR17HG overexpression. MIR17HG negatively regulates CLDN6 by binding its 3'UTR, defining a KHDRBS3-MIR17HG-CLDN6 regulatory axis.","method":"RNA immunoprecipitation, MTT assay, colony formation, seahorse glycolysis assay, xenograft model, 3'UTR reporter assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-protein interaction plus functional rescue experiments in vitro and in vivo, single lab","pmids":["35051418"],"is_preprint":false},{"year":2023,"finding":"KHDRBS3 physically binds to YWHAZ mRNA (encoding 14-3-3ζ) as demonstrated by RNA pull-down and RNA immunoprecipitation assays, thereby upregulating 14-3-3ζ protein expression and promoting glycolysis and malignant progression in hepatocellular carcinoma. Silencing 14-3-3ζ reverses the pro-tumorigenic effects of KHDRBS3 overexpression.","method":"RNA pull-down, RNA immunoprecipitation, lentiviral knockdown/overexpression, xenograft model, seahorse glycolysis assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-protein interaction validated by two orthogonal methods plus functional epistasis rescue experiment","pmids":["37848941"],"is_preprint":false},{"year":2023,"finding":"KHDRBS3 interacts with circHECTD1 (as shown by RIP and RNA pull-down), enhancing EZH2 mRNA stability and increasing EZH2 protein levels, thereby promoting proliferation and migration of brain vascular smooth muscle cells.","method":"RIP, RNA pull-down, qRT-PCR, knockdown/overexpression, CCK8, transwell assays","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA-protein interaction by two methods plus functional downstream validation, single lab","pmids":["36998321"],"is_preprint":false},{"year":2025,"finding":"circFOXP1-encoded protein p196 directly binds KHDRBS3 through its D2 domain (shown by Co-IP and RNA pull-down), forming a complex that stabilizes ULK1 mRNA, increasing ULK1 protein levels and activating autophagy to accelerate hepatocellular carcinoma progression.","method":"Co-immunoprecipitation, RNA pull-down, RIP, in vitro binding assay, loss/gain-of-function, xenograft","journal":"International journal of nanomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — multiple interaction assays with defined domain and functional epistasis in vitro and in vivo, single lab","pmids":["40292405"],"is_preprint":false},{"year":2001,"finding":"T-STAR (KHDRBS3) functions as a growth inhibitor; overexpression in SV40-transformed immortalized human fibroblasts strongly reduces colony formation, and deletion of the RNA-binding domain abrogates this growth-inhibitory effect. T-STAR is downregulated in immortalized cells that arose after proliferative crisis.","method":"mRNA differential display, overexpression with RNA-binding domain deletion mutant, colony formation assay","journal":"Cell growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain deletion mutagenesis with functional growth assay, links RNA-binding domain to growth inhibition","pmids":["11714634"],"is_preprint":false},{"year":2009,"finding":"Mouse T-STAR (KHDRBS3) directly binds Fabp9 mRNA through sequences in its coding region and 3'UTR, identified from testis extract using SNAAP (isolation of specific nucleic acids associated with proteins). This suggests T-STAR regulates metabolism and expression of Fabp9 in spermatogenesis.","method":"SNAAP method (protein-mRNA pulldown from testis extract), direct binding assay","journal":"Biochemistry. Biokhimiia","confidence":"Low","confidence_rationale":"Tier 3 — single pulldown method from tissue extract, limited mechanistic follow-up","pmids":["19916944"],"is_preprint":false}],"current_model":"KHDRBS3 (T-STAR/SLM-2/ETOILE) is a STAR-family RNA-binding protein that homodimerizes through a unique dimerization interface to achieve high-affinity, bipartite U(U/A)AA-repeat RNA binding, functioning primarily as a concentration-dependent splicing repressor of Neurexin1-3 AS4 exons and other neuronal pre-mRNAs in the brain; its RNA-binding and splicing activities are negatively regulated by BRK/Sik-mediated tyrosine phosphorylation, while its protein stability is controlled by SIAH1/2 E3 ubiquitin ligase-mediated proteasomal degradation; additionally, KHDRBS3 stabilizes specific mRNAs (YWHAZ, EZH2, ULK1) and circular RNAs through direct binding, linking it to glycolysis, drug resistance, and autophagy regulation in cancer contexts."