{"gene":"KHDRBS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2002,"finding":"Sam68 is a direct substrate of ERK (extracellular signal-regulated kinase) and binds exonic splice-regulatory elements of the CD44 v5 exon. ERK phosphorylation of Sam68 stimulates inclusion of the v5 exon in vitro, and forced Sam68 expression enhanced ERK-mediated v5 inclusion; mutation of ERK phosphorylation sites in Sam68 impaired this enhancement. Suppression of Sam68 abolished Ras-pathway-induced alternative splicing of endogenous CD44-v5.","method":"In vitro splicing assay, site-directed mutagenesis of ERK phosphorylation sites, forced expression and RNAi knockdown, RNA binding assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro splicing reconstitution with mutagenesis, combined with RNAi knockdown; multiple orthogonal methods in a single rigorous study","pmids":["12478298"],"is_preprint":false},{"year":2007,"finding":"Sam68 binds the Bcl-x mRNA and promotes inclusion of the proapoptotic Bcl-x(s) splice site. Depletion of Sam68 by RNAi caused accumulation of antiapoptotic Bcl-x(L), while up-regulation increased Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn kinase inverted this effect, favoring Bcl-x(L) splice site selection. Sam68 interacted with hnRNP A1, and depletion of hnRNP A1 or mutations impairing this interaction attenuated Bcl-x(s) splicing. A point mutation in the RNA-binding domain influenced both splicing activity and subnuclear localization.","method":"RNAi knockdown, overexpression, Co-IP, site-directed mutagenesis, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi with defined phenotype, mutagenesis, multiple orthogonal methods; replicated in part by other labs","pmids":["17371836"],"is_preprint":false},{"year":2003,"finding":"PRMT1 (protein arginine N-methyltransferase 1) associates with and methylates Sam68 in vivo, introducing asymmetrical dimethylarginines near the proline motif P3. Deletion of methylation sites or use of methylase inhibitors caused Sam68 accumulation in the cytoplasm. PRMT1-deficient embryonic stem cells also showed cytoplasmic Sam68. Methylase inhibition prevented Sam68-mediated export of unspliced HIV RNAs.","method":"Co-IP, mass spectrometry, methylation-specific antibody, inhibitor treatment, PRMT1-deficient cells, HIV RNA export assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo methylation confirmed by MS and specific antibody, multiple cell models, functional export assay","pmids":["12529443"],"is_preprint":false},{"year":1997,"finding":"Sam68 binds RNA with specificity and high affinity via a KH domain embedded in a larger GSG domain. SELEX identified high-affinity RNA sequences (Kd ~12–40 nM) containing a UAAA motif; mutation of UAAA to UACA abolished binding. The KH domain alone was insufficient; the broader GSG region was required. KH domain mutations analogous to loss-of-function mutations in FMR1 and GLD-1 abolished RNA binding.","method":"In vitro SELEX, filter-binding affinity assays, site-directed mutagenesis of KH domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab but multiple orthogonal methods","pmids":["9341174"],"is_preprint":false},{"year":2000,"finding":"Sik (mouse) / BRK (human) tyrosine kinase associates with Sam68 through its SH3 and SH2 domains, binding the proline-rich P3 region of Sam68. Sik phosphorylates Sam68 in the nucleus and abolishes Sam68's ability to bind RNA and act as a cellular Rev homologue (facilitating intron-containing RNA export).","method":"Co-IP, domain-deletion mapping, in vivo phosphorylation, RNA-binding assay, Rev-function assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, functional RNA-binding assay, replicated with both mouse Sik and human BRK","pmids":["10913193"],"is_preprint":false},{"year":1999,"finding":"The Src family kinase Fyn mediates tyrosine phosphorylation of Sam68, which negatively regulates Sam68 association with the nuclear splicing-associated factor YT521-B. Overexpression of Fyn dissolves nuclear dots containing YT521-B and Sam68. Fyn-phosphorylated Sam68 no longer colocalizes with YT521-B.","method":"Co-IP, immunofluorescence colocalization, Fyn overexpression, deletion analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, immunofluorescence, kinase overexpression; single lab","pmids":["10564280"],"is_preprint":false},{"year":1997,"finding":"Sam68 associates with Fyn and Lck (Src family kinases) in T cells via their SH2 and SH3 domains. CD3 cross-linking induces tyrosine phosphorylation of Sam68, and Sam68 is coimmunoprecipitated with PLCγ1, PI3K p85, Grb2, SHP-1, Cbl, and Jak3, indicating an adaptor function downstream of TCR-coupled kinases.","method":"Co-IP, purification and microsequencing, T cell stimulation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple signaling partners, single lab, functional TCR stimulation context","pmids":["9045636"],"is_preprint":false},{"year":2005,"finding":"BRK phosphorylates Sam68 on all three tyrosines in its nuclear localization signal (NLS), including the principal site Y440. This phosphorylation induces relocalization of Sam68 from the nucleus to non-nuclear compartments. EGF treatment in breast cancer cells promotes Sam68 phosphorylation at Y440 in a BRK-dependent manner (reversed by BRK siRNA). Sam68 overexpression suppresses BRK-induced cell proliferation.","method":"Phospho-specific antibodies, indirect immunofluorescence, BRK siRNA, EGF stimulation, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-specific antibodies mapped individual tyrosines, siRNA validation, EGF/BRK pathway, multiple methods in one study","pmids":["16179349"],"is_preprint":false},{"year":2009,"finding":"Sam68 is required for polysomal recruitment of specific mRNAs in male germ cells and for accumulation of the corresponding proteins. Sam68(-/-) male mice are infertile with defects in spermatogenesis. Sam68 associates with polyadenylated mRNAs in the cytoplasm during meiotic divisions and in round spermatids, interacting with the translational machinery.","method":"Sam68 knockout mice, polysome fractionation, RNA immunoprecipitation, heterologous translation system","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined fertility phenotype, polysome fractionation, RIP; multiple orthogonal methods","pmids":["19380878"],"is_preprint":false},{"year":2009,"finding":"Sam68 is required for alternative splicing of a set of exons during neurogenesis. Sam68 represses an exon in epsilon sarcoglycan (Sgce) through RNA-binding activity and intronic RNA elements. Sam68 protein is upregulated upon neuronal differentiation of P19 cells; Sam68 knockdown prevents neuronal differentiation of both P19 cells and primary neural progenitor cells, while overexpression promotes it.","method":"RNAi knockdown, splicing-sensitive microarrays, minigene assays, mutagenesis, shRNA in primary cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide splicing profiling plus minigene mutagenesis, validated in primary neural progenitor cells; multiple orthogonal methods","pmids":["18936165"],"is_preprint":false},{"year":2012,"finding":"Sam68 regulates alternative splicing of the mTOR transcript during adipogenesis by binding intronic splice elements in mTOR intron 5 required for 5' splice site usage. Sam68(-/-) adipocytes retain intron 5, introducing a premature stop codon that destabilizes mTOR mRNA, reducing mTOR levels, S6 and Akt phosphorylation, and adipogenic differentiation. Exogenous full-length mTOR rescues the adipogenesis defect.","method":"Sam68 KO mice, genome-wide exon profiling, CLIP, minigene assays, rescue with mTOR cDNA","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP binding, KO phenotype, rescue experiment, genome-wide profiling; multiple orthogonal methods in one rigorous study","pmids":["22424772"],"is_preprint":false},{"year":2009,"finding":"Sam68 enhances alternative splicing of cyclin D1b by binding the proximal region of CCND1 intron 4; this binding inversely correlates with recruitment of spliceosomal component U1-70K. Sam68 is recruited to the CCND1 gene (shown by ChIP) and binds cyclin D1 mRNA (shown by RIP). Phosphorylation of Sam68 by signal transduction pathways modulates its affinity for CCND1 intron 4 and splicing activity.","method":"ChIP, RNA co-IP, RNAi, overexpression, minigene reporter assay, phospho-mutant analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + RIP + minigene + RNAi; multiple orthogonal methods, functional mechanistic chain established","pmids":["20028857"],"is_preprint":false},{"year":2011,"finding":"Sam68 acts as a signaling adaptor at the TNF receptor complex I, where it facilitates RIP recruitment, ubiquitylation of RIP, cIAP1 recruitment, and TRAF2 maintenance, enabling TAK1-IKK kinase complex activation and NF-κB signaling. Sam68 is also part of the cytoplasmic caspase-8-FADD complex II; RIP recruitment and caspase activation are absent in Sam68 KO cells.","method":"Sam68 KO cells, Co-IP, ubiquitylation assays, kinase complex activation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined biochemical phenotypes, multiple complex components measured, two distinct complexes characterized","pmids":["21620750"],"is_preprint":false},{"year":2004,"finding":"Sam68 is acetylated in vivo in human mammary epithelial cell lines, with highest acetylation in tumorigenic breast cancer lines. The acetyltransferase CBP acetylates Sam68 in vitro and enhances its binding to poly(U) RNA. Sam68 acetylation positively correlates with its RNA-binding activity.","method":"In vivo acetylation detection, in vitro acetyltransferase assay with CBP, RNA-binding assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay plus in vivo correlation; single lab, two methods","pmids":["15021911"],"is_preprint":false},{"year":2006,"finding":"Sam68 is modified by SUMO, with PIAS1 acting as the E3 SUMO ligase. Lysine 96 is the major SUMO acceptor site. Mutation of K96 to arginine enhanced Sam68-induced apoptosis but inhibited its transcriptional repression of cyclin D1. A SUMO-1-Sam68 fusion inhibited apoptosis but strongly repressed cyclin D1 expression.","method":"In vivo sumoylation assay, PIAS1 co-expression, K96R mutagenesis, SUMO fusion protein, reporter assay, apoptosis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-identified by mutagenesis, E3 ligase identified, functional consequences of both gain and loss of sumoylation; single lab","pmids":["16568089"],"is_preprint":false},{"year":2007,"finding":"Arginine methylation of Sam68's RG-repeat regions by PRMT1 markedly reduces poly(U) RNA binding ability in vitro. The RG repeats of Sam68 directly bind poly(U); arginine methylation of these repeats abrogates binding. Overexpression of PRMT1 in cells increases Sam68 arginine methylation and decreases its poly(U) binding.","method":"In vitro methylation and RNA-binding assays, PRMT1 overexpression, methylation-binding correlation","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with PRMT1 plus cell-based validation; single lab, two orthogonal methods","pmids":["17764653"],"is_preprint":false},{"year":2001,"finding":"Sam68 functions as a docking protein linking p120GAP and PI3K in insulin receptor signaling. Insulin stimulation promotes Sam68 relocalization from nucleus to cytoplasm; tyrosine-phosphorylated Sam68 co-precipitates with p85 PI3K, IRS-1, and IR. Sam68 also associates with p120GAP after tyrosine phosphorylation by the IR, with this association mediated by GAP's SH2 domains. PI3K activity is increased in both anti-Sam68 and anti-GAP immunoprecipitates upon insulin stimulation.","method":"Co-immunoprecipitation, subcellular fractionation, PI3K activity assay, insulin receptor stimulation","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with multiple partners, PI3K activity assay, single lab","pmids":["11604231"],"is_preprint":false},{"year":2005,"finding":"Sam68(-/-) mice exhibit motor coordination defects: Sam68-null mice show more hindpaw faults in beam walking and fall from rotorod at lower speeds. Sam68 is highly expressed in the cerebellum, implicating it in motor coordination circuitry.","method":"Sam68 KO mice, behavioral assays (beam walking, rotorod, balance test)","journal":"Behavioural brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral phenotype; single lab, behavioral readout","pmids":["18325609"],"is_preprint":false},{"year":2005,"finding":"Sam68(-/-) mice show age-related protection from bone loss. Sam68-null bone marrow stromal cells have a differentiation advantage toward osteoblasts, and Sam68 knockdown in C3H10T1/2 cells promotes osteocalcin expression after BMP-2 