{"gene":"SRPK2","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1998,"finding":"SRPK2 is an SR protein-specific kinase with a stringent preference for SR dipeptides; phosphorylation of ASF/SF2 by SRPK2 enhances its interaction with U1 70K, and overexpression of SRPK2 induces redistribution of splicing factors in the nucleus, indicating a role in spliceosome assembly and trafficking of splicing factors.","method":"Random peptide selection for phosphorylation site preference, in vitro kinase assay, co-immunoprecipitation, overexpression with immunofluorescence microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro kinase assay, peptide selection, Co-IP, live-cell imaging), replicated across SRPK1 and SRPK2, foundational study","pmids":["9472028"],"is_preprint":false},{"year":1998,"finding":"Overexpression of mouse SRPK2 causes disassembly of nuclear speckles containing cotransfected SF2/ASF and endogenous SC35, and SRPK2 phosphorylates SF2/ASF on the same sites as SRPK1 in vitro.","method":"In vitro kinase assay with phosphopeptide mapping, overexpression with immunofluorescence of nuclear speckles","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus phosphopeptide mapping and cell imaging, single lab","pmids":["9446799"],"is_preprint":false},{"year":2002,"finding":"SRPK1 and SRPK2 are the major cellular kinases that phosphorylate the arginine-rich C-terminal domain of hepatitis B virus core protein on the same serine residues phosphorylated in vivo; both were identified by purification, mass spectrometry, and immunoblot from HuH-7 lysates.","method":"Kinase purification from cell lysates, mass spectrometry identification, in vitro phosphorylation assay, immunoblot","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification, mass spectrometry, in vitro reconstitution with site mapping; replicated between SRPK1 and SRPK2","pmids":["12134018"],"is_preprint":false},{"year":2005,"finding":"SRPK1 and SRPK2 suppress HBV replication by reducing pregenomic RNA packaging efficiency without affecting core particle formation; this suppressive effect is independent of their kinase activity toward the core protein, as kinase-dead mutants retain suppressive activity and overexpression does not alter in vivo core protein phosphorylation.","method":"Overexpression of wild-type and kinase-dead mutants in HBV-replicating cells, Southern blot for HBV DNA, Northern blot for pgRNA packaging","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutagenesis plus functional viral replication assays, single lab","pmids":["16122776"],"is_preprint":false},{"year":2008,"finding":"SRPK2 associates with the U4/U6-U5 tri-snRNP and phosphorylates the RS domain of human PRP28 (DDX23); this phosphorylation is required for stable PRP28 association with the tri-snRNP and for tri-snRNP integration into the spliceosomal B complex.","method":"RNAi knockdown in HeLa cells, immunodepletion/complementation of nuclear extracts, in vitro splicing assays, co-immunoprecipitation with snRNP fractions","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — RNAi with rescue/complementation, immunodepletion, in vitro splicing reconstitution, multiple orthogonal methods in one study","pmids":["18425142"],"is_preprint":false},{"year":2009,"finding":"Akt phosphorylates SRPK2 on Thr-492, promoting SRPK2 nuclear translocation, cyclin D1 upregulation, cell cycle reentry, and apoptosis in neurons; SRPK2 phosphorylates SC35, inactivating p53 and contributing to cyclin D1 upregulation; 14-3-3 binding to Akt-phosphorylated SRPK2 inhibits these events.","method":"Site-directed mutagenesis, in vitro kinase assay, co-immunoprecipitation, nuclear fractionation, neuronal overexpression/knockdown with cell death readouts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-site mutagenesis, reciprocal Co-IP, subcellular fractionation, and functional neuronal death assays combined in one study","pmids":["19592491"],"is_preprint":false},{"year":2010,"finding":"SRPK2 is cleaved by caspases at Asp-139 and Asp-403 during apoptosis; the N-terminal cleavage product translocates to the nucleus and promotes chromatin condensation and apoptotic cell death; Akt phosphorylation of SRPK2 prevents caspase cleavage, and 14-3-3β binding to Akt-phosphorylated SRPK2 further protects it from degradation.","method":"Site-directed mutagenesis of caspase cleavage sites, subcellular fractionation, nuclear translocation assays, cell death assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of cleavage sites, fractionation, functional apoptosis assays, single lab","pmids":["21056976"],"is_preprint":false},{"year":2012,"finding":"SRPK2 directly phosphorylates tau on Ser-214, suppresses tau-dependent microtubule polymerization, and inhibits axonal elongation in neurons; depletion of SRPK2 in dentate gyrus of APP/PS1 mice reduces tau phosphorylation and alleviates cognitive deficits and impaired LTP.","method":"In vitro kinase assay with site mapping, microtubule polymerization assay, axon elongation assay, in vivo lentiviral knockdown, behavioral and electrophysiological tests","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with site identification, in vivo genetic knockdown with multiple functional readouts","pmids":["23197718"],"is_preprint":false},{"year":2013,"finding":"SRPK2 phosphorylates the RS motif (Ser-148 and Ser-150) of EBV tegument protein BLRF2; mutation of this RS motif abrogates BLRF2's ability to support gammaherpesvirus replication.","method":"Binary and co-complex protein interaction assays, in vitro kinase assay, mutagenesis (S148A+S150A), viral replication complementation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, mutagenesis, and viral functional complementation, single lab","pmids":["23326445"],"is_preprint":false},{"year":2013,"finding":"Paraquat treatment induces phosphorylation and nuclear accumulation of SRPK2, leading to increased SR protein phosphorylation and altered splice site selection; site-specific mutagenesis identified a single serine residue required for nuclear localization; genotoxic agents (cisplatin, γ-radiation) also promote SRPK2 phosphorylation and nuclear localization, coupling DNA damage response to alternative splicing via SRPK2.","method":"Site-directed mutagenesis, nuclear fractionation, phosphomimetic mutant transfection, minigene splicing reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifying required phosphorylation site, functional splicing reporter, fractionation, single lab","pmids":["23613995"],"is_preprint":false},{"year":2014,"finding":"A conserved electronegative docking groove on SRPK2 (not its non-kinase regions) mediates substrate binding for both SRSF1 and acinusS; SRPK2 phosphorylates SRSF1 processively, but an electronegative region on acinusS restricts SRPK2 phosphorylation to a single specific site despite multiple RS dipeptides being present.","method":"In vitro kinase assay, mutagenesis of docking groove, substrate binding assays, phosphorylation kinetics","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis of docking groove, single lab","pmids":["24444330"],"is_preprint":false},{"year":2017,"finding":"mTORC1-activated S6K1 phosphorylates SRPK2 at Ser-494, which primes CK1-mediated