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of KHDRBS3 as a STAR-family RNA-binding protein related to SAM68 established its domain architecture and revealed that, unlike SLM-1, it is not a substrate for Src/Fyn kinases and does not engage canonical SH3-domain signaling partners, positioning it as a functionally distinct paralog.","evidence":"Biochemical kinase assays, SH2/SH3 pulldowns, yeast two-hybrid with testis cDNA, GFP localization in HeLa cells","pmids":["10077576","10332027"],"confidence":"High","gaps":["Endogenous signaling partners in vivo not defined","Nuclear subcompartment identity (adjacent to nucleolus) not characterized"]},{"year":2001,"claim":"Demonstrating that KHDRBS3 overexpression inhibits colony formation in an RNA-binding domain–dependent manner linked its RNA-binding activity to a growth-suppressive function, raising the question of which RNA targets mediate this effect.","evidence":"Overexpression and RNA-binding domain deletion mutant in SV40-immortalized fibroblasts, colony formation assay","pmids":["11714634"],"confidence":"Medium","gaps":["Target mRNAs mediating growth inhibition not identified","Mechanism of growth suppression (splicing, stability, or translational) unknown","Not replicated in non-immortalized cells"]},{"year":2004,"claim":"Two independent regulatory layers controlling KHDRBS3 activity were established: BRK/Sik tyrosine phosphorylation inhibits its RNA-binding capacity, while SIAH1/2-mediated ubiquitination targets it for proteasomal degradation, with the latter directly modulating its splicing-regulatory output.","evidence":"In vitro kinase assays with RNA-binding readout; yeast two-hybrid, Co-IP, minigene splicing assay, proteasome inhibitor rescue","pmids":["15471878","15163637"],"confidence":"High","gaps":["Physiological contexts triggering BRK-mediated phosphorylation not defined","Whether SIAH regulation operates in brain tissue unclear (rodent SIAH site divergent)","Tyrosine residue(s) targeted by BRK on KHDRBS3 not mapped"]},{"year":2009,"claim":"SELEX-based identification of U(U/A)AA bipartite repeat motifs as the high-affinity RNA target defined the cis-regulatory code for KHDRBS3, explaining how it selects its pre-mRNA substrates.","evidence":"In vitro SELEX with purified protein, binding affinity validation","pmids":["19457263"],"confidence":"High","gaps":["In vivo transcriptome-wide binding map not yet established at this point","Structural basis for bipartite recognition not yet resolved"]},{"year":2013,"claim":"Knockout mouse transcriptomics established KHDRBS3 as a physiological splicing repressor of Neurexin1-3 AS4 exons and Stxbp5l exon 23 in the brain, with splicing repression correlating with regional protein concentration and SAM68 unable to compensate, resolving the key in vivo targets.","evidence":"T-STAR null mouse, transcriptome-wide RNA-seq, minigene splicing assay, RT-PCR, response element mutagenesis","pmids":["23637638"],"confidence":"High","gaps":["Downstream functional consequences of Neurexin AS4 mis-splicing not yet tested","Whether splicing changes cause behavioral deficits not yet assessed"]},{"year":2016,"claim":"Structural determination revealed that KHDRBS3 dimerizes through a non-canonical interface, and disrupting this interface abolishes both high-affinity RNA binding and splicing activity, establishing dimerization as essential for function; concurrently, a second knockout study showed that Slm2 loss reduces cortical network activity and causes anxiety and impaired cognition.","evidence":"Crystal structure, NMR, dimerization-interface mutagenesis, splicing reporter; Slm2-null mouse with RNA-seq, multi-electrode array, behavioral testing","pmids":["26758068","28009295"],"confidence":"High","gaps":["How dimerization is regulated in vivo unknown","Whether behavioral phenotype maps to specific splice targets (e.g., Neurexins vs. Tomosyn2) not resolved"]},{"year":2017,"claim":"Domain-swap and binding-site-number experiments demonstrated that paralog specificity between KHDRBS3 and SAM68 on Neurexin2 AS4 is dictated by UWAA site density rather than differential protein-RNA contacts, establishing a quantitative model for target discrimination.","evidence":"Domain-swap mutagenesis, binding-site duplication, splicing reporters, in vivo cortex RNA binding","pmids":["27994030"],"confidence":"High","gaps":["Structural basis for the STAR-domain region that confers paralog discrimination not resolved","Genome-wide application of the density model not tested"]},{"year":2018,"claim":"Extension of KHDRBS3 splicing regulation to cancer contexts showed that it controls CD44 variant splicing downstream of SALL4, producing CD44v isoforms that promote stemness and drug resistance in breast, gastric, and colorectal cancers.","evidence":"shRNA/siRNA knockdown, overexpression, sphere/organoid formation, CD44 splicing analysis, xenograft models","pmids":["29356399","33046798","33423358"],"confidence":"Medium","gaps":["Whether CD44 is a direct KHDRBS3 splicing target (via UWAA motifs) or indirect not biochemically confirmed","Relative contribution of CD44v versus other splice targets to stemness phenotype unknown"]},{"year":2021,"claim":"KHDRBS3 was shown to function in the heart, binding sarcomere-encoding mRNAs and regulating titin alternative splicing and intron retention in dilated cardiomyopathy, and