induction. Sam68(-/-) MEFs show impaired adipocyte differentiation. Thus Sam68 is a positive regulator of adipocyte differentiation and negative regulator of osteoblast differentiation.","method":"Sam68 KO mice, shRNA knockdown, differentiation assays, histology","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype plus shRNA in cell culture; single lab, multiple cell types tested","pmids":["16362077"],"is_preprint":false},{"year":2005,"finding":"Sam68 translocates to the cytoplasm and associates with polysomes in mouse pachytene spermatocytes during meiotic divisions. This translocation correlates with serine/threonine phosphorylation and is blocked by ERK1/2 and cyclin B-cdc2 inhibitors. Both kinases associate with Sam68 in pachytene spermatocytes and phosphorylate regions flanking the RNA-binding motif.","method":"Subcellular fractionation, polysome sedimentation, kinase inhibitors, Co-IP with ERK and cyclin B-cdc2","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus polysome profiling, kinase association by Co-IP; single lab, multiple methods","pmids":["16221888"],"is_preprint":false},{"year":2004,"finding":"In hippocampal neurons, Sam68 undergoes activity-responsive translocation from nucleus to dendrites following KCl depolarization. Translocation requires calcium channel activity (blocked by nimodipine), is microtubule-dependent, and is partially blocked by CRM1 inhibitor leptomycin B. A fraction of dendritic GFP-Sam68 colocalizes with RNA clusters. The Sam68 N-terminus is required for nuclear retention.","method":"GFP-Sam68 live-cell imaging, calcium channel inhibitor, microtubule inhibitor, leptomycin B, RNA staining","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with defined pharmacological manipulations, functional domain tested; single lab","pmids":["14996936"],"is_preprint":false},{"year":2013,"finding":"Sam68 knockdown in hippocampal neurons decreases the amount of β-actin (actb) mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished synaptic β-actin protein. Genetic knockout or acute knockdown in vivo results in fewer excitatory synapses. Disruption of Sam68-actb mRNA binding phenocopies Sam68 knockdown.","method":"Sam68 KO mice, RNAi knockdown, synaptic polysome fractionation, spine morphology analysis, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice plus acute knockdown in vivo, synaptic polysome fractionation, morphological and electrophysiological readouts; multiple orthogonal methods","pmids":["23382180"],"is_preprint":false},{"year":1999,"finding":"Sam68's proline-rich motifs function as specific SH3 domain binding sites; the Src SH3 domain directs binding to an N-terminal proline motif of Sam68 (residues 38–45), and this SH3-mediated docking facilitates phosphorylation of Sam68 tyrosines by the Src kinase domain. Mutation of the Src SH3 binding site on Sam68, or addition of corresponding peptides, inhibits Src phosphorylation of Sam68 in vitro.","method":"In vitro SH3 domain binding, synthetic peptide competition, site-directed mutagenesis, in vitro kinase assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase and binding assays with mutagenesis and peptide competition; single lab","pmids":["10467411"],"is_preprint":false},{"year":2002,"finding":"Sam68 physically interacts with CBP through the CBP CH3 domain, in part through a conserved FXD/EXXXL motif. Sam68 and CBP interact in vivo and colocalize in nuclear sub-domains. Sam68 has transcriptional repression activity independent of its RNA-binding activity.","method":"Co-IP, domain mapping, transcriptional reporter assay, immunofluorescence colocalization","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mapping, functional reporter; single lab, two methods","pmids":["12496368"],"is_preprint":false},{"year":2009,"finding":"Sam68-deficient cells exhibit sustained Src activity after cell attachment, leading to constitutive tyrosine phosphorylation and activation of p190RhoGAP and its association with p120rasGAP, and deregulated RhoA and Rac1 activity. Sam68 localizes near the plasma membrane after cell attachment (TIRF microscopy), coinciding with phosphorylation of its C-terminal tyrosines and association with Csk. Loss of Sam68 impairs cell polarity and migration.","method":"Sam68 KO MEFs, TIRF microscopy, Co-IP, phospho-specific antibodies, Rho GTPase activity assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — TIRF localization with function, KO with defined signaling phenotype (multiple GTPases), Co-IP; multiple orthogonal methods","pmids":["19139276"],"is_preprint":false},{"year":2009,"finding":"Sam68 exists in equilibrium between a large (>1 MDa) ribonucleoprotein complex (~40 proteins, RNA-dependent) and a smaller (200–450 kDa) complex in HeLa cells. EGF or PMA treatment dissociates Sam68 from the large complex, shifting it to the smaller complex. The appearance of Sam68 in the small complex correlates with its ability to promote CD44 alternative splicing and cell migration.","method":"Immunoprecipitation-mass spectrometry, size-exclusion chromatography, RNase treatment, EGF/PMA stimulation, splicing assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex characterization, RNase sensitivity, EGF stimulation with functional readout; single lab","pmids":["19762470"],"is_preprint":false},{"year":2016,"finding":"Sam68 deficiency abolishes DNA damage-stimulated poly(ADP-ribose) (PAR) production. Sam68 is recruited to DNA lesions and directly interacts with PARP1; this interaction is required for PARP1-mediated PAR production. Sam68-deleted cells and mice are hypersensitive to DNA-damaging agents. Sam68 is also required for NF-κB transactivation of anti-apoptotic genes downstream of PAR production.","method":"Sam68 KO cells and mice, biochemical fractionation, Co-IP, PAR production assays, DNA damage sensitivity assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells and in vivo KO mice, Co-IP with PARP1, PAR assay, DNA damage phenotype; multiple orthogonal methods","pmids":["27635653"],"is_preprint":false},{"year":2016,"finding":"Sam68 is required for genotoxic stress-initiated NF-κB activation through PAR-dependent signaling in colon cancer. Sam68 deletion abolishes DNA damage-stimulated PAR production and PAR-dependent NF-κB transactivation of anti-apoptotic genes; Sam68-deleted cells are hypersensitive to genotoxic stress. Sam68 upregulation in colon cancer coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription.","method":"Sam68 KO cells and mice, genotoxic stress assays, PAR production assays, tumor burden assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus tumor model; overlap with PMID 27635653 for the PAR/PARP1 mechanism","pmids":["27458801"],"is_preprint":false},{"year":2016,"finding":"Sam68 promotes self-renewal of neural progenitor cells (NPCs) by binding an intronic polyadenylation site in Aldh1a3 pre-mRNA, preventing premature transcript termination and favoring expression of functional ALDH1A3 enzyme. Khdrbs1 KO NPCs show lower ALDH1A3 expression and activity, reduced glycolysis, and depleted embryonic NPC pool.","method":"Khdrbs1 KO mice, 3'-end processing assays, CLIP, minigene polyadenylation assay, metabolic assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined NPC phenotype, CLIP showing direct RNA binding, 3'-end processing assay; multiple orthogonal methods","pmids":["27845622"],"is_preprint":false},{"year":2016,"finding":"Sam68 acts as a transcriptional coactivator of p53 in response to DNA damage. Sam68 physically interacts with p53 in an RNA-dependent manner; this interaction is essential for coactivator function. Both Sam68 and p53 are recruited to promoters of p53-responsive genes. Sam68 depletion causes defects in DNA damage-induced cell cycle arrest and apoptosis mediated by p53.","method":"CRISPR/Cas9 KO cell lines (isogenic p53 WT vs KO), Co-IP, ChIP, reporter assays, cell cycle and apoptosis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR isogenic cell lines, Co-IP, ChIP, functional gene expression; multiple orthogonal methods in single study","pmids":["27365047"],"is_preprint":false},{"year":2018,"finding":"SAM68 (KHDRBS1) is required for NORAD lncRNA function in antagonizing Pumilio. SAM68 interacts with NORAD, and this interaction is required for NORAD-mediated antagonism of Pumilio repressors; the interaction provides a paradigm for how repeated elements in a lncRNA facilitate function through an RNA-binding protein.","method":"Co-IP/RNA-IP, functional NORAD assays, SAM68 knockdown","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-protein interaction with functional consequence; single lab, two methods","pmids":["29386330"],"is_preprint":false},{"year":2019,"finding":"Sam68 binds Alu-rich intronic sequences in the SMN pre-mRNA (shown by CLIP), promoting widespread alternative circular RNA (circRNA) biogenesis. Mutagenesis of Sam68 binding sites in SMN IRAlus and Sam68 silencing reduce circRNA formation in vitro and in vivo.","method":"CLIP, mutagenesis, Sam68 silencing, circRNA detection assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP plus mutagenesis plus silencing; single lab, three methods","pmids":["31777926"],"is_preprint":false},{"year":2019,"finding":"Sam68 interacts with U1A (core component of U1 snRNP) through its C-terminal tyrosine-rich (YY) domain, and this interaction promotes U1 snRNP recruitment to the 5' splice site of mTOR intron 5. Deletion of the U1A-SAM68 interaction domain or mutation of SAM68 binding sites in mTOR intron 5 abrogates U1A recruitment and 5' splice site recognition, causing premature termination and polyadenylation.","method":"Co-IP, domain mapping, minigene assays, mutagenesis, U1A knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapped interaction, mutagenesis of both protein and RNA, functional splicing assay; multiple orthogonal methods","pmids":["30767021"],"is_preprint":false},{"year":2019,"finding":"Sam68 cooperates with U1snRNP to regulate alternative last exon (ALE) usage during male meiosis. Loss of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites. Sam68 physically associates with U1snRNP, and U1snRNP recruitment to Sam68-regulated ALEs is impaired in Sam68(-/-) germ cells.","method":"Sam68 KO mice, RNA-seq, Co-IP of Sam68 and U1snRNP, splicing/polyadenylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with genome-wide analysis, Co-IP, functional polyadenylation assay; multiple orthogonal methods","pmids":["30865884"],"is_preprint":false},{"year":2015,"finding":"Sam68 regulates isoform expression of S6 kinase (Rps6kb1) during adipogenesis. Sam68 binds RNA encoded by Rps6kb1 intron 6 (shown by CLIP) and prevents SRSF1-mediated alternative splicing that generates inhibitory p31S6K1. Sam68-deficient adipocytes express p31S6K1, inhibiting adipogenesis; depletion of p31S6K1 partially restores adipogenesis.","method":"CLIP, minigene assays, siRNA, Sam68 KO adipocytes, p31S6K1 overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP plus minigene plus rescue experiment; multiple orthogonal methods","pmids":["25776557"],"is_preprint":false},{"year":2015,"finding":"SMAR1 negatively regulates Sam68's splicing activity through HDAC6-mediated deacetylation of Sam68. SMAR1 maintains Sam68 in a deacetylated (less active) state via HDAC6. ERK-mediated phosphorylation of SMAR1 (at T345 and T360) localizes SMAR1 to the cytoplasm, releases the inhibitory SMAR1-HDAC6-Sam68 complex, and facilitates Sam68 acetylation and alternative splicing of CD44 variant exons.","method":"Co-IP, knockdown, HDAC6 inhibition, phosphomimetic mutagenesis, CD44 minigene reporter, in vivo tail-vein injection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying ternary complex, mutagenesis, functional splicing readout, in vivo metastasis model; multiple methods","pmids":["26080397"],"is_preprint":false},{"year":2016,"finding":"The methyltransferase Set7/9 (KMT7) co-immunoprecipitates with Sam68 and methylates Sam68 on K208. Knockout of Set7/9 decreases Sam68 protein levels in cells, resulting in altered cell cycle and apoptosis regulation. The RG-rich domain of Sam68 mediates the interaction with Set7/9's MORN domain.","method":"Pull-down, Co-IP, in vitro methylation assay, Set7/9 KO cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro methylation with site identification, KO functional consequence; single lab","pmids":["32178870"],"is_preprint":false},{"year":2021,"finding":"Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination, thereby stabilizing CRTC2 protein levels. Sam68 promotes hepatic gluconeogenesis: global and hepatic Sam68 deletion significantly reduces blood glucose