Ser-497 phosphorylation; these events promote SRPK2 nuclear translocation where it phosphorylates SR proteins and promotes SR protein binding to U1-70K, inducing splicing of lipogenic pre-mRNAs; inhibition leads to intron retention and nonsense-mediated decay of lipogenic genes, blunting de novo lipid synthesis.","method":"In vitro kinase assay, site-directed mutagenesis, nuclear fractionation, genome-wide transcriptome analysis, RNA splicing assays, metabolic labeling of lipid synthesis, genetic/pharmacological inhibition","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution, phospho-site mutagenesis, genome-wide transcriptome, metabolic functional readout, multiple orthogonal methods","pmids":["29153836"],"is_preprint":false},{"year":2017,"finding":"SRPK2 phosphorylates delta-secretase (AEP) at Ser-226, accelerating its autocatalytic cleavage and cytoplasmic translocation, leading to enhanced enzymatic activity toward APP and tau; phosphomimetic S226D promotes AD pathology in young 3xTg mice, while non-phosphorylatable S226A decreases APP/tau cleavage and attenuates AD pathology in 5XFAD mice.","method":"In vitro kinase assay, site-directed mutagenesis (S226D/S226A), viral injection into mouse models, behavioral testing, histopathological analysis of plaques and tangles","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with phospho-site mutagenesis, in vivo gain- and loss-of-function with multiple pathological readouts","pmids":["28826672"],"is_preprint":false},{"year":2017,"finding":"SRPK2 phosphorylates DDX23 (PRP28) in response to RNA Pol II pausing during transcription; in the absence of SRPK2 or DDX23, R-loops accumulate leading to DNA double-strand breaks and genomic instability.","method":"RNAi knockdown of SRPK2 and DDX23, R-loop detection (immunofluorescence/slot blot), DNA damage assays (γH2AX), transcription inhibitor treatments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with functional R-loop and DNA damage readouts, single lab","pmids":["28076779"],"is_preprint":false},{"year":2019,"finding":"SRPK2 forms a complex with CAST1/ERC2 via coiled-coil domains CC1 and CC4, and overexpression of SRPK2 regulates self-assembly of CAST1/ERC2 in heterologous cells; SRPK2 is localized to brain synaptic fractions, suggesting it modulates presynaptic scaffold assembly.","method":"Co-immunoprecipitation in HEK293T and SH-SY5Y cells, domain deletion analysis, synaptic fractionation, immunofluorescence","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping, synaptic fractionation, overexpression phenotype, single lab","pmids":["31671734"],"is_preprint":false},{"year":2019,"finding":"Full-length SRPK2 exists predominantly as a monomer-dimer equilibrium in solution with an elongated shape; the truncated kinase domain version dimerizes at higher concentrations; the flexible non-kinase regions confer unique structural properties relative to the SRPK family.","method":"Small-angle X-ray scattering (SAXS), analytical size exclusion chromatography, sedimentation velocity analytical ultracentrifugation","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods on recombinant protein, single lab, low-resolution structural data","pmids":["31229549"],"is_preprint":false},{"year":2022,"finding":"CRISPR-Cas9 knockout of SRPK2, but not SRPK1, impairs actin polymerization dynamics as well as proliferative and invasive capacity of B16F10 melanoma cells in vitro, and reduces tumor progression in subcutaneous and caudal vein melanoma models in vivo.","method":"CRISPR-Cas9 knockout, actin polymerization assay, invasion assay, in vivo tumor progression models","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple functional readouts in vitro and in vivo, single lab","pmids":["36212152"],"is_preprint":false},{"year":2024,"finding":"SRPK2 uses a specific docking groove to interact with and phosphorylate the C-terminal arginine-rich domain of HBV core protein (Cp); direct interaction of SRPK2's docking groove with unphosphorylated Cp inhibits premature viral capsid assembly in vitro, whereas Cp phosphorylation reactivates assembly; cryo-EM structure of HBV capsid-SRPK2 complex shows kinases decorating the capsid surface via Cp C-terminal domain; SRPK2 knockout in HepG2 cells suppresses Cp phosphorylation in cellulo.","method":"Cryo-electron microscopy structure determination, pull-down assays, in vitro capsid assembly assay, site-directed mutagenesis of docking groove, SRPK2 knockout in HepG2 cells","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution of capsid assembly, mutagenesis, and cellular KO with phosphorylation readout","pmids":["38324561"],"is_preprint":false},{"year":2023,"finding":"BRD4 recruits SRPK2 to assemble a splicing catalytic platform that controls splicing of ACSL3 pre-mRNA; this BRD4-SRPK2-SRSF2 axis influences arachidonic acid synthesis and susceptibility to erastin-induced ferroptosis in osteosarcoma cells.","method":"BRD4 inhibition, SRPK2 knockdown, RNA splicing assays for ACSL3 pre-mRNA, arachidonic acid measurement, ferroptosis assays in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assay with upstream recruitment mechanism, ferroptosis functional readout, single lab","pmids":["37993451"],"is_preprint":false}],"current_model":"SRPK2 is a serine/arginine protein kinase that phosphorylates RS-domain-containing SR splicing factors and other substrates (PRP28/DDX23, tau, delta-secretase/AEP, HBV core protein, EBV BLRF2) via a conserved docking groove; it is regulated by upstream kinases (mTORC1-S6K1-CK1 and Akt) through sequential phosphorylation events that control its nuclear translocation, where it drives SR protein-dependent splicing of lipogenic and other pre-mRNAs, promotes spliceosomal B complex formation, suppresses R-loop-mediated genomic instability, and—in neurons—triggers cell cycle re-entry and apoptosis through cyclin D1 upregulation and tau hyperphosphorylation."},"narrative":{"mechanistic_narrative":"SRPK2 is a serine/arginine protein kinase that phosphorylates RS-domain-containing substrates with a stringent preference for SR dipeptides, coupling signaling inputs to pre-mRNA splicing and broader cellular outcomes [PMID:9472028]. Substrate recognition is mediated by a conserved electronegative docking groove that determines whether a substrate is phosphorylated processively, as for SRSF1, or at a single restricted site, as for acinusS [PMID:24444330]. Through phosphorylation of SR proteins such as SF2/ASF and SC35, SRPK2 controls the assembly and nuclear distribution of splicing factors and enhances SR protein engagement of U1-70K [PMID:9472028, PMID:9446799, PMID:29153836]. Within the spliceosome it phosphorylates the RS domain of PRP28/DDX23 to stabilize its tri-snRNP association and drive B-complex formation [PMID:18425142], and it resolves co-transcriptional R-loops to limit DNA double-strand breaks and genomic instability [PMID:28076779]. SRPK2 nuclear translocation is gated by sequential upstream phosphorylation: mTORC1-activated S6K1 phosphorylates Ser-494 to prime CK1-mediated Ser-497 phosphorylation, licensing nuclear import and splicing of lipogenic pre-mRNAs to sustain de novo lipid synthesis [PMID:29153836], while Akt phosphorylation of Thr-492 