in neurons where its knockdown weakens LRRTM2-induced synapse formation by altering Neurexin AS4 splicing.","evidence":"CLIP-seq/RNA-seq in human heart tissue; shRNA knockdown in cerebellar neurons with artificial synapse formation assay","pmids":["34273561","34196888"],"confidence":"Medium","gaps":["Causality between KHDRBS3 dysregulation and cardiomyopathy not established","Whether cardiac splicing targets use canonical UWAA motifs not assessed"]},{"year":2023,"claim":"Beyond splicing, KHDRBS3 was established as an mRNA stability regulator: it binds and stabilizes YWHAZ and EZH2 mRNAs to promote glycolysis and cell proliferation, respectively, and cooperates with circFOXP1-encoded protein p196 to stabilize ULK1 mRNA and activate autophagy in hepatocellular carcinoma.","evidence":"RNA pull-down, RIP, mRNA stability assays, functional epistasis with knockdown/overexpression, xenograft models","pmids":["37848941","36998321","40292405"],"confidence":"Medium","gaps":["Mechanism by which KHDRBS3 stabilizes mRNA (e.g., competition with decay factors) not defined","Whether mRNA stabilization requires dimerization not tested","Single-lab findings for each target, not independently replicated"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for KHDRBS3's mRNA stabilization function versus its splicing repression function; whether its cardiac splicing targets are causative in cardiomyopathy; and how post-translational modifications (BRK phosphorylation, SIAH ubiquitination) are regulated in physiological and disease contexts in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo CLIP-seq map in brain to comprehensively define direct targets","No structural model for mRNA stabilization mode","Functional relationship between splicing and mRNA stability activities unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,4,5,6,7,9,14,18,19,20]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[6,8,9,10,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6,10,13,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,6,7,8,9,10,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,8,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,13,15,17,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":["T-STAR/SLM-2 homodimer"],"partners":["KHDRBS1","SIAH1","SIAH2","PTK6","RBMY1A1","SERPINB5","MTDH"],"other_free_text":[]},"mechanistic_narrative":"KHDRBS3 (T-STAR/SLM-2) is a STAR-family RNA-binding protein that functions as a concentration-dependent splicing repressor in the brain and regulates mRNA stability in diverse tissues. It homodimerizes through an unusual interface to achieve high-affinity binding to bipartite U(U/A)AA-repeat RNA motifs, and this dimerization is essential for its splicing-regulatory activity on key neuronal targets including Neurexin1-3 AS4 exons, where the density of UWAA binding sites determines paralog specificity between KHDRBS3 and SAM68 [PMID:26758068, PMID:27994030, PMID:23637638]. Loss of KHDRBS3 in mice impairs cortical neural network activity, synapse formation, and causes behavioral deficits including anxiety and impaired novel object recognition [PMID:28009295, PMID:34196888]. KHDRBS3 RNA-binding activity is negatively regulated by BRK/Sik tyrosine phosphorylation, and its protein stability is controlled by SIAH1/2 E3 ubiquitin ligase-mediated proteasomal degradation; in cancer contexts, KHDRBS3 regulates CD44 variant splicing to promote stemness and drug resistance, and stabilizes mRNAs encoding YWHAZ, EZH2, and ULK1 [PMID:15471878, PMID:15163637, PMID:33046798, PMID:37848941]."},"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; KHDRBS3","url":"https://www.omim.org/entry/610421"},{"mim_id":"602489","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 1; KHDRBS1","url":"https://www.omim.org/entry/602489"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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T-STAR/ETOILE fused with GFP accumulates in a novel nuclear compartment adjacent to the nucleolus when transfected into HeLa cells.\",\n      \"method\": \"Yeast two-hybrid screen, GFP transfection/live imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid plus localization experiment, single lab, foundational discovery paper\",\n      \"pmids\": [\"10332027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SLM-2 (KHDRBS3) is an RNA-binding protein containing a GSG/STAR domain with ~70% sequence identity to SAM68. Unlike SLM-1, SLM-2 is not tyrosine phosphorylated by Src or p59(fyn), and does not associate with SH3 domains of p59(fyn), Grb-2, PLCγ-1, or p120(rasGAP), distinguishing it functionally from SLM-1 as a signaling adapter.