and glucagon-induced gluconeogenic gene expression. Sam68 truncation mutants lacking C-terminal (Sam68ΔC) or N-terminal (Sam68ΔN) domains respectively fail to bind CRTC2 or to stabilize CRTC2 protein.","method":"Sam68 global and hepatocyte-specific KO mice, Co-IP, ubiquitination assay, truncation mutagenesis, glucose tolerance tests","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO in vivo, Co-IP, ubiquitination assay, domain-defined mutagenesis; multiple orthogonal methods","pmids":["34099657"],"is_preprint":false},{"year":2021,"finding":"SAM68 promotes aerobic glycolysis and lung adenocarcinoma tumorigenesis by mediating alternative splicing of pyruvate kinase (PKM) pre-mRNA to favor PKM2 over PKM1. Mechanistically, SAM68 binds the 351–443 aa region to the RGG motif of hnRNP A1, enhancing hnRNP A1 binding to PKM exon 9 and promoting PKM2 formation.","method":"RNA-IP, Western blot, minigene splicing assays, domain mapping, in vitro and in vivo tumor models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, domain mapping, functional splicing and metabolic readout; single lab","pmids":["33537092"],"is_preprint":false},{"year":2008,"finding":"Sam68 interacts with the androgen receptor (AR) in vivo in LNCaP prostate cancer cells and is dynamically recruited to androgen response elements within the PSA gene promoter (by ChIP). Wild-type Sam68 and an RNA-binding-impaired mutant (V229F) both function as ligand-dependent AR co-activators in reporter assays. Conversely, Sam68-mediated splicing of a Sam68-responsive exon under androgen-responsive promoter control is strongly repressed by AR/androgens and reversed by Sam68 expression; V229F Sam68 enhances this splicing repression, demonstrating separable transcriptional co-activation and splicing functions.","method":"Co-IP, ChIP, luciferase reporter assay, minigene splicing assay, V229F mutagenesis","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, minigene with mutagenesis; single lab, multiple methods","pmids":["18273831"],"is_preprint":false},{"year":2015,"finding":"Sam68 controls expression of AR-V7 splice variant in an RNA-binding-dependent manner using a minigene reporter for exon 3b inclusion. Sam68 directly interacts with AR-V7 protein through a shared domain with full-length AR. Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner and controls expression of the AR-V7 target gene UBE2C.","method":"Minigene reporter assay, Co-IP, luciferase reporter assay, RNAi knockdown, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene, Co-IP, luciferase reporter; single lab, multiple methods","pmids":["26310125"],"is_preprint":false},{"year":2016,"finding":"Sam68 binds Alu-rich intronic sequences in the SMN pre-mRNA and promotes circRNA biogenesis. The crystal/NMR structure of T-STAR and Sam68 in complex with RNA established that STAR proteins bind RNA as homodimers through an unexpected dimerization interface distinct from other STAR family members; this dimerization interface is crucial for splicing regulatory activity, and increased RNA affinity through dimer formation enables target selection within the transcriptome.","method":"X-ray crystallography, NMR, RNA-binding assays, splicing minigene assays with dimerization-interface mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution structure plus mutagenesis of the dimerization interface plus functional splicing assay; multiple orthogonal methods in one study","pmids":["26758068"],"is_preprint":false},{"year":2009,"finding":"Sam68 binds bipartite RNA motifs consisting of direct U(U/A)AA repeats, requiring both half-sites for high-affinity binding; this bipartite requirement was demonstrated by SELEX and confirmed for Sam68, SLM-2, QKI, and GLD-1.","method":"SELEX, filter-binding assays, mutant RNA probes","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro SELEX plus binding assays; single lab, two methods","pmids":["19457263"],"is_preprint":false},{"year":2001,"finding":"Sam68 contains two arginine-glycine (RG)-rich regions that confer nonspecific RNA binding to its GSG domain. A minimal 26-aa RG-rich sequence from Sam68 is sufficient to confer homopolymeric RNA binding to the GSG domain of QKI-7 (a different STAR protein) and to enable it to functionally substitute for HIV-1 Rev in RNA nuclear export.","method":"Domain-deletion analysis, chimeric protein construction, RNA-binding assay, HIV Rev reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — chimeric protein reconstitution with functional Rev assay; single lab","pmids":["11395494"],"is_preprint":false},{"year":2002,"finding":"Sam68 enhances cytoplasmic utilization (translation) of CTE-containing intron-containing mRNA by ~60–70-fold at the protein level with only modest effect on cytoplasmic RNA levels, demonstrating a post-export translational enhancement function. An RNA-binding-deficient Sam68 mutant (G178E) does not enhance CTE function. Activated Sik/BRK (which hyperphosphorylates Sam68) inhibits this activity in a dose-dependent manner.","method":"Reporter gene expression assay, RNA analysis, Sik/BRK co-expression, G178E point mutant","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with mutagenesis and kinase regulation; single lab","pmids":["12482964"],"is_preprint":false},{"year":2010,"finding":"Sam68 is sequestered by CGG repeat-expanded RNA in FXTAS, losing its splicing-regulatory function. Sam68 is recruited first among RNA-binding proteins to CGG repeat aggregates. Regulation of Sam68 tyrosine phosphorylation modulates its localization within CGG aggregates. Tautomycin prevents both Sam68 and CGG RNA aggregate formation.","method":"Fluorescence imaging of intranuclear aggregates, splicing assays in patient cells, phosphorylation modulation experiments, tautomycin treatment","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of Sam68 sequestration, patient-derived cells, pharmacological rescue; single lab","pmids":["20186122"],"is_preprint":false},{"year":2012,"finding":"FMDV 3C protease cleaves Sam68 at its C-terminus (which contains the NLS), causing redistribution of Sam68 to the cytoplasm. Sam68 interacts with the FMDV IRES within the 5' non-translated region and its knockdown decreases FMDV IRES-driven translation activity and reduces viral titers by 1000-fold.","method":"siRNA knockdown, IRES reporter assay, protease cleavage assay, viral titer measurement","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protease cleavage assay, functional IRES reporter, siRNA with viral titer; single lab","pmids":["22280896"],"is_preprint":false},{"year":2019,"finding":"c-MYC directly binds to and activates the Sam68 (KHDRBS1) gene promoter, and also affects productive splicing of the nascent Sam68 transcript by modulating transcriptional elongation rate. Sam68 and c-MYC levels positively correlate in prostate cancer patients. c-MYC-dependent Sam68 expression is under control of external cues (androgens, mitogens).","method":"ChIP, promoter reporter assay, transcriptional elongation assay, patient data correlation, androgen/mitogen stimulation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus elongation assay; single lab","pmids":["31066450"],"is_preprint":false},{"year":2009,"finding":"Sam68 cytoplasmic mutants suppress HIV-1 Nef expression by inducing stress granules and sequestering nef mRNA in those granules. Domain aa269–321 and the KH domain are required for stress granule induction. Nef suppression is specific, conferred by Sam68 binding to nef mRNA 3'UTR.","method":"Sam68 cytoplasmic mutant expression, stress granule imaging, mRNA localization assay, domain deletion","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping, functional Nef suppression, RNA localization assay; single lab","pmids":["19150430"],"is_preprint":false},{"year":2009,"finding":"Sam68 is recruited to cytoplasmic stress granules under oxidative stress by complexing with the core stress granule component TIA-1. Both domain aa269–321 and the KH domain are essential for Sam68 stress granule recruitment. Sam68 knockdown has no effect on stress granule assembly, showing Sam68 is not a constitutive SG component.","method":"Immunofluorescence, Co-IP with TIA-1, domain deletion mutants, Sam68 knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus imaging plus domain mapping; single lab","pmids":["19615357"],"is_preprint":false},{"year":2002,"finding":"Sam68 forms a complex with the HIV-1 Rev protein; mutagenesis identified residues 321–410 of Sam68 as directly involved in Rev binding, and Rev double mutation L78D/E79L eliminated binding to Sam68. Sam68 expression promotes Rev nuclear export; down-modulation of Sam68 causes nuclear retention and colocalization of Rev and CRM1, demonstrating involvement in CRM1-mediated Rev nuclear export.","method":"Mutagenesis, Co-IP, antisense knockdown, digital fluorescence microscopy, Rev-dependent reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with mutagenesis, Rev localization imaging, knockdown with functional assay; single lab","pmids":["11932418"],"is_preprint":false}],"current_model":"KHDRBS1/Sam68 is a multifunctional STAR-family KH-domain RNA-binding protein that binds bipartite U(U/A)AA RNA motifs as a homodimer (structurally established), regulates alternative pre-mRNA splicing in response to extracellular signals (ERK/Ras, Fyn, BRK phosphorylation), controls 3'-end processing, mRNA translation, and nuclear export of specific transcripts, and functions as a signaling adaptor linking receptor tyrosine kinases to small GTPases, NF-κB, PARP1/PAR-dependent DNA-damage responses, TNF receptor complexes, and the p53 transcriptional program; its activity is post-translationally regulated by phosphorylation (Src, Fyn, ERK, BRK), arginine methylation by PRMT1 (reducing RNA binding), acetylation by CBP (enhancing RNA binding), sumoylation by PIAS1 (modulating apoptosis vs. cyclin D1 repression), and methylation by Set7/9 on K208, with subcellular localization tightly coupled to these modifications."},"narrative":{"mechanistic_narrative":"KHDRBS1 (Sam68) is a STAR-family KH-domain RNA-binding protein that couples extracellular and genotoxic signaling to post-transcriptional gene regulation and serves as a multifunctional signaling adaptor [PMID:12478298, PMID:26758068]. Its RNA recognition rests on a KH domain embedded in a larger GSG region that binds bipartite U(U/A)AA motifs, and structural work showed STAR proteins engage RNA as homodimers through a dimerization interface essential for splicing activity [PMID:9341174, PMID:19457263, PMID:26758068]. A dominant function is signal-responsive alternative splicing: ERK phosphorylation of Sam68 drives CD44 variable-exon inclusion, while it governs Bcl-x splice-site choice, neuronal Sgce exons, cyclin D1b, mTOR, and S6 kinase isoform selection by binding intronic regulatory elements [PMID:12478298, PMID:17371836, PMID:18936165, PMID:20028857, PMID:22424772, PMID:25776557]. For several targets Sam68 functions through partner RNA-binding proteins and the spliceosome, recruiting U1 snRNP via its C-terminal YY domain to control 5' splice-site usage and alternative last-exon/3'-end processing, and cooperating with hnRNP A1 [PMID:30767021, PMID:30865884, PMID:17371836, PMID:33537092]. Beyond splicing, Sam68 promotes intronic polyadenylation read-through, circRNA biogenesis, cytoplasmic mRNA translation and polysomal recruitment, and nuclear export of intron-containing transcripts [PMID:27845622, PMID:31777926, PMID:19380878, PMID:12482964]. As a signaling adaptor it links Src-family and receptor tyrosine kinases to small GTPases, PI3K, the TNF-receptor/NF-κB axis, and PARP1/PAR-dependent DNA-damage responses, and it acts as an RNA-dependent transcriptional coactivator of p53 [PMID:19139276, PMID:11604231, PMID:21620750, PMID:27635653, PMID:27365047]. Sam68 activity and localization are controlled by an extensive post-translational code: tyrosine phosphorylation by Fyn, BRK/Sik, and Src; arginine methylation by PRMT1 (reducing RNA binding); acetylation by CBP (enhancing RNA binding); sumoylation by PIAS1; and methylation by Set7/9 [PMID:10564280, PMID:16179349, PMID:10467411, PMID:12529443, PMID:17764653, PMID:15021911, PMID:16568089, PMID:32178870]. In vivo, Sam68 knockout produces male infertility, motor-coordination deficits, altered bone/fat differentiation, defective dendritic spine formation, and impaired hepatic gluconeogenesis, reflecting its tissue-specific RNA targets [PMID:19380878, PMID:18325609, PMID:16362077, PMID:23382180, PMID:34099657].","teleology":[{"year":1997,"claim":"Established that Sam68 is a sequence-specific RNA-binding