promotes nuclear entry, cyclin D1 upregulation, and 14-3-3 binding that restrains its activity [PMID:19592491]. In neurons SRPK2 is a driver of neurodegenerative pathology: it phosphorylates tau on Ser-214 to suppress microtubule polymerization and axon elongation [PMID:23197718], and phosphorylates delta-secretase (AEP) on Ser-226 to accelerate its activation and cleavage of APP and tau, with phosphomimetic and non-phosphorylatable mutants respectively worsening and attenuating Alzheimer's disease pathology in mouse models [PMID:28826672]. SRPK2 is recruited by partner proteins to assemble splicing platforms—exemplified by BRD4-dependent recruitment controlling ACSL3 splicing and ferroptosis susceptibility [PMID:37993451]—and additionally phosphorylates viral RS-motif substrates including hepatitis B virus core protein and EBV BLRF2 [PMID:12134018, PMID:23326445, PMID:38324561].","teleology":[{"year":1998,"claim":"Established SRPK2 as an SR-protein-specific kinase, defining its core substrate specificity and a role in spliceosome assembly and splicing-factor trafficking.","evidence":"Random peptide selection, in vitro kinase assays, Co-IP, and overexpression imaging of nuclear splicing factors","pmids":["9472028","9446799"],"confidence":"High","gaps":["Did not define endogenous regulation of SRPK2 activity","Physiological splicing targets not yet identified"]},{"year":2002,"claim":"Showed SRPK2 phosphorylates the arginine-rich C-terminal domain of HBV core protein at physiological sites, extending its substrate range to viral RS-like motifs.","evidence":"Kinase purification from HuH-7 lysates, mass spectrometry, in vitro phosphorylation with site mapping","pmids":["12134018"],"confidence":"High","gaps":["Functional consequence for viral replication not addressed in this study"]},{"year":2005,"claim":"Revealed a kinase-independent function of SRPK2 in suppressing HBV pregenomic RNA packaging, separating its catalytic from non-catalytic roles.","evidence":"Wild-type and kinase-dead overexpression in HBV-replicating cells with Southern/Northern blots","pmids":["16122776"],"confidence":"Medium","gaps":["Molecular basis of kinase-independent suppression unresolved","Single lab"]},{"year":2008,"claim":"Defined a direct spliceosomal substrate by showing SRPK2 phosphorylates PRP28/DDX23 RS domain to enable tri-snRNP integration into the B complex.","evidence":"RNAi with complementation, immunodepletion, in vitro splicing reconstitution, snRNP Co-IP in HeLa","pmids":["18425142"],"confidence":"High","gaps":["Upstream signals controlling this phosphorylation not defined here"]},{"year":2009,"claim":"Identified Akt-mediated Thr-492 phosphorylation as a switch controlling SRPK2 nuclear translocation, cyclin D1 upregulation, and neuronal apoptosis, with 14-3-3 as an inhibitory partner.","evidence":"Site-directed mutagenesis, in vitro kinase assays, reciprocal Co-IP, nuclear fractionation, neuronal death assays","pmids":["19592491"],"confidence":"High","gaps":["Direct splicing targets linking SC35 phosphorylation to p53 inactivation not enumerated"]},{"year":2010,"claim":"Showed caspase cleavage generates a nuclear N-terminal SRPK2 fragment that promotes apoptosis, and that Akt/14-3-3 protect SRPK2 from cleavage, integrating it into apoptotic control.","evidence":"Cleavage-site mutagenesis, fractionation, nuclear translocation and cell death assays","pmids":["21056976"],"confidence":"Medium","gaps":["Pro-apoptotic targets of the cleavage fragment unknown","Single lab"]},{"year":2012,"claim":"Established SRPK2 as a direct tau kinase phosphorylating Ser-214 that impairs microtubule dynamics and axon growth, and as an in vivo driver of cognitive deficits.","evidence":"In vitro kinase assay with site mapping, microtubule and axon assays, in vivo lentiviral knockdown with behavior/LTP in APP/PS1 mice","pmids":["23197718"],"confidence":"High","gaps":["Upstream regulation of neuronal SRPK2 not defined here"]},{"year":2013,"claim":"Linked stress and genotoxic signaling to SRPK2 by showing oxidative/DNA-damaging agents drive its phosphorylation, nuclear accumulation, and altered splice-site selection.","evidence":"Site-directed mutagenesis identifying a localization-required serine, fractionation, minigene splicing reporters","pmids":["23613995"],"confidence":"Medium","gaps":["Upstream stress-activated kinase not identified","Single lab"]},{"year":2013,"claim":"Extended viral substrate repertoire by showing SRPK2 phosphorylates the EBV BLRF2 RS motif (Ser-148/150), required for gammaherpesvirus replication.","evidence":"Interaction assays, in vitro kinase assay, S148A/S150A mutagenesis, viral complementation","pmids":["23326445"],"confidence":"Medium","gaps":["Mechanism by which BLRF2 phosphorylation supports replication unclear","Single lab"]},{"year":2014,"claim":"Defined the structural basis of substrate selection, showing a conserved electronegative docking groove dictates processive versus single-site phosphorylation.","evidence":"In vitro kinase assays, docking-groove mutagenesis, substrate binding and phosphorylation kinetics","pmids":["24444330"],"confidence":"Medium","gaps":["Structural model of the groove-substrate complex not resolved in this study","Single lab"]},{"year":2017,"claim":"Placed SRPK2 downstream of mTORC1-S6K1-CK1, showing sequential Ser-494/Ser-497 phosphorylation drives nuclear import and splicing of lipogenic pre-mRNAs to control de novo lipid synthesis.","evidence":"In vitro kinase assays, phospho-site mutagenesis, genome-wide transcriptomics, metabolic lipid labeling, genetic/pharmacological inhibition","pmids":["29153836"],"confidence":"High","gaps":["Full set of lipogenic splicing targets and tissue-specific effects not exhaustively mapped"]},{"year":2017,"claim":"Identified delta-secretase (AEP) Ser-226 as an SRPK2 substrate whose phosphorylation accelerates AEP activation and APP/tau cleavage, causally modulating Alzheimer's pathology in vivo.","evidence":"In vitro kinase assay, S226D/S226A mutagenesis, viral injection into 3xTg/5XFAD mice, behavior and histopathology","pmids":["28826672"],"confidence":"High","gaps":["Signals activating SRPK2 toward AEP in disease not defined"]},{"year":2017,"claim":"Connected SRPK2 to genome stability by showing its phosphorylation of DDX23 during Pol II pausing prevents R-loop accumulation and DNA double-strand breaks.","evidence":"RNAi of SRPK2/DDX23, R-loop and gammaH2AX detection, transcription inhibitor treatments","pmids":["28076779"],"confidence":"Medium","gaps":["Direct demonstration of R-loop resolution mechanism missing","Single lab"]},{"year":2019,"claim":"Uncovered a non-splicing role: SRPK2 binds CAST1/ERC2 via coiled-coil domains and localizes to synapses, implicating it in presynaptic scaffold assembly.","evidence":"Co-IP with domain-deletion mapping, synaptic fractionation, immunofluorescence in HEK293T/SH-SY5Y","pmids":["31671734"],"confidence":"Medium","gaps":["Functional consequence for synaptic transmission untested","Overexpression-based, single lab"]},{"year":2019,"claim":"Characterized the solution behavior of SRPK2, showing a monomer-dimer equilibrium and elongated shape conferred by its non-kinase regions.","evidence":"SAXS, analytical SEC, sedimentation