\",\n      \"method\": \"In vitro kinase assay, SH2/SH3 domain pulldown, RNA-binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical assays (kinase assays, domain pulldowns, RNA binding) with clear negative controls\",\n      \"pmids\": [\"10077576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The nuclear tyrosine kinase BRK/Sik phosphorylates SLM-1 and SLM-2 (KHDRBS3), and this phosphorylation inhibits their RNA-binding activities. Active BRK/Sik expression increases nuclear retention of BRK/Sik itself.\",\n      \"method\": \"In vitro kinase assay, RNA-binding assay, mutagenesis, co-expression in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with functional RNA-binding readout, replicated with multiple methods\",\n      \"pmids\": [\"15471878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"T-STAR (KHDRBS3) is targeted for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 and SIAH2, which bind to an octapeptide sequence in human T-STAR. This SIAH-mediated degradation modulates T-STAR-dependent alternative splicing activity. Rodent T-STAR orthologues are not targeted by SIAH1 due to sequence divergence at the binding site.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, minigene splicing assay, Western blot, proteasome inhibitor treatment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including functional splicing assay plus mutagenesis rescue experiment\",\n      \"pmids\": [\"15163637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SLM-2 (KHDRBS3) binds RNA via direct U(U/A)AA repeat bipartite motifs identified by SELEX. The bipartite nature of the consensus sequence is essential for high-affinity RNA binding by SLM-2.\",\n      \"method\": \"SELEX (Systematic Evolution of Ligands by EXponential enrichment), in vitro RNA binding assay\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro SELEX with binding validation, clear mechanistic finding\",\n      \"pmids\": [\"19457263\"],\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 in turn interacts with FBXO32 mRNA, as demonstrated by RNA co-immunoprecipitation assay. KHDRBS3 is primarily detected in the nucleus of normal mucosal cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, RNA co-immunoprecipitation, Western blot, immunohistochemistry\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP plus RNA-Co-IP, single lab\",\n      \"pmids\": [\"21725612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"T-STAR (KHDRBS3) functions as a potent splicing repressor of the alternatively spliced segment 4 (AS4) exons from Neurexin1-3 genes and exon 23 of Stxbp5l, identified by transcriptome-wide splicing analysis in T-STAR null mice. T-STAR regulates Neurexin2 AS4 through a UWAA-rich response element immediately downstream of the regulated exon. T-STAR protein concentration in forebrain-derived structures like hippocampus correlates with degree of Nrxn1-3 AS4 splicing repression. In the absence of T-STAR, Sam68 cannot compensate for Nrxn2 AS4 repression despite co-expression.\",\n      \"method\": \"T-STAR null mouse model, transcriptome-wide RNA-seq, minigene transfection splicing assay, RT-PCR, mutational analysis of response element\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — knockout mouse with transcriptome-wide validation plus mechanistic cell assays, multiple orthogonal approaches\",\n      \"pmids\": [\"23637638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"T-STAR and Sam68 STAR proteins dimerize through an unexpected dimerization interface, and this dimerization is crucial for their biological activity in alternative splicing regulation. Crystal/NMR structure established atomic-resolution RNA binding mode; dimer formation increases RNA affinity and enables functional target selection within the transcriptome.\",\n      \"method\": \"Crystal structure, NMR, mutagenesis of dimerization interface, RNA binding assay, splicing reporter assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination plus mutagenesis with functional splicing validation, strong mechanistic study\",\n      \"pmids\": [\"26758068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLM2 (KHDRBS3) controls alternative splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask in addition to Neurexin1-3 AS4. SLM2 levels are maintained by a homeostatic feedback auto-regulation pathway. Loss of SLM2 decreases cortical neural network activity dependent on synaptic connections between SLM2-expressing pyramidal neurons and interneurons, and Slm2-null mice show anxiety and impaired novel object recognition.\",\n      \"method\": \"Slm2-null mouse, RNA-seq splicing analysis, multi-electrode array cortical network activity recording, behavioral testing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knockout mouse with transcriptome-wide splicing analysis plus electrophysiology and behavior, multiple orthogonal methods\",\n      \"pmids\": [\"28009295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The density of shared RNA binding sites (UWAA repeats) around a target exon, rather than different paralog-specific protein-RNA contacts, determines functional specificity between SLM2 (KHDRBS3) and Sam68 on the Neurexin2 AS4 exon. Doubling binding site numbers switched paralog sensitivity. Protein domain-swap experiments identified a region including the STAR domain that differentiates SLM2 and Sam68 splicing activity.