protein, defining the molecular basis for its post-transcriptional functions.","evidence":"In vitro SELEX and filter-binding with KH-domain mutagenesis identifying a UAAA-containing high-affinity motif","pmids":["9341174"],"confidence":"High","gaps":["Did not establish in vivo targets","GSG-region requirement defined but structural basis unknown"]},{"year":1997,"claim":"Connected Sam68 to receptor signaling by showing it is a phosphorylation substrate and adaptor downstream of T-cell receptor-coupled Src-family kinases.","evidence":"Co-IP and microsequencing in CD3-stimulated T cells linking Sam68 to Fyn, Lck, PLCγ1, PI3K p85, Grb2, SHP-1, Cbl, Jak3","pmids":["9045636"],"confidence":"Medium","gaps":["Functional consequence of each interaction not dissected","Single lab Co-IP"]},{"year":2000,"claim":"Showed tyrosine phosphorylation directly toggles Sam68 RNA-binding and nuclear-export functions, linking kinase signaling to its RNA activity.","evidence":"Sik/BRK domain-mapping, in vivo phosphorylation, RNA-binding and Rev-function assays","pmids":["10913193"],"confidence":"High","gaps":["Individual tyrosine sites not mapped in this study","Endogenous RNA targets affected not identified"]},{"year":2002,"claim":"Demonstrated that Sam68 is an effector of the Ras/ERK pathway in alternative splicing, establishing signal-regulated splicing as a core function.","evidence":"In vitro splicing reconstitution, ERK phosphosite mutagenesis, RNAi knockdown on CD44 v5","pmids":["12478298"],"confidence":"High","gaps":["Mechanism of exon recognition at the spliceosome not resolved","Generalization beyond CD44 not shown here"]},{"year":2003,"claim":"Identified arginine methylation by PRMT1 as a determinant of Sam68 localization and export activity, adding a second PTM layer.","evidence":"Co-IP, mass spectrometry, PRMT1-deficient cells, HIV RNA export assay","pmids":["12529443"],"confidence":"High","gaps":["Quantitative coupling of methylation to RNA affinity addressed later","Interplay with phosphorylation not resolved"]},{"year":2004,"claim":"Showed CBP acetylation enhances Sam68 RNA binding, providing a positive-regulatory PTM relevant to breast cancer.","evidence":"In vivo acetylation detection, in vitro CBP acetyltransferase and poly(U)-binding assays","pmids":["15021911"],"confidence":"Medium","gaps":["Acetylated lysine sites not mapped","Single lab correlation"]},{"year":2005,"claim":"Mapped the specific NLS tyrosines whose BRK phosphorylation drives nuclear export, linking EGF signaling to Sam68 relocalization.","evidence":"Phospho-specific antibodies, immunofluorescence, BRK siRNA, EGF stimulation in breast cancer cells","pmids":["16179349"],"confidence":"High","gaps":["Cytoplasmic functions of exported Sam68 not fully defined here"]},{"year":2006,"claim":"Established sumoylation by PIAS1 at K96 as a switch between apoptosis promotion and cyclin D1 repression.","evidence":"In vivo sumoylation assay, K96R mutagenesis, SUMO-Sam68 fusion, apoptosis and reporter assays","pmids":["16568089"],"confidence":"Medium","gaps":["Mechanistic basis of the apoptosis/repression switch unresolved","Single lab"]},{"year":2007,"claim":"Extended signal-regulated splicing to apoptotic decisions, showing Fyn phosphorylation inverts Sam68 control of Bcl-x splicing.","evidence":"RNAi, overexpression, reciprocal Co-IP with hnRNP A1, mutagenesis","pmids":["17371836"],"confidence":"High","gaps":["Stoichiometry/cooperation with hnRNP A1 not fully defined"]},{"year":2009,"claim":"Defined Sam68 as a master regulator of developmental and cell-fate splicing programs across neurogenesis, with parallel adaptor roles at the plasma membrane controlling GTPase signaling and migration.","evidence":"Splicing-sensitive microarrays and minigenes (Sgce); Sam68 KO MEFs, TIRF, Rho/Rac assays; complex equilibrium MS/SEC; KO mouse spermatogenesis polysome studies","pmids":["18936165","19139276","19762470","19380878"],"confidence":"High","gaps":["How a single protein selects distinct target sets per tissue unresolved","Composition of the >1 MDa RNP only partially defined"]},{"year":2009,"claim":"Refined the RNA-recognition code, showing a bipartite U(U/A)AA requirement and that RG repeats confer nonspecific RNA binding.","evidence":"SELEX and binding assays (bipartite motif); chimeric protein and RG-region transfer experiments","pmids":["19457263","11395494"],"confidence":"Medium","gaps":["In vivo prevalence of bipartite sites not surveyed","Single lab biochemistry"]},{"year":2012,"claim":"Linked Sam68-controlled splicing to metabolic differentiation, with intron retention of mTOR explaining adipogenic defects.","evidence":"Sam68 KO mice, CLIP, minigenes, rescue with mTOR cDNA","pmids":["22424772"],"confidence":"High","gaps":["Direct spliceosomal mechanism at intron 5 resolved only later"]},{"year":2013,"claim":"Established a translational/dendritic function: Sam68 delivers actb mRNA to synaptic polysomes to support spine formation.","evidence":"Sam68 KO mice, RNAi, synaptic polysome fractionation, spine morphology and electrophysiology","pmids":["23382180"],"confidence":"High","gaps":["Mechanism of dendritic mRNA transport not detailed","Other synaptic mRNA cargoes not enumerated"]},{"year":2016,"claim":"Revealed direct roles in the DNA-damage response — as a PARP1 partner enabling PAR/NF-κB anti-apoptotic signaling and as an RNA-dependent p53 transcriptional coactivator.","evidence":"Sam68 KO cells/mice with PARP1 Co-IP and PAR assays; CRISPR isogenic p53 lines with Co-IP and ChIP; intronic polyadenylation control of Aldh1a3 in NPCs","pmids":["27635653","27458801","27365047","27845622"],"confidence":"High","gaps":["Direct vs indirect recruitment to lesions not fully separated","RNA dependence of p53 coactivation not molecularly defined"]},{"year":2016,"claim":"Provided the structural basis for STAR-family RNA recognition, showing homodimerization enables transcriptome target selection.","evidence":"X-ray/NMR structures of Sam68/T-STAR with RNA and dimerization-interface mutagenesis plus splicing minigenes","pmids":["26758068"],"confidence":"High","gaps":["Structural impact of PTMs on dimer/RNA binding not modeled"]},{"year":2019,"claim":"Defined the spliceosomal mechanism, showing Sam68 recruits U1 snRNP via its YY domain to enforce 5' splice-site usage and suppress premature termination/polyadenylation.","evidence":"Co-IP/domain mapping, minigenes and mutagenesis on mTOR intron 5; Sam68 KO mice with RNA-seq and U1snRNP Co-IP for ALE usage in meiosis","pmids":["30767021","30865884"],"confidence":"High","gaps":["Generality of U1 recruitment across all Sam68 targets not established"]},{"year":2021,"claim":"Extended Sam68 to protein-stability control of metabolism, stabilizing CRTC2 to drive hepatic gluconeogenesis.","evidence":"Global and hepatocyte-specific KO mice, Co-IP, ubiquitination assay, truncation mutants, glucose tolerance tests","pmids":["34099657"],"confidence":"High","gaps":["Whether CRTC2 stabilization is RNA-dependent unclear","Direct deubiquitinase coupling not identified"]},{"year":null,"claim":"How the combinatorial PTM code, dimerization state, and complex equilibrium together select which RNA targets or signaling outputs Sam68 engages in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking PTM state to target choice","Cell-type-specific cofactor logic undefined","Structural effect of PTMs on the dimer interface unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3,9,10,11,28,32,41,42]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[29,39,40,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,16,24,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[8,44]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[37,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5,7,11,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,7,8,16,19,44]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[5,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,9,10,11,28,32,33,34,38]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,12,16,24]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[26,27,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[29,39,40,47]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,26,27,6]}],"complexes":["TNF receptor complex I","caspase-8-FADD complex II","U1 snRNP-associated splicing complex","cytoplasmic stress granules"],"partners":["PARP1","TP53","HNRNPA1","PTK6","FYN","PRMT1","CREBBP","SNRNP70"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07666","full_name":"KH domain-containing, RNA-binding, signal transduction-associated protein 1","aliases":["GAP-associated tyrosine phosphoprotein p62","Src-associated in mitosis 68 kDa protein","Sam68","p21 Ras GTPase-activating protein-associated p62","p68"],"length_aa":443,"mass_kda":48.2,"function":"Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors. Once phosphorylated, functions as an adapter protein in signal transduction cascades by binding to SH2 and SH3 domain-containing proteins. Role in G2-M progression in the cell cycle. Represses CBP-dependent transcriptional activation apparently by competing with other nuclear factors for binding to CBP. Also acts as a putative regulator of mRNA stability and/or translation rates and mediates mRNA nuclear export. Positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. According to some authors, is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species according to (PubMed:22253824). RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). Can regulate CD44 alternative splicing in a Ras pathway-dependent manner (PubMed:26080397). In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1 (PubMed:17371836, PubMed:20186123). Can regulate alternative splicing of NRXN1 and NRXN3 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. In a neuronal activity-dependent manner cooperates synergistically with KHDRBS2/SLIM-1 in regulation of NRXN1 exon skipping at AS4. The cooperation with KHDRBS2/SLIM-1 is antagonistic for regulation of NXRN3 alternative splicing at AS4 (By similarity) Isoform 3, which is expressed in growth-arrested cells only, inhibits S phase","subcellular_location":"Nucleus; Cytoplasm; Membrane","url":"https://www.uniprot.org/uniprotkb/Q07666/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KHDRBS1","classification":"Not Classified","n_dependent_lines":79,"n_total_lines":1208,"dependency_fraction":0.06539735099337748},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPL","stoichiometry":4.0},{"gene":"RBMX","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"HNRNPC","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KHDRBS1","total_profiled":1310},"omim":[{"mim_id":"617283","title":"YTH DOMAIN-CONTAINING PROTEIN 1; YTHDC1","url":"https://www.omim.org/entry/617283"},{"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":"609590","title":"QKI, KH DOMAIN-CONTAINING RNA-BINDING PROTEIN; QKI","url":"https://www.omim.org/entry/609590"},{"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":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KHDRBS1"},"hgnc":{"alias_symbol":["Sam68","p62","FLJ34027"],"prev_symbol":[]},"alphafold":{"accession":"Q07666","domains":[{"cath_id":"3.30.1370.10","chopping":"153-274","consensus_level":"high","plddt":92.3497,"start":153,"end":274},{"cath_id":"1.10.287","chopping":"101-133","consensus_level":"high","plddt":89.1691,"start":101,"end":133}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07666","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07666-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07666-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KHDRBS1","jax_strain_url":"https://www.jax.org/strain/search?query=KHDRBS1"},"sequence":{"accession":"Q07666","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07666.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07666/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07666"}},"corpus_meta":[{"pmid":"12478298","id":"PMC_12478298","title":"Signal-dependent regulation of splicing via phosphorylation of Sam68.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12478298","citation_count":383,"is_preprint":false},{"pmid":"20186122","id":"PMC_20186122","title":"Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20186122","citation_count":305,"is_preprint":false},{"pmid":"17371836","id":"PMC_17371836","title":"The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x.","date":"2007","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17371836","citation_count":270,"is_preprint":false},{"pmid":"12529443","id":"PMC_12529443","title":"Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1.","date":"2003","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/12529443","citation_count":223,"is_preprint":false},{"pmid":"14643926","id":"PMC_14643926","title":"Sam68, the KH domain-containing superSTAR.