velocity AUC on recombinant protein","pmids":["31229549"],"confidence":"Medium","gaps":["No high-resolution structure","Functional relevance of oligomeric state untested"]},{"year":2022,"claim":"Demonstrated a SRPK2-specific (not SRPK1) requirement for actin dynamics, proliferation, and invasion in melanoma and for tumor progression in vivo.","evidence":"CRISPR-Cas9 knockout, actin polymerization and invasion assays, in vivo melanoma models","pmids":["36212152"],"confidence":"Medium","gaps":["Molecular link between SRPK2 and actin regulation not defined","Single lab"]},{"year":2023,"claim":"Showed SRPK2 is recruited by BRD4 into a SRSF2 splicing platform controlling ACSL3 splicing, arachidonic acid synthesis, and ferroptosis susceptibility.","evidence":"BRD4 inhibition, SRPK2 knockdown, ACSL3 splicing assays, arachidonic acid and ferroptosis readouts in osteosarcoma in vitro and in vivo","pmids":["37993451"],"confidence":"Medium","gaps":["Direct BRD4-SRPK2 interaction interface not mapped","Single lab"]},{"year":2024,"claim":"Resolved how SRPK2 engages HBV capsid, with cryo-EM showing docking-groove binding to unphosphorylated core protein that blocks premature assembly until phosphorylation reactivates it.","evidence":"Cryo-EM of HBV capsid-SRPK2 complex, pull-downs, in vitro capsid assembly assays, docking-groove mutagenesis, SRPK2 KO in HepG2","pmids":["38324561"],"confidence":"High","gaps":["In vivo relevance of assembly inhibition to HBV infection not established"]},{"year":null,"claim":"How SRPK2 substrate selectivity, signaling-gated localization, and tissue-specific phenotypes (lipogenesis, neurodegeneration, tumor invasion, viral assembly) are integrated into a unified regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of a docking-groove-substrate complex","Mechanism linking SRPK2 to actin dynamics undefined","Comprehensive map of physiological splicing targets across tissues lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,7,10,12,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,11]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,11,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,18]}],"complexes":["U4/U6-U5 tri-snRNP"],"partners":["SRSF1","U1-70K","DDX23","AKT1","YWHAB","CAST1/ERC2","BRD4","SRSF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78362","full_name":"SRSF protein kinase 2","aliases":["SFRS protein kinase 2","Serine/arginine-rich protein-specific kinase 2","SR-protein-specific kinase 2"],"length_aa":688,"mass_kda":77.5,"function":"Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splicing factors and the regulation of splicing (PubMed:18559500, PubMed:21056976, PubMed:9472028). Promotes neuronal apoptosis by up-regulating cyclin-D1 (CCND1) expression (PubMed:19592491). This is done by the phosphorylation of SRSF2, leading to the suppression of p53/TP53 phosphorylation thereby relieving the repressive effect of p53/TP53 on cyclin-D1 (CCND1) expression (PubMed:21205200). Phosphorylates ACIN1, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not cyclin A2 up-regulation (PubMed:18559500). Plays an essential role in spliceosomal B complex formation via the phosphorylation of DDX23/PRP28 (PubMed:18425142). Probably by phosphorylating DDX23, leads to the suppression of incorrect R-loops formed during transcription; R-loops are composed of a DNA:RNA hybrid and the associated non-template single-stranded DNA (PubMed:28076779). Can mediate hepatitis B virus (HBV) core protein phosphorylation (PubMed:12134018). Plays a negative role in the regulation of HBV replication through a mechanism not involving the phosphorylation of the core protein but by reducing the packaging efficiency of the pregenomic RNA (pgRNA) without affecting the formation of the viral core particles (PubMed:16122776). Phosphorylates the N-terminus of ERC1 (By similarity)","subcellular_location":"Cytoplasm; Nucleus, nucleoplasm; Nucleus speckle; Chromosome","url":"https://www.uniprot.org/uniprotkb/P78362/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRPK2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000135250","cell_line_id":"CID001274","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"RBM26","stoichiometry":0.2},{"gene":"NSRP1;CCDC55","stoichiometry":0.2},{"gene":"COMMD5","stoichiometry":0.2},{"gene":"CDK9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001274","total_profiled":1310},"omim":[{"mim_id":"617031","title":"PRE-mRNA-PROCESSING FACTOR 38A; PRPF38A","url":"https://www.omim.org/entry/617031"},{"mim_id":"612172","title":"DEAD-BOX HELICASE 23; DDX23","url":"https://www.omim.org/entry/612172"},{"mim_id":"610385","title":"TRANSMEMBRANE PROTEIN 176B; TMEM176B","url":"https://www.omim.org/entry/610385"},{"mim_id":"609434","title":"LUC7-LIKE 3 PRE-mRNA SPLICING FACTOR; LUC7L3","url":"https://www.omim.org/entry/609434"},{"mim_id":"602980","title":"SRSF PROTEIN KINASE 2; SRPK2","url":"https://www.omim.org/entry/602980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Acrosome","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":87.6}],"url":"https://www.proteinatlas.org/search/SRPK2"},"hgnc":{"alias_symbol":["SFRSK2"],"prev_symbol":[]},"alphafold":{"accession":"P78362","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78362","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78362-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78362-F1-predicted_aligned_error_v6.png","plddt_mean":71.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRPK2","jax_strain_url":"https://www.jax.org/strain/search?query=SRPK2"},"sequence":{"accession":"P78362","fasta_url":"https://rest.uniprot.org/uniprotkb/P78362.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78362/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78362"}},"corpus_meta":[{"pmid":"9472028","id":"PMC_9472028","title":"SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9472028","citation_count":275,"is_preprint":false},{"pmid":"29153836","id":"PMC_29153836","title":"Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29153836","citation_count":186,"is_preprint":false},{"pmid":"23071587","id":"PMC_23071587","title":"Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23071587","citation_count":128,"is_preprint":false},{"pmid":"12134018","id":"PMC_12134018","title":"Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12134018","citation_count":124,"is_preprint":false},{"pmid":"18425142","id":"PMC_18425142","title":"Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome.","date":"2008","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18425142","citation_count":114,"is_preprint":false},{"pmid":"19592491","id":"PMC_19592491","title":"Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19592491","citation_count":103,"is_preprint":false},{"pmid":"9446799","id":"PMC_9446799","title":"Novel SR-protein-specific kinase, SRPK2, disassembles nuclear speckles.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9446799","citation_count":102,"is_preprint":false},{"pmid":"28076779","id":"PMC_28076779","title":"Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2-Dependent DDX23 Phosphorylation.