\",\n      \"method\": \"Domain-swap mutagenesis, binding site mutagenesis/addition, splicing reporter assay, in vivo cortex RNA binding analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple mutagenesis experiments with functional splicing readouts, mechanistic model validated by domain swaps and site number manipulation\",\n      \"pmids\": [\"27994030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SALL4 upregulates KHDRBS3 expression, and KHDRBS3 in turn modulates CD44 alternative splicing, producing a CD44 variant (CD44v) lacking exons 8 and 9 that promotes cancer stemness (sphere formation, anoikis resistance) in basal-like breast cancer cells.\",\n      \"method\": \"shRNA knockdown, gene overexpression, sphere formation assay, splicing analysis, anoikis resistance assay\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD/OE with defined splicing and stemness phenotypes, single lab\",\n      \"pmids\": [\"29356399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Metadherin interacts with T-STAR (KHDRBS3) and Sam68, demonstrated by yeast two-hybrid and immunoprecipitation. Metadherin influences splice site selection in a dose-dependent manner in CD44v5-luc minigene reporter assays, and T-STAR is significantly overexpressed in prostate cancer tissue compared to benign prostate.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, CD44v5-luc minigene splicing reporter assay, immunohistochemistry\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal interaction assays plus functional splicing reporter, single lab\",\n      \"pmids\": [\"31450747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KHDRBS3 binds to circular RNA cDENND4C and increases its stability in glioma endothelial cells (GECs). The KHDRBS3/cDENND4C/miR-577 regulatory axis controls blood-tumor barrier permeability by modulating tight junction proteins ZO-1, occludin, and claudin-1.\",\n      \"method\": \"RNA immunoprecipitation, RNA stability assay, knockdown/overexpression, tight junction protein Western blot, BTB permeability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-protein interaction validated by RIP plus functional permeability readout, single lab\",\n      \"pmids\": [\"31296839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KHDRBS3 promotes cancer stem cell-like features in gastric cancer organoids by regulating CD44 variant expression, contributing to 5-FU resistance and multi-drug resistance. KHDRBS3 was identified as a splicing regulator of CD44 variants in this cancer context.\",\n      \"method\": \"Organoid culture, 5-FU resistance induction, microarray, siRNA knockdown, CD44 variant splicing analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional organoid system with defined molecular mechanism (CD44 splicing), single lab\",\n      \"pmids\": [\"33046798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLM2 (KHDRBS3) binds to mRNAs encoding sarcomere constituents (MYL2, TNNI3, TNNT2, TPM1/2, TTN) in the human heart. Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and promotes alternative splicing of mRNA regions encoding the PEVK domain and I-band region of titin in dilated cardiomyopathy.\",\n      \"method\": \"RNA-seq in human heart, CLIP-seq/RNA immunoprecipitation, alternative splicing analysis, tissue-enrichment analysis\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq plus binding analysis in human tissue, mechanistic splicing mechanism defined, single lab\",\n      \"pmids\": [\"34273561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KHDRBS3 promotes drug resistance and anchorage-independent growth in colorectal cancer by regulating CD44 variant expression and the Wnt signaling pathway. KHDRBS3-positive cells show efficient tumor formation and lung metastasis in immunodeficient mice.\",\n      \"method\": \"siRNA knockdown, organoid formation, spheroid assay, xenograft mouse model, CD44 splicing analysis, Wnt pathway analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD with in vivo xenograft validation plus defined molecular mechanism, single lab\",\n      \"pmids\": [\"33423358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLM2 (KHDRBS3) knockdown in neurons reduces NRX AS4(-) isoform expression and weakens LRRTM2-induced synapse formation in cerebellar cultures. SLM2 modifies network formation in VIP-positive GABAergic interneurons through regulation of Nrxn splicing.