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/14643926","citation_count":221,"is_preprint":false},{"pmid":"10564280","id":"PMC_10564280","title":"The interaction and colocalization of Sam68 with the splicing-associated factor YT521-B in nuclear dots is regulated by the Src family kinase p59(fyn).","date":"1999","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10564280","citation_count":167,"is_preprint":false},{"pmid":"17237817","id":"PMC_17237817","title":"The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17237817","citation_count":152,"is_preprint":false},{"pmid":"9341174","id":"PMC_9341174","title":"Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9341174","citation_count":150,"is_preprint":false},{"pmid":"8637866","id":"PMC_8637866","title":"Human protein Sam68 relocalization and interaction with poliovirus RNA polymerase in infected cells.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8637866","citation_count":144,"is_preprint":false},{"pmid":"20028857","id":"PMC_20028857","title":"Alternative splicing of the cyclin D1 proto-oncogene is regulated by the RNA-binding protein Sam68.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20028857","citation_count":140,"is_preprint":false},{"pmid":"21565971","id":"PMC_21565971","title":"The RNA-binding protein Sam68 is a multifunctional player in human cancer.","date":"2011","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21565971","citation_count":136,"is_preprint":false},{"pmid":"10913193","id":"PMC_10913193","title":"Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10913193","citation_count":135,"is_preprint":false},{"pmid":"30064438","id":"PMC_30064438","title":"The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68.","date":"2018","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30064438","citation_count":120,"is_preprint":false},{"pmid":"19380878","id":"PMC_19380878","title":"Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis.","date":"2009","source":"The Journal of cell 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ERK phosphorylation of Sam68 stimulates inclusion of the v5 exon in vitro, and forced Sam68 expression enhanced ERK-mediated v5 inclusion; mutation of ERK phosphorylation sites in Sam68 impaired this enhancement. Suppression of Sam68 abolished Ras-pathway-induced alternative splicing of endogenous CD44-v5.\",\n      \"method\": \"In vitro splicing assay, site-directed mutagenesis of ERK phosphorylation sites, forced expression and RNAi knockdown, RNA binding assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro splicing reconstitution with mutagenesis, combined with RNAi knockdown; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12478298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sam68 binds the Bcl-x mRNA and promotes inclusion of the proapoptotic Bcl-x(s) splice site. Depletion of Sam68 by RNAi caused accumulation of antiapoptotic Bcl-x(L), while up-regulation increased Bcl-x(s). Tyrosine phosphorylation of Sam68 by Fyn kinase inverted this effect, favoring Bcl-x(L) splice site selection. Sam68 interacted with hnRNP A1, and depletion of hnRNP A1 or mutations impairing this interaction attenuated Bcl-x(s) splicing. A point mutation in the RNA-binding domain influenced both splicing activity and subnuclear localization.\",\n      \"method\": \"RNAi knockdown, overexpression, Co-IP, site-directed mutagenesis, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi with defined phenotype, mutagenesis, multiple orthogonal methods; replicated in part by other labs\",\n      \"pmids\": [\"17371836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PRMT1 (protein arginine N-methyltransferase 1) associates with and methylates Sam68 in vivo, introducing asymmetrical dimethylarginines near the proline motif P3. Deletion of methylation sites or use of methylase inhibitors caused Sam68 accumulation in the cytoplasm. PRMT1-deficient embryonic stem cells also showed cytoplasmic Sam68. Methylase inhibition prevented Sam68-mediated export of unspliced HIV RNAs.\",\n      \"method\": \"Co-IP, mass spectrometry, methylation-specific antibody, inhibitor treatment, PRMT1-deficient cells, HIV RNA export assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo methylation confirmed by MS and specific antibody, multiple cell models, functional export assay\",\n      \"pmids\": [\"12529443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Sam68 binds RNA with specificity and high affinity via a KH domain embedded in a larger GSG domain. SELEX identified high-affinity RNA sequences (Kd ~12–40 nM) containing a UAAA motif; mutation of UAAA to UACA abolished binding. The KH domain alone was insufficient; the broader GSG region was required. KH domain mutations analogous to loss-of-function mutations in FMR1 and GLD-1 abolished RNA binding.\",\n      \"method\": \"In vitro SELEX, filter-binding affinity assays, site-directed mutagenesis of KH domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9341174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Sik (mouse) / BRK (human) tyrosine kinase associates with Sam68 through its SH3 and SH2 domains, binding the proline-rich P3 region of Sam68. Sik phosphorylates Sam68 in the nucleus and abolishes Sam68's ability to bind RNA and act as a cellular Rev homologue (facilitating intron-containing RNA export).\",\n      \"method\": \"Co-IP, domain-deletion mapping, in vivo phosphorylation, RNA-binding assay, Rev-function assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, functional RNA-binding assay, replicated with both mouse Sik and human BRK\",\n      \"pmids\": [\"10913193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The Src family kinase Fyn mediates tyrosine phosphorylation of Sam68, which negatively regulates Sam68 association with the nuclear splicing-associated factor YT521-B. Overexpression of Fyn dissolves nuclear dots containing YT521-B and Sam68. Fyn-phosphorylated Sam68 no longer colocalizes with YT521-B.\",\n      \"method\": \"Co-IP, immunofluorescence colocalization, Fyn overexpression, deletion analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, immunofluorescence, kinase overexpression; single lab\",\n      \"pmids\": [\"10564280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Sam68 associates with Fyn and Lck (Src family kinases) in T cells via their SH2 and SH3 domains. CD3 cross-linking induces tyrosine phosphorylation of Sam68, and Sam68 is coimmunoprecipitated with PLCγ1, PI3K p85, Grb2, SHP-1, Cbl, and Jak3, indicating an adaptor function downstream of TCR-coupled kinases.\",\n      \"method\": \"Co-IP, purification and microsequencing, T cell stimulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple signaling partners, single lab, functional TCR stimulation context\",\n      \"pmids\": [\"9045636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BRK phosphorylates Sam68 on all three tyrosines in its nuclear localization signal (NLS), including the principal site Y440. This phosphorylation induces relocalization of Sam68 from the nucleus to non-nuclear compartments. EGF treatment in breast cancer cells promotes Sam68 phosphorylation at Y440 in a BRK-dependent manner (reversed by BRK siRNA). Sam68 overexpression suppresses BRK-induced cell proliferation.\",\n      \"method\": \"Phospho-specific antibodies, indirect immunofluorescence, BRK siRNA, EGF stimulation, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-specific antibodies mapped individual tyrosines, siRNA validation, EGF/BRK pathway, multiple methods in one study\",\n      \"pmids\": [\"16179349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 is required for polysomal recruitment of specific mRNAs in male germ cells and for accumulation of the corresponding proteins. Sam68(-/-) male mice are infertile with defects in spermatogenesis. Sam68 associates with polyadenylated mRNAs in the cytoplasm during meiotic divisions and in round spermatids, interacting with the translational machinery.\",\n      \"method\": \"Sam68 knockout mice, polysome fractionation, RNA immunoprecipitation, heterologous translation system\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined fertility phenotype, polysome fractionation, RIP; multiple orthogonal methods\",\n      \"pmids\": [\"19380878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 is required for alternative splicing of a set of exons during neurogenesis. Sam68 represses an exon in epsilon sarcoglycan (Sgce) through RNA-binding activity and intronic RNA elements. Sam68 protein is upregulated upon neuronal differentiation of P19 cells; Sam68 knockdown prevents neuronal differentiation of both P19 cells and primary neural progenitor cells, while overexpression promotes it.\",\n      \"method\": \"RNAi knockdown, splicing-sensitive microarrays, minigene assays, mutagenesis, shRNA in primary cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide splicing profiling plus minigene mutagenesis, validated in primary neural progenitor cells; multiple orthogonal methods\",\n      \"pmids\": [\"18936165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sam68 regulates alternative splicing of the mTOR transcript during adipogenesis by binding intronic splice elements in mTOR intron 5 required for 5' splice site usage. Sam68(-/-) adipocytes retain intron 5, introducing a premature stop codon that destabilizes mTOR mRNA, reducing mTOR levels, S6 and Akt phosphorylation, and adipogenic differentiation. Exogenous full-length mTOR rescues the adipogenesis defect.\",\n      \"method\": \"Sam68 KO mice, genome-wide exon profiling, CLIP, minigene assays, rescue with mTOR cDNA\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP binding, KO phenotype, rescue experiment, genome-wide profiling; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"22424772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 enhances alternative splicing of cyclin D1b by binding the proximal region of CCND1 intron 4; this binding inversely correlates with recruitment of spliceosomal component U1-70K. Sam68 is recruited to the CCND1 gene (shown by ChIP) and binds cyclin D1 mRNA (shown by RIP). Phosphorylation of Sam68 by signal transduction pathways modulates its affinity for CCND1 intron 4 and splicing activity.\",\n      \"method\": \"ChIP, RNA co-IP, RNAi, overexpression, minigene reporter assay, phospho-mutant analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + RIP + minigene + RNAi; multiple orthogonal methods, functional mechanistic chain established\",\n      \"pmids\": [\"20028857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sam68 acts as a signaling adaptor at the TNF receptor complex I, where it facilitates RIP recruitment, ubiquitylation of RIP, cIAP1 recruitment, and TRAF2 maintenance, enabling TAK1-IKK kinase complex activation and NF-κB signaling. Sam68 is also part of the cytoplasmic caspase-8-FADD complex II; RIP recruitment and caspase activation are absent in Sam68 KO cells.\",\n      \"method\": \"Sam68 KO cells, Co-IP, ubiquitylation assays, kinase complex activation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined biochemical phenotypes, multiple complex components measured, two distinct complexes characterized\",\n      \"pmids\": [\"21620750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sam68 is acetylated in vivo in human mammary epithelial cell lines, with highest acetylation in tumorigenic breast cancer lines. The acetyltransferase CBP acetylates Sam68 in vitro and enhances its binding to poly(U) RNA. Sam68 acetylation positively correlates with its RNA-binding activity.\",\n      \"method\": \"In vivo acetylation detection, in vitro acetyltransferase assay with CBP, RNA-binding assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay plus in vivo correlation; single lab, two methods\",\n      \"pmids\": [\"15021911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sam68 is modified by SUMO, with PIAS1 acting as the E3 SUMO ligase. Lysine 96 is the major SUMO acceptor site. Mutation of K96 to arginine enhanced Sam68-induced apoptosis but inhibited its transcriptional repression of cyclin D1. A SUMO-1-Sam68 fusion inhibited apoptosis but strongly repressed cyclin D1 expression.