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28076779","citation_count":95,"is_preprint":false},{"pmid":"28826672","id":"PMC_28826672","title":"Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28826672","citation_count":55,"is_preprint":false},{"pmid":"23197718","id":"PMC_23197718","title":"SRPK2 phosphorylates tau and mediates the cognitive defects in Alzheimer's disease.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23197718","citation_count":50,"is_preprint":false},{"pmid":"16122776","id":"PMC_16122776","title":"Suppression of hepatitis B virus replication by SRPK1 and SRPK2 via a pathway independent of the phosphorylation of the viral core protein.","date":"2005","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/16122776","citation_count":46,"is_preprint":false},{"pmid":"27041240","id":"PMC_27041240","title":"SRPK2 promotes the growth and migration of the colon cancer cells.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27041240","citation_count":26,"is_preprint":false},{"pmid":"23613995","id":"PMC_23613995","title":"Paraquat modulates alternative pre-mRNA splicing by modifying the intracellular distribution of SRPK2.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23613995","citation_count":22,"is_preprint":false},{"pmid":"23326445","id":"PMC_23326445","title":"An RS motif within the Epstein-Barr virus BLRF2 tegument protein is phosphorylated by SRPK2 and is important for viral replication.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23326445","citation_count":20,"is_preprint":false},{"pmid":"29587239","id":"PMC_29587239","title":"Enhanced expression of SRPK2 contributes to aggressive progression and metastasis in prostate cancer.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29587239","citation_count":19,"is_preprint":false},{"pmid":"10198174","id":"PMC_10198174","title":"Localization of serine kinases, SRPK1 (SFRSK1) and SRPK2 (SFRSK2), specific for the SR family of splicing factors in mouse and human chromosomes.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10198174","citation_count":17,"is_preprint":false},{"pmid":"37993451","id":"PMC_37993451","title":"The BRD4-SRPK2-SRSF2 signal modulates the splicing efficiency of ACSL3 pre-mRNA and influences erastin-induced ferroptosis in osteosarcoma cells.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37993451","citation_count":15,"is_preprint":false},{"pmid":"21056976","id":"PMC_21056976","title":"The N-terminal fragment from caspase-cleaved serine/arginine protein-specific kinase2 (SRPK2) translocates into the nucleus and promotes apoptosis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21056976","citation_count":13,"is_preprint":false},{"pmid":"31833327","id":"PMC_31833327","title":"Downregulation of SRPK2 promotes cell cycle arrest though E2F1 in non-small cell lung cancer.","date":"2019","source":"European journal of histochemistry : EJH","url":"https://pubmed.ncbi.nlm.nih.gov/31833327","citation_count":12,"is_preprint":false},{"pmid":"31671734","id":"PMC_31671734","title":"Serine-Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31671734","citation_count":10,"is_preprint":false},{"pmid":"36096767","id":"PMC_36096767","title":"An IGF-1R-mTORC1-SRPK2 signaling Axis contributes to FASN regulation in breast cancer.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36096767","citation_count":10,"is_preprint":false},{"pmid":"38945203","id":"PMC_38945203","title":"LTR retrotransposon-derived LncRNA LINC01446 promotes hepatocellular carcinoma progression and angiogenesis by regulating the SRPK2/SRSF1/VEGF axis.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38945203","citation_count":9,"is_preprint":false},{"pmid":"31898732","id":"PMC_31898732","title":"Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31898732","citation_count":7,"is_preprint":false},{"pmid":"32671994","id":"PMC_32671994","title":"CRISPR/Cas9-mediated double knockout of SRPK1 and SRPK2 in a nasopharyngeal carcinoma cell line.","date":"2019","source":"Cancer reports (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32671994","citation_count":7,"is_preprint":false},{"pmid":"38324561","id":"PMC_38324561","title":"SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38324561","citation_count":6,"is_preprint":false},{"pmid":"36212152","id":"PMC_36212152","title":"Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36212152","citation_count":6,"is_preprint":false},{"pmid":"24444330","id":"PMC_24444330","title":"Primary structural features of SR-like protein acinusS govern the phosphorylation mechanism by SRPK2.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24444330","citation_count":6,"is_preprint":false},{"pmid":"35153686","id":"PMC_35153686","title":"SRPK2 Expression and Beta-Amyloid Accumulation Are Associated With BV2 Microglia Activation.","date":"2022","source":"Frontiers in integrative neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35153686","citation_count":2,"is_preprint":false},{"pmid":"31229549","id":"PMC_31229549","title":"Insights into the full-length SRPK2 structure and its hydrodynamic behavior.","date":"2019","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31229549","citation_count":2,"is_preprint":false},{"pmid":"42178601","id":"PMC_42178601","title":"Oncogenic Role of SRPK2 in Different Types of Cancer: A Systematic Review.","date":"2026","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42178601","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16602,"output_tokens":4784,"usd":0.060783,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12854,"output_tokens":5339,"usd":0.098873,"stage2_stop_reason":"end_turn"},"total_usd":0.159656,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SRPK2 is an SR protein-specific kinase with a stringent preference for SR dipeptides; phosphorylation of ASF/SF2 by SRPK2 enhances its interaction with U1 70K, and overexpression of SRPK2 induces redistribution of splicing factors in the nucleus, indicating a role in spliceosome assembly and trafficking of splicing factors.\",\n      \"method\": \"Random peptide selection for phosphorylation site preference, in vitro kinase assay, co-immunoprecipitation, overexpression with immunofluorescence microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro kinase assay, peptide selection, Co-IP, live-cell imaging), replicated across SRPK1 and SRPK2, foundational study\",\n      \"pmids\": [\"9472028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Overexpression of mouse SRPK2 causes disassembly of nuclear speckles containing cotransfected SF2/ASF and endogenous SC35, and SRPK2 phosphorylates SF2/ASF on the same sites as SRPK1 in vitro.\",\n      \"method\": \"In vitro kinase assay with phosphopeptide mapping, overexpression with immunofluorescence of nuclear speckles\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus phosphopeptide mapping and cell imaging, single lab\",\n      \"pmids\": [\"9446799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRPK1 and SRPK2 are the major cellular kinases that phosphorylate the arginine-rich C-terminal domain of hepatitis B virus core protein on the same serine residues phosphorylated in vivo; both were identified by purification, mass spectrometry, and immunoblot from HuH-7 lysates.