\",\n      \"method\": \"shRNA knockdown in neurons, artificial synapse formation assay, immunostaining, RT-PCR for AS4 isoforms\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with defined synaptic phenotype and splicing readout in neurons\",\n      \"pmids\": [\"34196888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KHDRBS3 interacts with lncRNA MIR17HG in epithelial ovarian cancer cells. Overexpression of KHDRBS3 promotes glycolysis and paclitaxel resistance, effects rescued by MIR17HG overexpression. MIR17HG negatively regulates CLDN6 by binding its 3'UTR, defining a KHDRBS3-MIR17HG-CLDN6 regulatory axis.\",\n      \"method\": \"RNA immunoprecipitation, MTT assay, colony formation, seahorse glycolysis assay, xenograft model, 3'UTR reporter assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-protein interaction plus functional rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"35051418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KHDRBS3 physically binds to YWHAZ mRNA (encoding 14-3-3ζ) as demonstrated by RNA pull-down and RNA immunoprecipitation assays, thereby upregulating 14-3-3ζ protein expression and promoting glycolysis and malignant progression in hepatocellular carcinoma. Silencing 14-3-3ζ reverses the pro-tumorigenic effects of KHDRBS3 overexpression.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, lentiviral knockdown/overexpression, xenograft model, seahorse glycolysis assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein interaction validated by two orthogonal methods plus functional epistasis rescue experiment\",\n      \"pmids\": [\"37848941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KHDRBS3 interacts with circHECTD1 (as shown by RIP and RNA pull-down), enhancing EZH2 mRNA stability and increasing EZH2 protein levels, thereby promoting proliferation and migration of brain vascular smooth muscle cells.\",\n      \"method\": \"RIP, RNA pull-down, qRT-PCR, knockdown/overexpression, CCK8, transwell assays\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA-protein interaction by two methods plus functional downstream validation, single lab\",\n      \"pmids\": [\"36998321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circFOXP1-encoded protein p196 directly binds KHDRBS3 through its D2 domain (shown by Co-IP and RNA pull-down), forming a complex that stabilizes ULK1 mRNA, increasing ULK1 protein levels and activating autophagy to accelerate hepatocellular carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation, RNA pull-down, RIP, in vitro binding assay, loss/gain-of-function, xenograft\",\n      \"journal\": \"International journal of nanomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple interaction assays with defined domain and functional epistasis in vitro and in vivo, single lab\",\n      \"pmids\": [\"40292405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"T-STAR (KHDRBS3) functions as a growth inhibitor; overexpression in SV40-transformed immortalized human fibroblasts strongly reduces colony formation, and deletion of the RNA-binding domain abrogates this growth-inhibitory effect. T-STAR is downregulated in immortalized cells that arose after proliferative crisis.\",\n      \"method\": \"mRNA differential display, overexpression with RNA-binding domain deletion mutant, colony formation assay\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain deletion mutagenesis with functional growth assay, links RNA-binding domain to growth inhibition\",\n      \"pmids\": [\"11714634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse T-STAR (KHDRBS3) directly binds Fabp9 mRNA through sequences in its coding region and 3'UTR, identified from testis extract using SNAAP (isolation of specific nucleic acids associated with proteins). This suggests T-STAR regulates metabolism and expression of Fabp9 in spermatogenesis.\",\n      \"method\": \"SNAAP method (protein-mRNA pulldown from testis extract), direct binding assay\",\n      \"journal\": \"Biochemistry. Biokhimiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown method from tissue extract, limited mechanistic follow-up\",\n      \"pmids\": [\"19916944\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KHDRBS3 (T-STAR/SLM-2/ETOILE) is a STAR-family RNA-binding protein that homodimerizes through a unique dimerization interface to achieve high-affinity, bipartite U(U/A)AA-repeat RNA binding, functioning primarily as a concentration-dependent splicing repressor of Neurexin1-3 AS4 exons and other neuronal pre-mRNAs in the brain; its RNA-binding and splicing activities are negatively regulated by BRK/Sik-mediated tyrosine phosphorylation, while its protein stability is controlled by SIAH1/2 E3 ubiquitin ligase-mediated proteasomal degradation; additionally, KHDRBS3 stabilizes specific mRNAs (YWHAZ, EZH2, ULK1) and circular RNAs through direct binding, linking it to glycolysis, drug resistance, and autophagy