\",\n      \"method\": \"In vivo sumoylation assay, PIAS1 co-expression, K96R mutagenesis, SUMO fusion protein, reporter assay, apoptosis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-identified by mutagenesis, E3 ligase identified, functional consequences of both gain and loss of sumoylation; single lab\",\n      \"pmids\": [\"16568089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Arginine methylation of Sam68's RG-repeat regions by PRMT1 markedly reduces poly(U) RNA binding ability in vitro. The RG repeats of Sam68 directly bind poly(U); arginine methylation of these repeats abrogates binding. Overexpression of PRMT1 in cells increases Sam68 arginine methylation and decreases its poly(U) binding.\",\n      \"method\": \"In vitro methylation and RNA-binding assays, PRMT1 overexpression, methylation-binding correlation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with PRMT1 plus cell-based validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"17764653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sam68 functions as a docking protein linking p120GAP and PI3K in insulin receptor signaling. Insulin stimulation promotes Sam68 relocalization from nucleus to cytoplasm; tyrosine-phosphorylated Sam68 co-precipitates with p85 PI3K, IRS-1, and IR. Sam68 also associates with p120GAP after tyrosine phosphorylation by the IR, with this association mediated by GAP's SH2 domains. PI3K activity is increased in both anti-Sam68 and anti-GAP immunoprecipitates upon insulin stimulation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, PI3K activity assay, insulin receptor stimulation\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with multiple partners, PI3K activity assay, single lab\",\n      \"pmids\": [\"11604231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sam68(-/-) mice exhibit motor coordination defects: Sam68-null mice show more hindpaw faults in beam walking and fall from rotorod at lower speeds. Sam68 is highly expressed in the cerebellum, implicating it in motor coordination circuitry.\",\n      \"method\": \"Sam68 KO mice, behavioral assays (beam walking, rotorod, balance test)\",\n      \"journal\": \"Behavioural brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral phenotype; single lab, behavioral readout\",\n      \"pmids\": [\"18325609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sam68(-/-) mice show age-related protection from bone loss. Sam68-null bone marrow stromal cells have a differentiation advantage toward osteoblasts, and Sam68 knockdown in C3H10T1/2 cells promotes osteocalcin expression after BMP-2 induction. Sam68(-/-) MEFs show impaired adipocyte differentiation. Thus Sam68 is a positive regulator of adipocyte differentiation and negative regulator of osteoblast differentiation.\",\n      \"method\": \"Sam68 KO mice, shRNA knockdown, differentiation assays, histology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype plus shRNA in cell culture; single lab, multiple cell types tested\",\n      \"pmids\": [\"16362077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Sam68 translocates to the cytoplasm and associates with polysomes in mouse pachytene spermatocytes during meiotic divisions. This translocation correlates with serine/threonine phosphorylation and is blocked by ERK1/2 and cyclin B-cdc2 inhibitors. Both kinases associate with Sam68 in pachytene spermatocytes and phosphorylate regions flanking the RNA-binding motif.\",\n      \"method\": \"Subcellular fractionation, polysome sedimentation, kinase inhibitors, Co-IP with ERK and cyclin B-cdc2\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus polysome profiling, kinase association by Co-IP; single lab, multiple methods\",\n      \"pmids\": [\"16221888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In hippocampal neurons, Sam68 undergoes activity-responsive translocation from nucleus to dendrites following KCl depolarization. Translocation requires calcium channel activity (blocked by nimodipine), is microtubule-dependent, and is partially blocked by CRM1 inhibitor leptomycin B. A fraction of dendritic GFP-Sam68 colocalizes with RNA clusters. The Sam68 N-terminus is required for nuclear retention.\",\n      \"method\": \"GFP-Sam68 live-cell imaging, calcium channel inhibitor, microtubule inhibitor, leptomycin B, RNA staining\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with defined pharmacological manipulations, functional domain tested; single lab\",\n      \"pmids\": [\"14996936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sam68 knockdown in hippocampal neurons decreases the amount of β-actin (actb) mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished synaptic β-actin protein. Genetic knockout or acute knockdown in vivo results in fewer excitatory synapses. Disruption of Sam68-actb mRNA binding phenocopies Sam68 knockdown.\",\n      \"method\": \"Sam68 KO mice, RNAi knockdown, synaptic polysome fractionation, spine morphology analysis, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice plus acute knockdown in vivo, synaptic polysome fractionation, morphological and electrophysiological readouts; multiple orthogonal methods\",\n      \"pmids\": [\"23382180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Sam68's proline-rich motifs function as specific SH3 domain binding sites; the Src SH3 domain directs binding to an N-terminal proline motif of Sam68 (residues 38–45), and this SH3-mediated docking facilitates phosphorylation of Sam68 tyrosines by the Src kinase domain. Mutation of the Src SH3 binding site on Sam68, or addition of corresponding peptides, inhibits Src phosphorylation of Sam68 in vitro.\",\n      \"method\": \"In vitro SH3 domain binding, synthetic peptide competition, site-directed mutagenesis, in vitro kinase assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase and binding assays with mutagenesis and peptide competition; single lab\",\n      \"pmids\": [\"10467411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sam68 physically interacts with CBP through the CBP CH3 domain, in part through a conserved FXD/EXXXL motif. Sam68 and CBP interact in vivo and colocalize in nuclear sub-domains. Sam68 has transcriptional repression activity independent of its RNA-binding activity.\",\n      \"method\": \"Co-IP, domain mapping, transcriptional reporter assay, immunofluorescence colocalization\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mapping, functional reporter; single lab, two methods\",\n      \"pmids\": [\"12496368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68-deficient cells exhibit sustained Src activity after cell attachment, leading to constitutive tyrosine phosphorylation and activation of p190RhoGAP and its association with p120rasGAP, and deregulated RhoA and Rac1 activity. Sam68 localizes near the plasma membrane after cell attachment (TIRF microscopy), coinciding with phosphorylation of its C-terminal tyrosines and association with Csk. Loss of Sam68 impairs cell polarity and migration.\",\n      \"method\": \"Sam68 KO MEFs, TIRF microscopy, Co-IP, phospho-specific antibodies, Rho GTPase activity assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TIRF localization with function, KO with defined signaling phenotype (multiple GTPases), Co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"19139276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 exists in equilibrium between a large (>1 MDa) ribonucleoprotein complex (~40 proteins, RNA-dependent) and a smaller (200–450 kDa) complex in HeLa cells. EGF or PMA treatment dissociates Sam68 from the large complex, shifting it to the smaller complex. The appearance of Sam68 in the small complex correlates with its ability to promote CD44 alternative splicing and cell migration.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, size-exclusion chromatography, RNase treatment, EGF/PMA stimulation, splicing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex characterization, RNase sensitivity, EGF stimulation with functional readout; single lab\",\n      \"pmids\": [\"19762470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sam68 deficiency abolishes DNA damage-stimulated poly(ADP-ribose) (PAR) production. Sam68 is recruited to DNA lesions and directly interacts with PARP1; this interaction is required for PARP1-mediated PAR production. Sam68-deleted cells and mice are hypersensitive to DNA-damaging agents. Sam68 is also required for NF-κB transactivation of anti-apoptotic genes downstream of PAR production.\",\n      \"method\": \"Sam68 KO cells and mice, biochemical fractionation, Co-IP, PAR production assays, DNA damage sensitivity assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells and in vivo KO mice, Co-IP with PARP1, PAR assay, DNA damage phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"27635653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sam68 is required for genotoxic stress-initiated NF-κB activation through PAR-dependent signaling in colon cancer. Sam68 deletion abolishes DNA damage-stimulated PAR production and PAR-dependent NF-κB transactivation of anti-apoptotic genes; Sam68-deleted cells are hypersensitive to genotoxic stress. Sam68 upregulation in colon cancer coincides with elevated PAR production and NF-κB-mediated anti-apoptotic transcription.\",\n      \"method\": \"Sam68 KO cells and mice, genotoxic stress assays, PAR production assays, tumor burden assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus tumor model; overlap with PMID 27635653 for the PAR/PARP1 mechanism\",\n      \"pmids\": [\"27458801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sam68 promotes self-renewal of neural progenitor cells (NPCs) by binding an intronic polyadenylation site in Aldh1a3 pre-mRNA, preventing premature transcript termination and favoring expression of functional ALDH1A3 enzyme. Khdrbs1 KO NPCs show lower ALDH1A3 expression and activity, reduced glycolysis, and depleted embryonic NPC pool.\",\n      \"method\": \"Khdrbs1 KO mice, 3'-end processing assays, CLIP, minigene polyadenylation assay, metabolic assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined NPC phenotype, CLIP showing direct RNA binding, 3'-end processing assay; multiple orthogonal methods\",\n      \"pmids\": [\"27845622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sam68 acts as a transcriptional coactivator of p53 in response to DNA damage. Sam68 physically interacts with p53 in an RNA-dependent manner; this interaction is essential for coactivator function. Both Sam68 and p53 are recruited to promoters of p53-responsive genes. Sam68 depletion causes defects in DNA damage-induced cell cycle arrest and apoptosis mediated by p53.\",\n      \"method\": \"CRISPR/Cas9 KO cell lines (isogenic p53 WT vs KO), Co-IP, ChIP, reporter assays, cell cycle and apoptosis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR isogenic cell lines, Co-IP, ChIP, functional gene expression; multiple orthogonal methods in single study\",\n      \"pmids\": [\"27365047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAM68 (KHDRBS1) is required for NORAD lncRNA function in antagonizing Pumilio. SAM68 interacts with NORAD, and this interaction is required for NORAD-mediated antagonism of Pumilio repressors; the interaction provides a paradigm for how repeated elements in a lncRNA facilitate function through an RNA-binding protein.\",\n      \"method\": \"Co-IP/RNA-IP, functional NORAD assays, SAM68 knockdown\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-protein interaction with functional consequence; single lab, two methods\",\n      \"pmids\": [\"29386330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sam68 binds Alu-rich intronic sequences in the SMN pre-mRNA (shown by CLIP), promoting widespread alternative circular RNA (circRNA) biogenesis. Mutagenesis of Sam68 binding sites in SMN IRAlus and Sam68 silencing reduce circRNA formation in vitro and in vivo.\",\n      \"method\": \"CLIP, mutagenesis, Sam68 silencing, circRNA detection assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP plus mutagenesis plus silencing; single lab, three methods\",\n      \"pmids\": [\"31777926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sam68 interacts with U1A (core component of U1 snRNP) through its C-terminal tyrosine-rich (YY) domain, and this interaction promotes U1 snRNP recruitment to the 5' splice site of mTOR intron 5. Deletion of the U1A-SAM68 interaction domain or mutation of SAM68 binding sites in mTOR intron 5 abrogates U1A recruitment and 5' splice site recognition, causing premature termination and polyadenylation.