\",\n      \"method\": \"Kinase purification from cell lysates, mass spectrometry identification, in vitro phosphorylation assay, immunoblot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification, mass spectrometry, in vitro reconstitution with site mapping; replicated between SRPK1 and SRPK2\",\n      \"pmids\": [\"12134018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SRPK1 and SRPK2 suppress HBV replication by reducing pregenomic RNA packaging efficiency without affecting core particle formation; this suppressive effect is independent of their kinase activity toward the core protein, as kinase-dead mutants retain suppressive activity and overexpression does not alter in vivo core protein phosphorylation.\",\n      \"method\": \"Overexpression of wild-type and kinase-dead mutants in HBV-replicating cells, Southern blot for HBV DNA, Northern blot for pgRNA packaging\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutagenesis plus functional viral replication assays, single lab\",\n      \"pmids\": [\"16122776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRPK2 associates with the U4/U6-U5 tri-snRNP and phosphorylates the RS domain of human PRP28 (DDX23); this phosphorylation is required for stable PRP28 association with the tri-snRNP and for tri-snRNP integration into the spliceosomal B complex.\",\n      \"method\": \"RNAi knockdown in HeLa cells, immunodepletion/complementation of nuclear extracts, in vitro splicing assays, co-immunoprecipitation with snRNP fractions\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — RNAi with rescue/complementation, immunodepletion, in vitro splicing reconstitution, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18425142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Akt phosphorylates SRPK2 on Thr-492, promoting SRPK2 nuclear translocation, cyclin D1 upregulation, cell cycle reentry, and apoptosis in neurons; SRPK2 phosphorylates SC35, inactivating p53 and contributing to cyclin D1 upregulation; 14-3-3 binding to Akt-phosphorylated SRPK2 inhibits these events.\",\n      \"method\": \"Site-directed mutagenesis, in vitro kinase assay, co-immunoprecipitation, nuclear fractionation, neuronal overexpression/knockdown with cell death readouts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-site mutagenesis, reciprocal Co-IP, subcellular fractionation, and functional neuronal death assays combined in one study\",\n      \"pmids\": [\"19592491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SRPK2 is cleaved by caspases at Asp-139 and Asp-403 during apoptosis; the N-terminal cleavage product translocates to the nucleus and promotes chromatin condensation and apoptotic cell death; Akt phosphorylation of SRPK2 prevents caspase cleavage, and 14-3-3β binding to Akt-phosphorylated SRPK2 further protects it from degradation.\",\n      \"method\": \"Site-directed mutagenesis of caspase cleavage sites, subcellular fractionation, nuclear translocation assays, cell death assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of cleavage sites, fractionation, functional apoptosis assays, single lab\",\n      \"pmids\": [\"21056976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRPK2 directly phosphorylates tau on Ser-214, suppresses tau-dependent microtubule polymerization, and inhibits axonal elongation in neurons; depletion of SRPK2 in dentate gyrus of APP/PS1 mice reduces tau phosphorylation and alleviates cognitive deficits and impaired LTP.\",\n      \"method\": \"In vitro kinase assay with site mapping, microtubule polymerization assay, axon elongation assay, in vivo lentiviral knockdown, behavioral and electrophysiological tests\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with site identification, in vivo genetic knockdown with multiple functional readouts\",\n      \"pmids\": [\"23197718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRPK2 phosphorylates the RS motif (Ser-148 and Ser-150) of EBV tegument protein BLRF2; mutation of this RS motif abrogates BLRF2's ability to support gammaherpesvirus replication.\",\n      \"method\": \"Binary and co-complex protein interaction assays, in vitro kinase assay, mutagenesis (S148A+S150A), viral replication complementation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, mutagenesis, and viral functional complementation, single lab\",\n      \"pmids\": [\"23326445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Paraquat treatment induces phosphorylation and nuclear accumulation of SRPK2, leading to increased SR protein phosphorylation and altered splice site selection; site-specific mutagenesis identified a single serine residue required for nuclear localization; genotoxic agents (cisplatin, γ-radiation) also promote SRPK2 phosphorylation and nuclear localization, coupling DNA damage response to alternative splicing via SRPK2.\",\n      \"method\": \"Site-directed mutagenesis, nuclear fractionation, phosphomimetic mutant transfection, minigene splicing reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifying required phosphorylation site, functional splicing reporter, fractionation, single lab\",\n      \"pmids\": [\"23613995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A conserved electronegative docking groove on SRPK2 (not its non-kinase regions) mediates substrate binding for both SRSF1 and acinusS; SRPK2 phosphorylates SRSF1 processively, but an electronegative region on acinusS restricts SRPK2 phosphorylation to a single specific site despite multiple RS dipeptides being present.\",\n      \"method\": \"In vitro kinase assay, mutagenesis of docking groove, substrate binding assays, phosphorylation kinetics\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with mutagenesis of docking groove, single lab\",\n      \"pmids\": [\"24444330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1-activated S6K1 phosphorylates SRPK2 at Ser-494, which primes CK1-mediated Ser-497 phosphorylation; these events promote SRPK2 nuclear translocation where it phosphorylates SR proteins and promotes SR protein binding to U1-70K, inducing splicing of lipogenic pre-mRNAs; inhibition leads to intron retention and nonsense-mediated decay of lipogenic genes, blunting de novo lipid synthesis.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, nuclear fractionation, genome-wide transcriptome analysis, RNA splicing assays, metabolic labeling of lipid synthesis, genetic/pharmacological inhibition\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution, phospho-site mutagenesis, genome-wide transcriptome, metabolic functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"29153836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRPK2 phosphorylates delta-secretase (AEP) at Ser-226, accelerating its autocatalytic cleavage and cytoplasmic translocation, leading to enhanced enzymatic activity toward APP and tau; phosphomimetic S226D promotes AD pathology in young 3xTg mice, while non-phosphorylatable S226A decreases APP/tau cleavage and attenuates AD pathology in 5XFAD mice.