regulation in cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KHDRBS3 (T-STAR/SLM-2) is a STAR-family RNA-binding protein that functions as a concentration-dependent splicing repressor in the brain and regulates mRNA stability in diverse tissues. It homodimerizes through an unusual interface to achieve high-affinity binding to bipartite U(U/A)AA-repeat RNA motifs, and this dimerization is essential for its splicing-regulatory activity on key neuronal targets including Neurexin1-3 AS4 exons, where the density of UWAA binding sites determines paralog specificity between KHDRBS3 and SAM68 [PMID:26758068, PMID:27994030, PMID:23637638]. Loss of KHDRBS3 in mice impairs cortical neural network activity, synapse formation, and causes behavioral deficits including anxiety and impaired novel object recognition [PMID:28009295, PMID:34196888]. KHDRBS3 RNA-binding activity is negatively regulated by BRK/Sik tyrosine phosphorylation, and its protein stability is controlled by SIAH1/2 E3 ubiquitin ligase-mediated proteasomal degradation; in cancer contexts, KHDRBS3 regulates CD44 variant splicing to promote stemness and drug resistance, and stabilizes mRNAs encoding YWHAZ, EZH2, and ULK1 [PMID:15471878, PMID:15163637, PMID:33046798, PMID:37848941].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of KHDRBS3 as a STAR-family RNA-binding protein related to SAM68 established its domain architecture and revealed that, unlike SLM-1, it is not a substrate for Src/Fyn kinases and does not engage canonical SH3-domain signaling partners, positioning it as a functionally distinct paralog.\",\n      \"evidence\": \"Biochemical kinase assays, SH2/SH3 pulldowns, yeast two-hybrid with testis cDNA, GFP localization in HeLa cells\",\n      \"pmids\": [\"10077576\", \"10332027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous signaling partners in vivo not defined\", \"Nuclear subcompartment identity (adjacent to nucleolus) not characterized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that KHDRBS3 overexpression inhibits colony formation in an RNA-binding domain–dependent manner linked its RNA-binding activity to a growth-suppressive function, raising the question of which RNA targets mediate this effect.\",\n      \"evidence\": \"Overexpression and RNA-binding domain deletion mutant in SV40-immortalized fibroblasts, colony formation assay\",\n      \"pmids\": [\"11714634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target mRNAs mediating growth inhibition not identified\", \"Mechanism of growth suppression (splicing, stability, or translational) unknown\", \"Not replicated in non-immortalized cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two independent regulatory layers controlling KHDRBS3 activity were established: BRK/Sik tyrosine phosphorylation inhibits its RNA-binding capacity, while SIAH1/2-mediated ubiquitination targets it for proteasomal degradation, with the latter directly modulating its splicing-regulatory output.\",\n      \"evidence\": \"In vitro kinase assays with RNA-binding readout; yeast two-hybrid, Co-IP, minigene splicing assay, proteasome inhibitor rescue\",\n      \"pmids\": [\"15471878\", \"15163637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts triggering BRK-mediated phosphorylation not defined\", \"Whether SIAH regulation operates in brain tissue unclear (rodent SIAH site divergent)\", \"Tyrosine residue(s) targeted by BRK on KHDRBS3 not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"SELEX-based identification of U(U/A)AA bipartite repeat motifs as the high-affinity RNA target defined the cis-regulatory code for KHDRBS3, explaining how it selects its pre-mRNA substrates.\",\n      \"evidence\": \"In vitro SELEX with purified protein, binding affinity validation\",\n      \"pmids\": [\"19457263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo transcriptome-wide binding map not yet established at this point\", \"Structural basis for bipartite recognition not yet resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Knockout mouse transcriptomics established KHDRBS3 as a physiological splicing repressor of Neurexin1-3 AS4 exons and Stxbp5l exon 23 in the brain, with splicing repression correlating with regional protein concentration and SAM68 unable to compensate, resolving the key in vivo targets.\",\n      \"evidence\": \"T-STAR null mouse, transcriptome-wide RNA-seq, minigene splicing assay, RT-PCR, response element mutagenesis\",\n      \"pmids\": [\"23637638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream functional consequences of Neurexin AS4 mis-splicing not yet tested\", \"Whether splicing changes cause behavioral deficits not yet assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Structural determination revealed that KHDRBS3 dimerizes through a non-canonical interface, and disrupting this interface abolishes both high-affinity RNA binding and splicing activity, establishing dimerization as essential for function; concurrently, a second knockout study showed that Slm2 loss reduces cortical network activity and causes anxiety and impaired cognition.