\",\n      \"method\": \"Co-IP, domain mapping, minigene assays, mutagenesis, U1A knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapped interaction, mutagenesis of both protein and RNA, functional splicing assay; multiple orthogonal methods\",\n      \"pmids\": [\"30767021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sam68 cooperates with U1snRNP to regulate alternative last exon (ALE) usage during male meiosis. Loss of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites. Sam68 physically associates with U1snRNP, and U1snRNP recruitment to Sam68-regulated ALEs is impaired in Sam68(-/-) germ cells.\",\n      \"method\": \"Sam68 KO mice, RNA-seq, Co-IP of Sam68 and U1snRNP, splicing/polyadenylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with genome-wide analysis, Co-IP, functional polyadenylation assay; multiple orthogonal methods\",\n      \"pmids\": [\"30865884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sam68 regulates isoform expression of S6 kinase (Rps6kb1) during adipogenesis. Sam68 binds RNA encoded by Rps6kb1 intron 6 (shown by CLIP) and prevents SRSF1-mediated alternative splicing that generates inhibitory p31S6K1. Sam68-deficient adipocytes express p31S6K1, inhibiting adipogenesis; depletion of p31S6K1 partially restores adipogenesis.\",\n      \"method\": \"CLIP, minigene assays, siRNA, Sam68 KO adipocytes, p31S6K1 overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP plus minigene plus rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"25776557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMAR1 negatively regulates Sam68's splicing activity through HDAC6-mediated deacetylation of Sam68. SMAR1 maintains Sam68 in a deacetylated (less active) state via HDAC6. ERK-mediated phosphorylation of SMAR1 (at T345 and T360) localizes SMAR1 to the cytoplasm, releases the inhibitory SMAR1-HDAC6-Sam68 complex, and facilitates Sam68 acetylation and alternative splicing of CD44 variant exons.\",\n      \"method\": \"Co-IP, knockdown, HDAC6 inhibition, phosphomimetic mutagenesis, CD44 minigene reporter, in vivo tail-vein injection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying ternary complex, mutagenesis, functional splicing readout, in vivo metastasis model; multiple methods\",\n      \"pmids\": [\"26080397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The methyltransferase Set7/9 (KMT7) co-immunoprecipitates with Sam68 and methylates Sam68 on K208. Knockout of Set7/9 decreases Sam68 protein levels in cells, resulting in altered cell cycle and apoptosis regulation. The RG-rich domain of Sam68 mediates the interaction with Set7/9's MORN domain.\",\n      \"method\": \"Pull-down, Co-IP, in vitro methylation assay, Set7/9 KO cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro methylation with site identification, KO functional consequence; single lab\",\n      \"pmids\": [\"32178870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination, thereby stabilizing CRTC2 protein levels. Sam68 promotes hepatic gluconeogenesis: global and hepatic Sam68 deletion significantly reduces blood glucose and glucagon-induced gluconeogenic gene expression. Sam68 truncation mutants lacking C-terminal (Sam68ΔC) or N-terminal (Sam68ΔN) domains respectively fail to bind CRTC2 or to stabilize CRTC2 protein.\",\n      \"method\": \"Sam68 global and hepatocyte-specific KO mice, Co-IP, ubiquitination assay, truncation mutagenesis, glucose tolerance tests\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO in vivo, Co-IP, ubiquitination assay, domain-defined mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"34099657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAM68 promotes aerobic glycolysis and lung adenocarcinoma tumorigenesis by mediating alternative splicing of pyruvate kinase (PKM) pre-mRNA to favor PKM2 over PKM1. Mechanistically, SAM68 binds the 351–443 aa region to the RGG motif of hnRNP A1, enhancing hnRNP A1 binding to PKM exon 9 and promoting PKM2 formation.\",\n      \"method\": \"RNA-IP, Western blot, minigene splicing assays, domain mapping, in vitro and in vivo tumor models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, domain mapping, functional splicing and metabolic readout; single lab\",\n      \"pmids\": [\"33537092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sam68 interacts with the androgen receptor (AR) in vivo in LNCaP prostate cancer cells and is dynamically recruited to androgen response elements within the PSA gene promoter (by ChIP). Wild-type Sam68 and an RNA-binding-impaired mutant (V229F) both function as ligand-dependent AR co-activators in reporter assays. Conversely, Sam68-mediated splicing of a Sam68-responsive exon under androgen-responsive promoter control is strongly repressed by AR/androgens and reversed by Sam68 expression; V229F Sam68 enhances this splicing repression, demonstrating separable transcriptional co-activation and splicing functions.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter assay, minigene splicing assay, V229F mutagenesis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, minigene with mutagenesis; single lab, multiple methods\",\n      \"pmids\": [\"18273831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sam68 controls expression of AR-V7 splice variant in an RNA-binding-dependent manner using a minigene reporter for exon 3b inclusion. Sam68 directly interacts with AR-V7 protein through a shared domain with full-length AR. Sam68 co-activates ligand-independent AR-V7 transcriptional activity in an RNA-binding-independent manner and controls expression of the AR-V7 target gene UBE2C.\",\n      \"method\": \"Minigene reporter assay, Co-IP, luciferase reporter assay, RNAi knockdown, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene, Co-IP, luciferase reporter; single lab, multiple methods\",\n      \"pmids\": [\"26310125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sam68 binds Alu-rich intronic sequences in the SMN pre-mRNA and promotes circRNA biogenesis. The crystal/NMR structure of T-STAR and Sam68 in complex with RNA established that STAR proteins bind RNA as homodimers through an unexpected dimerization interface distinct from other STAR family members; this dimerization interface is crucial for splicing regulatory activity, and increased RNA affinity through dimer formation enables target selection within the transcriptome.\",\n      \"method\": \"X-ray crystallography, NMR, RNA-binding assays, splicing minigene assays with dimerization-interface mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution structure plus mutagenesis of the dimerization interface plus functional splicing assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"26758068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 binds bipartite RNA motifs consisting of direct U(U/A)AA repeats, requiring both half-sites for high-affinity binding; this bipartite requirement was demonstrated by SELEX and confirmed for Sam68, SLM-2, QKI, and GLD-1.\",\n      \"method\": \"SELEX, filter-binding assays, mutant RNA probes\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro SELEX plus binding assays; single lab, two methods\",\n      \"pmids\": [\"19457263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sam68 contains two arginine-glycine (RG)-rich regions that confer nonspecific RNA binding to its GSG domain. A minimal 26-aa RG-rich sequence from Sam68 is sufficient to confer homopolymeric RNA binding to the GSG domain of QKI-7 (a different STAR protein) and to enable it to functionally substitute for HIV-1 Rev in RNA nuclear export.\",\n      \"method\": \"Domain-deletion analysis, chimeric protein construction, RNA-binding assay, HIV Rev reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — chimeric protein reconstitution with functional Rev assay; single lab\",\n      \"pmids\": [\"11395494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sam68 enhances cytoplasmic utilization (translation) of CTE-containing intron-containing mRNA by ~60–70-fold at the protein level with only modest effect on cytoplasmic RNA levels, demonstrating a post-export translational enhancement function. An RNA-binding-deficient Sam68 mutant (G178E) does not enhance CTE function. Activated Sik/BRK (which hyperphosphorylates Sam68) inhibits this activity in a dose-dependent manner.\",\n      \"method\": \"Reporter gene expression assay, RNA analysis, Sik/BRK co-expression, G178E point mutant\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with mutagenesis and kinase regulation; single lab\",\n      \"pmids\": [\"12482964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sam68 is sequestered by CGG repeat-expanded RNA in FXTAS, losing its splicing-regulatory function. Sam68 is recruited first among RNA-binding proteins to CGG repeat aggregates. Regulation of Sam68 tyrosine phosphorylation modulates its localization within CGG aggregates. Tautomycin prevents both Sam68 and CGG RNA aggregate formation.\",\n      \"method\": \"Fluorescence imaging of intranuclear aggregates, splicing assays in patient cells, phosphorylation modulation experiments, tautomycin treatment\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of Sam68 sequestration, patient-derived cells, pharmacological rescue; single lab\",\n      \"pmids\": [\"20186122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FMDV 3C protease cleaves Sam68 at its C-terminus (which contains the NLS), causing redistribution of Sam68 to the cytoplasm. Sam68 interacts with the FMDV IRES within the 5' non-translated region and its knockdown decreases FMDV IRES-driven translation activity and reduces viral titers by 1000-fold.\",\n      \"method\": \"siRNA knockdown, IRES reporter assay, protease cleavage assay, viral titer measurement\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protease cleavage assay, functional IRES reporter, siRNA with viral titer; single lab\",\n      \"pmids\": [\"22280896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"c-MYC directly binds to and activates the Sam68 (KHDRBS1) gene promoter, and also affects productive splicing of the nascent Sam68 transcript by modulating transcriptional elongation rate. Sam68 and c-MYC levels positively correlate in prostate cancer patients. c-MYC-dependent Sam68 expression is under control of external cues (androgens, mitogens).\",\n      \"method\": \"ChIP, promoter reporter assay, transcriptional elongation assay, patient data correlation, androgen/mitogen stimulation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus elongation assay; single lab\",\n      \"pmids\": [\"31066450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 cytoplasmic mutants suppress HIV-1 Nef expression by inducing stress granules and sequestering nef mRNA in those granules. Domain aa269–321 and the KH domain are required for stress granule induction. Nef suppression is specific, conferred by Sam68 binding to nef mRNA 3'UTR.\",\n      \"method\": \"Sam68 cytoplasmic mutant expression, stress granule imaging, mRNA localization assay, domain deletion\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, functional Nef suppression, RNA localization assay; single lab\",\n      \"pmids\": [\"19150430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sam68 is recruited to cytoplasmic stress granules under oxidative stress by complexing with the core stress granule component TIA-1. Both domain aa269–321 and the KH domain are essential for Sam68 stress granule recruitment. Sam68 knockdown has no effect on stress granule assembly, showing Sam68 is not a constitutive SG component.\",\n      \"method\": \"Immunofluorescence, Co-IP with TIA-1, domain deletion mutants, Sam68 knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus imaging plus domain mapping; single lab\",\n      \"pmids\": [\"19615357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sam68 forms a complex with the HIV-1 Rev protein; mutagenesis identified residues 321–410 of Sam68 as directly involved in Rev binding, and Rev double mutation L78D/E79L eliminated binding to Sam68. Sam68 expression promotes Rev nuclear export; down-modulation of Sam68 causes nuclear retention and colocalization of Rev and CRM1, demonstrating involvement in CRM1-mediated Rev nuclear export.