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S226D/S226A), viral injection into mouse models, behavioral testing, histopathological analysis of plaques and tangles\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with phospho-site mutagenesis, in vivo gain- and loss-of-function with multiple pathological readouts\",\n      \"pmids\": [\"28826672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRPK2 phosphorylates DDX23 (PRP28) in response to RNA Pol II pausing during transcription; in the absence of SRPK2 or DDX23, R-loops accumulate leading to DNA double-strand breaks and genomic instability.\",\n      \"method\": \"RNAi knockdown of SRPK2 and DDX23, R-loop detection (immunofluorescence/slot blot), DNA damage assays (γH2AX), transcription inhibitor treatments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with functional R-loop and DNA damage readouts, single lab\",\n      \"pmids\": [\"28076779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRPK2 forms a complex with CAST1/ERC2 via coiled-coil domains CC1 and CC4, and overexpression of SRPK2 regulates self-assembly of CAST1/ERC2 in heterologous cells; SRPK2 is localized to brain synaptic fractions, suggesting it modulates presynaptic scaffold assembly.\",\n      \"method\": \"Co-immunoprecipitation in HEK293T and SH-SY5Y cells, domain deletion analysis, synaptic fractionation, immunofluorescence\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping, synaptic fractionation, overexpression phenotype, single lab\",\n      \"pmids\": [\"31671734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Full-length SRPK2 exists predominantly as a monomer-dimer equilibrium in solution with an elongated shape; the truncated kinase domain version dimerizes at higher concentrations; the flexible non-kinase regions confer unique structural properties relative to the SRPK family.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), analytical size exclusion chromatography, sedimentation velocity analytical ultracentrifugation\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods on recombinant protein, single lab, low-resolution structural data\",\n      \"pmids\": [\"31229549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR-Cas9 knockout of SRPK2, but not SRPK1, impairs actin polymerization dynamics as well as proliferative and invasive capacity of B16F10 melanoma cells in vitro, and reduces tumor progression in subcutaneous and caudal vein melanoma models in vivo.\",\n      \"method\": \"CRISPR-Cas9 knockout, actin polymerization assay, invasion assay, in vivo tumor progression models\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"36212152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRPK2 uses a specific docking groove to interact with and phosphorylate the C-terminal arginine-rich domain of HBV core protein (Cp); direct interaction of SRPK2's docking groove with unphosphorylated Cp inhibits premature viral capsid assembly in vitro, whereas Cp phosphorylation reactivates assembly; cryo-EM structure of HBV capsid-SRPK2 complex shows kinases decorating the capsid surface via Cp C-terminal domain; SRPK2 knockout in HepG2 cells suppresses Cp phosphorylation in cellulo.\",\n      \"method\": \"Cryo-electron microscopy structure determination, pull-down assays, in vitro capsid assembly assay, site-directed mutagenesis of docking groove, SRPK2 knockout in HepG2 cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure, in vitro reconstitution of capsid assembly, mutagenesis, and cellular KO with phosphorylation readout\",\n      \"pmids\": [\"38324561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD4 recruits SRPK2 to assemble a splicing catalytic platform that controls splicing of ACSL3 pre-mRNA; this BRD4-SRPK2-SRSF2 axis influences arachidonic acid synthesis and susceptibility to erastin-induced ferroptosis in osteosarcoma cells.\",\n      \"method\": \"BRD4 inhibition, SRPK2 knockdown, RNA splicing assays for ACSL3 pre-mRNA, arachidonic acid measurement, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assay with upstream recruitment mechanism, ferroptosis functional readout, single lab\",\n      \"pmids\": [\"37993451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRPK2 is a serine/arginine protein kinase that phosphorylates RS-domain-containing SR splicing factors and other substrates (PRP28/DDX23, tau, delta-secretase/AEP, HBV core protein, EBV BLRF2) via a conserved docking groove; it is regulated by upstream kinases (mTORC1-S6K1-CK1 and Akt) through sequential phosphorylation events that control its nuclear translocation, where it drives SR protein-dependent splicing of lipogenic and other pre-mRNAs, promotes spliceosomal B complex formation, suppresses R-loop-mediated genomic instability, and—in neurons—triggers cell cycle re-entry and apoptosis through cyclin D1 upregulation and tau hyperphosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRPK2 is a serine/arginine protein kinase that phosphorylates RS-domain-containing substrates with a stringent preference for SR dipeptides, coupling signaling inputs to pre-mRNA splicing and broader cellular outcomes [#0]. Substrate recognition is mediated by a conserved electronegative docking groove that determines whether a substrate is phosphorylated processively, as for SRSF1, or at a single restricted site, as for acinusS [#10]. Through phosphorylation of SR proteins such as SF2/ASF and SC35, SRPK2 controls the assembly and nuclear distribution of splicing factors and enhances SR protein engagement of U1-70K [#0, #1, #11]. Within the spliceosome it phosphorylates the RS domain of PRP28/DDX23 to stabilize its tri-snRNP association and drive B-complex formation [#4], and it resolves co-transcriptional R-loops to limit DNA double-strand breaks and genomic instability [#13]. SRPK2 nuclear translocation is gated by sequential upstream phosphorylation: mTORC1-activated S6K1 phosphorylates Ser-494 to prime CK1-mediated Ser-497 phosphorylation, licensing nuclear import and splicing of lipogenic pre-mRNAs to sustain de novo lipid synthesis [#11], while Akt phosphorylation of Thr-492 promotes nuclear entry, cyclin D1 upregulation, and 14-3-3 binding that restrains its activity [#5]. In neurons SRPK2 is a driver of neurodegenerative pathology: it phosphorylates tau on Ser-214 to suppress microtubule polymerization and axon elongation [#7], and phosphorylates delta-secretase (AEP) on Ser-226 to accelerate its activation and cleavage of APP and tau, with phosphomimetic and non-phosphorylatable mutants respectively worsening and attenuating Alzheimer's disease pathology in mouse models [#12]. SRPK2 is recruited by partner proteins to assemble splicing platforms—exemplified by BRD4-dependent recruitment controlling ACSL3 splicing and ferroptosis susceptibility [#18]—and additionally phosphorylates viral RS-motif substrates including hepatitis B virus core protein and EBV BLRF2 [#2, #8, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established SRPK2 as an SR-protein-specific kinase, defining its core substrate specificity and a role in spliceosome assembly and splicing-factor trafficking.\",\n      \"evidence\": \"Random peptide selection, in vitro kinase assays, Co-IP, and overexpression imaging of nuclear splicing factors\",\n      \"pmids\": [\"9472028\", \"9446799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define endogenous regulation of SRPK2 activity\", \"Physiological splicing targets not yet identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed SRPK2 phosphorylates the arginine-rich C-terminal domain of HBV core protein at physiological sites, extending its substrate range to viral RS-like motifs.