\",\n      \"evidence\": \"Crystal structure, NMR, dimerization-interface mutagenesis, splicing reporter; Slm2-null mouse with RNA-seq, multi-electrode array, behavioral testing\",\n      \"pmids\": [\"26758068\", \"28009295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimerization is regulated in vivo unknown\", \"Whether behavioral phenotype maps to specific splice targets (e.g., Neurexins vs. Tomosyn2) not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Domain-swap and binding-site-number experiments demonstrated that paralog specificity between KHDRBS3 and SAM68 on Neurexin2 AS4 is dictated by UWAA site density rather than differential protein-RNA contacts, establishing a quantitative model for target discrimination.\",\n      \"evidence\": \"Domain-swap mutagenesis, binding-site duplication, splicing reporters, in vivo cortex RNA binding\",\n      \"pmids\": [\"27994030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for the STAR-domain region that confers paralog discrimination not resolved\", \"Genome-wide application of the density model not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extension of KHDRBS3 splicing regulation to cancer contexts showed that it controls CD44 variant splicing downstream of SALL4, producing CD44v isoforms that promote stemness and drug resistance in breast, gastric, and colorectal cancers.\",\n      \"evidence\": \"shRNA/siRNA knockdown, overexpression, sphere/organoid formation, CD44 splicing analysis, xenograft models\",\n      \"pmids\": [\"29356399\", \"33046798\", \"33423358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CD44 is a direct KHDRBS3 splicing target (via UWAA motifs) or indirect not biochemically confirmed\", \"Relative contribution of CD44v versus other splice targets to stemness phenotype unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"KHDRBS3 was shown to function in the heart, binding sarcomere-encoding mRNAs and regulating titin alternative splicing and intron retention in dilated cardiomyopathy, and in neurons where its knockdown weakens LRRTM2-induced synapse formation by altering Neurexin AS4 splicing.\",\n      \"evidence\": \"CLIP-seq/RNA-seq in human heart tissue; shRNA knockdown in cerebellar neurons with artificial synapse formation assay\",\n      \"pmids\": [\"34273561\", \"34196888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between KHDRBS3 dysregulation and cardiomyopathy not established\", \"Whether cardiac splicing targets use canonical UWAA motifs not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Beyond splicing, KHDRBS3 was established as an mRNA stability regulator: it binds and stabilizes YWHAZ and EZH2 mRNAs to promote glycolysis and cell proliferation, respectively, and cooperates with circFOXP1-encoded protein p196 to stabilize ULK1 mRNA and activate autophagy in hepatocellular carcinoma.\",\n      \"evidence\": \"RNA pull-down, RIP, mRNA stability assays, functional epistasis with knockdown/overexpression, xenograft models\",\n      \"pmids\": [\"37848941\", \"36998321\", \"40292405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which KHDRBS3 stabilizes mRNA (e.g., competition with decay factors) not defined\", \"Whether mRNA stabilization requires dimerization not tested\", \"Single-lab findings for each target, not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for KHDRBS3's mRNA stabilization function versus its splicing repression function; whether its cardiac splicing targets are causative in cardiomyopathy; and how post-translational modifications (BRK phosphorylation, SIAH ubiquitination) are regulated in physiological and disease contexts in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo CLIP-seq map in brain to comprehensively define direct targets\", \"No structural model for mRNA stabilization mode\", \"Functional relationship between splicing and mRNA stability activities unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 4, 5, 6, 7, 9, 14, 18, 19, 20]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [6, 8, 9, 10, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6, 10, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 6, 7, 8, 9, 10, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 8, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 13, 15, 17, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"T-STAR/SLM-2 homodimer\"\n    ],\n    \"partners\": [\n      \"KHDRBS1\",\n      \"SIAH1\",\n      \"SIAH2\",\n      \"PTK6\",\n      \"RBMY1A1\",\n      \"SERPINB5\",\n      \"MTDH\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}