\",\n      \"method\": \"Mutagenesis, Co-IP, antisense knockdown, digital fluorescence microscopy, Rev-dependent reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with mutagenesis, Rev localization imaging, knockdown with functional assay; single lab\",\n      \"pmids\": [\"11932418\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KHDRBS1/Sam68 is a multifunctional STAR-family KH-domain RNA-binding protein that binds bipartite U(U/A)AA RNA motifs as a homodimer (structurally established), regulates alternative pre-mRNA splicing in response to extracellular signals (ERK/Ras, Fyn, BRK phosphorylation), controls 3'-end processing, mRNA translation, and nuclear export of specific transcripts, and functions as a signaling adaptor linking receptor tyrosine kinases to small GTPases, NF-κB, PARP1/PAR-dependent DNA-damage responses, TNF receptor complexes, and the p53 transcriptional program; its activity is post-translationally regulated by phosphorylation (Src, Fyn, ERK, BRK), arginine methylation by PRMT1 (reducing RNA binding), acetylation by CBP (enhancing RNA binding), sumoylation by PIAS1 (modulating apoptosis vs. cyclin D1 repression), and methylation by Set7/9 on K208, with subcellular localization tightly coupled to these modifications.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KHDRBS1 (Sam68) is a STAR-family KH-domain RNA-binding protein that couples extracellular and genotoxic signaling to post-transcriptional gene regulation and serves as a multifunctional signaling adaptor [#0, #41]. Its RNA recognition rests on a KH domain embedded in a larger GSG region that binds bipartite U(U/A)AA motifs, and structural work showed STAR proteins engage RNA as homodimers through a dimerization interface essential for splicing activity [#3, #42, #41]. A dominant function is signal-responsive alternative splicing: ERK phosphorylation of Sam68 drives CD44 variable-exon inclusion, while it governs Bcl-x splice-site choice, neuronal Sgce exons, cyclin D1b, mTOR, and S6 kinase isoform selection by binding intronic regulatory elements [#0, #1, #9, #11, #10, #34]. For several targets Sam68 functions through partner RNA-binding proteins and the spliceosome, recruiting U1 snRNP via its C-terminal YY domain to control 5' splice-site usage and alternative last-exon/3'-end processing, and cooperating with hnRNP A1 [#32, #33, #1, #38]. Beyond splicing, Sam68 promotes intronic polyadenylation read-through, circRNA biogenesis, cytoplasmic mRNA translation and polysomal recruitment, and nuclear export of intron-containing transcripts [#28, #31, #8, #44]. As a signaling adaptor it links Src-family and receptor tyrosine kinases to small GTPases, PI3K, the TNF-receptor/NF-\\u03baB axis, and PARP1/PAR-dependent DNA-damage responses, and it acts as an RNA-dependent transcriptional coactivator of p53 [#24, #16, #12, #26, #29]. Sam68 activity and localization are controlled by an extensive post-translational code: tyrosine phosphorylation by Fyn, BRK/Sik, and Src; arginine methylation by PRMT1 (reducing RNA binding); acetylation by CBP (enhancing RNA binding); sumoylation by PIAS1; and methylation by Set7/9 [#5, #7, #22, #2, #15, #13, #14, #36]. In vivo, Sam68 knockout produces male infertility, motor-coordination deficits, altered bone/fat differentiation, defective dendritic spine formation, and impaired hepatic gluconeogenesis, reflecting its tissue-specific RNA targets [#8, #17, #18, #21, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that Sam68 is a sequence-specific RNA-binding protein, defining the molecular basis for its post-transcriptional functions.\",\n      \"evidence\": \"In vitro SELEX and filter-binding with KH-domain mutagenesis identifying a UAAA-containing high-affinity motif\",\n      \"pmids\": [\"9341174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo targets\", \"GSG-region requirement defined but structural basis unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected Sam68 to receptor signaling by showing it is a phosphorylation substrate and adaptor downstream of T-cell receptor-coupled Src-family kinases.\",\n      \"evidence\": \"Co-IP and microsequencing in CD3-stimulated T cells linking Sam68 to Fyn, Lck, PLC\\u03b31, PI3K p85, Grb2, SHP-1, Cbl, Jak3\",\n      \"pmids\": [\"9045636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of each interaction not dissected\", \"Single lab Co-IP\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed tyrosine phosphorylation directly toggles Sam68 RNA-binding and nuclear-export functions, linking kinase signaling to its RNA activity.\",\n      \"evidence\": \"Sik/BRK domain-mapping, in vivo phosphorylation, RNA-binding and Rev-function assays\",\n      \"pmids\": [\"10913193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual tyrosine sites not mapped in this study\", \"Endogenous RNA targets affected not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that Sam68 is an effector of the Ras/ERK pathway in alternative splicing, establishing signal-regulated splicing as a core function.\",\n      \"evidence\": \"In vitro splicing reconstitution, ERK phosphosite mutagenesis, RNAi knockdown on CD44 v5\",\n      \"pmids\": [\"12478298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of exon recognition at the spliceosome not resolved\", \"Generalization beyond CD44 not shown here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified arginine methylation by PRMT1 as a determinant of Sam68 localization and export activity, adding a second PTM layer.\",\n      \"evidence\": \"Co-IP, mass spectrometry, PRMT1-deficient cells, HIV RNA export assay\",\n      \"pmids\": [\"12529443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative coupling of methylation to RNA affinity addressed later\", \"Interplay with phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed CBP acetylation enhances Sam68 RNA binding, providing a positive-regulatory PTM relevant to breast cancer.\",\n      \"evidence\": \"In vivo acetylation detection, in vitro CBP acetyltransferase and poly(U)-binding assays\",\n      \"pmids\": [\"15021911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylated lysine sites not mapped\", \"Single lab correlation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the specific NLS tyrosines whose BRK phosphorylation drives nuclear export, linking EGF signaling to Sam68 relocalization.\",\n      \"evidence\": \"Phospho-specific antibodies, immunofluorescence, BRK siRNA, EGF stimulation in breast cancer cells\",\n      \"pmids\": [\"16179349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic functions of exported Sam68 not fully defined here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established sumoylation by PIAS1 at K96 as a switch between apoptosis promotion and cyclin D1 repression.\",\n      \"evidence\": \"In vivo sumoylation assay, K96R mutagenesis, SUMO-Sam68 fusion, apoptosis and reporter assays\",\n      \"pmids\": [\"16568089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of the apoptosis/repression switch unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended signal-regulated splicing to apoptotic decisions, showing Fyn phosphorylation inverts Sam68 control of Bcl-x splicing.\",\n      \"evidence\": \"RNAi, overexpression, reciprocal Co-IP with hnRNP A1, mutagenesis\",\n      \"pmids\": [\"17371836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry/cooperation with hnRNP A1 not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined Sam68 as a master regulator of developmental and cell-fate splicing programs across neurogenesis, with parallel adaptor roles at the plasma membrane controlling GTPase signaling and migration.\",\n      \"evidence\": \"Splicing-sensitive microarrays and minigenes (Sgce); Sam68 KO MEFs, TIRF, Rho/Rac assays; complex equilibrium MS/SEC; KO mouse spermatogenesis polysome studies\",\n      \"pmids\": [\"18936165\", \"19139276\", \"19762470\", \"19380878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein selects distinct target sets per tissue unresolved\", \"Composition of the >1 MDa RNP only partially defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Refined the RNA-recognition code, showing a bipartite U(U/A)AA requirement and that RG repeats confer nonspecific RNA binding.\",\n      \"evidence\": \"SELEX and binding assays (bipartite motif); chimeric protein and RG-region transfer experiments\",\n      \"pmids\": [\"19457263\", \"11395494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo prevalence of bipartite sites not surveyed\", \"Single lab biochemistry\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked Sam68-controlled splicing to metabolic differentiation, with intron retention of mTOR explaining adipogenic defects.\",\n      \"evidence\": \"Sam68 KO mice, CLIP, minigenes, rescue with mTOR cDNA\",\n      \"pmids\": [\"22424772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct spliceosomal mechanism at intron 5 resolved only later\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a translational/dendritic function: Sam68 delivers actb mRNA to synaptic polysomes to support spine formation.\",\n      \"evidence\": \"Sam68 KO mice, RNAi, synaptic polysome fractionation, spine morphology and electrophysiology\",\n      \"pmids\": [\"23382180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dendritic mRNA transport not detailed\", \"Other synaptic mRNA cargoes not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed direct roles in the DNA-damage response — as a PARP1 partner enabling PAR/NF-\\u03baB anti-apoptotic signaling and as an RNA-dependent p53 transcriptional coactivator.\",\n      \"evidence\": \"Sam68 KO cells/mice with PARP1 Co-IP and PAR assays; CRISPR isogenic p53 lines with Co-IP and ChIP; intronic polyadenylation control of Aldh1a3 in NPCs\",\n      \"pmids\": [\"27635653\", \"27458801\", \"27365047\", \"27845622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect recruitment to lesions not fully separated\", \"RNA dependence of p53 coactivation not molecularly defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for STAR-family RNA recognition, showing homodimerization enables transcriptome target selection.\",\n      \"evidence\": \"X-ray/NMR structures of Sam68/T-STAR with RNA and dimerization-interface mutagenesis plus splicing minigenes\",\n      \"pmids\": [\"26758068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural impact of PTMs on dimer/RNA binding not modeled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the spliceosomal mechanism, showing Sam68 recruits U1 snRNP via its YY domain to enforce 5' splice-site usage and suppress premature termination/polyadenylation.\",\n      \"evidence\": \"Co-IP/domain mapping, minigenes and mutagenesis on mTOR intron 5; Sam68 KO mice with RNA-seq and U1snRNP Co-IP for ALE usage in meiosis\",\n      \"pmids\": [\"30767021\", \"30865884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of U1 recruitment across all Sam68 targets not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended Sam68 to protein-stability control of metabolism, stabilizing CRTC2 to drive hepatic gluconeogenesis.\",\n      \"evidence\": \"Global and hepatocyte-specific KO mice, Co-IP, ubiquitination assay, truncation mutants, glucose tolerance tests\",\n      \"pmids\": [\"34099657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRTC2 stabilization is RNA-dependent unclear\", \"Direct deubiquitinase coupling not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the combinatorial PTM code, dimerization state, and complex equilibrium together select which RNA targets or signaling outputs Sam68 engages in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking PTM state to target choice\", \"Cell-type-specific cofactor logic undefined\", \"Structural effect of PTMs on the dimer interface unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3, 9, 10, 11, 28, 32, 41, 42]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [29, 39, 40, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 16, 24, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [8, 44]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [37, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5, 7, 11, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 7, 8, 16, 19, 44]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [5, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 9, 10, 11, 28, 32, 33, 34, 38]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 12, 16, 24]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [26, 27, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [29, 39, 40, 47]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 26, 27, 6]}\n    ],\n    \"complexes\": [\n      \"TNF receptor complex I\",\n      \"caspase-8-FADD complex II\",\n      \"U1 snRNP-associated splicing complex\",\n      \"cytoplasmic stress granules\"\n    ],\n    \"partners\": [\n      \"PARP1\",\n      \"TP53\",\n      \"HNRNPA1\",\n      \"PTK6\",\n      \"FYN\",\n      \"PRMT1\",\n      \"CREBBP\",\n      \"SNRNP70\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}