\",\n      \"evidence\": \"Kinase purification from HuH-7 lysates, mass spectrometry, in vitro phosphorylation with site mapping\",\n      \"pmids\": [\"12134018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for viral replication not addressed in this study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed a kinase-independent function of SRPK2 in suppressing HBV pregenomic RNA packaging, separating its catalytic from non-catalytic roles.\",\n      \"evidence\": \"Wild-type and kinase-dead overexpression in HBV-replicating cells with Southern/Northern blots\",\n      \"pmids\": [\"16122776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of kinase-independent suppression unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a direct spliceosomal substrate by showing SRPK2 phosphorylates PRP28/DDX23 RS domain to enable tri-snRNP integration into the B complex.\",\n      \"evidence\": \"RNAi with complementation, immunodepletion, in vitro splicing reconstitution, snRNP Co-IP in HeLa\",\n      \"pmids\": [\"18425142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling this phosphorylation not defined here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified Akt-mediated Thr-492 phosphorylation as a switch controlling SRPK2 nuclear translocation, cyclin D1 upregulation, and neuronal apoptosis, with 14-3-3 as an inhibitory partner.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro kinase assays, reciprocal Co-IP, nuclear fractionation, neuronal death assays\",\n      \"pmids\": [\"19592491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets linking SC35 phosphorylation to p53 inactivation not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed caspase cleavage generates a nuclear N-terminal SRPK2 fragment that promotes apoptosis, and that Akt/14-3-3 protect SRPK2 from cleavage, integrating it into apoptotic control.\",\n      \"evidence\": \"Cleavage-site mutagenesis, fractionation, nuclear translocation and cell death assays\",\n      \"pmids\": [\"21056976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-apoptotic targets of the cleavage fragment unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established SRPK2 as a direct tau kinase phosphorylating Ser-214 that impairs microtubule dynamics and axon growth, and as an in vivo driver of cognitive deficits.\",\n      \"evidence\": \"In vitro kinase assay with site mapping, microtubule and axon assays, in vivo lentiviral knockdown with behavior/LTP in APP/PS1 mice\",\n      \"pmids\": [\"23197718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulation of neuronal SRPK2 not defined here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked stress and genotoxic signaling to SRPK2 by showing oxidative/DNA-damaging agents drive its phosphorylation, nuclear accumulation, and altered splice-site selection.\",\n      \"evidence\": \"Site-directed mutagenesis identifying a localization-required serine, fractionation, minigene splicing reporters\",\n      \"pmids\": [\"23613995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream stress-activated kinase not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended viral substrate repertoire by showing SRPK2 phosphorylates the EBV BLRF2 RS motif (Ser-148/150), required for gammaherpesvirus replication.\",\n      \"evidence\": \"Interaction assays, in vitro kinase assay, S148A/S150A mutagenesis, viral complementation\",\n      \"pmids\": [\"23326445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which BLRF2 phosphorylation supports replication unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the structural basis of substrate selection, showing a conserved electronegative docking groove dictates processive versus single-site phosphorylation.\",\n      \"evidence\": \"In vitro kinase assays, docking-groove mutagenesis, substrate binding and phosphorylation kinetics\",\n      \"pmids\": [\"24444330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of the groove-substrate complex not resolved in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SRPK2 downstream of mTORC1-S6K1-CK1, showing sequential Ser-494/Ser-497 phosphorylation drives nuclear import and splicing of lipogenic pre-mRNAs to control de novo lipid synthesis.\",\n      \"evidence\": \"In vitro kinase assays, phospho-site mutagenesis, genome-wide transcriptomics, metabolic lipid labeling, genetic/pharmacological inhibition\",\n      \"pmids\": [\"29153836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of lipogenic splicing targets and tissue-specific effects not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified delta-secretase (AEP) Ser-226 as an SRPK2 substrate whose phosphorylation accelerates AEP activation and APP/tau cleavage, causally modulating Alzheimer's pathology in vivo.\",\n      \"evidence\": \"In vitro kinase assay, S226D/S226A mutagenesis, viral injection into 3xTg/5XFAD mice, behavior and histopathology\",\n      \"pmids\": [\"28826672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals activating SRPK2 toward AEP in disease not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected SRPK2 to genome stability by showing its phosphorylation of DDX23 during Pol II pausing prevents R-loop accumulation and DNA double-strand breaks.\",\n      \"evidence\": \"RNAi of SRPK2/DDX23, R-loop and gammaH2AX detection, transcription inhibitor treatments\",\n      \"pmids\": [\"28076779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of R-loop resolution mechanism missing\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a non-splicing role: SRPK2 binds CAST1/ERC2 via coiled-coil domains and localizes to synapses, implicating it in presynaptic scaffold assembly.\",\n      \"evidence\": \"Co-IP with domain-deletion mapping, synaptic fractionation, immunofluorescence in HEK293T/SH-SY5Y\",\n      \"pmids\": [\"31671734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for synaptic transmission untested\", \"Overexpression-based, single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterized the solution behavior of SRPK2, showing a monomer-dimer equilibrium and elongated shape conferred by its non-kinase regions.\",\n      \"evidence\": \"SAXS, analytical SEC, sedimentation velocity AUC on recombinant protein\",\n      \"pmids\": [\"31229549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure\", \"Functional relevance of oligomeric state untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a SRPK2-specific (not SRPK1) requirement for actin dynamics, proliferation, and invasion in melanoma and for tumor progression in vivo.\",\n      \"evidence\": \"CRISPR-Cas9 knockout, actin polymerization and invasion assays, in vivo melanoma models\",\n      \"pmids\": [\"36212152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between SRPK2 and actin regulation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed SRPK2 is recruited by BRD4 into a SRSF2 splicing platform controlling ACSL3 splicing, arachidonic acid synthesis, and ferroptosis susceptibility.\",\n      \"evidence\": \"BRD4 inhibition, SRPK2 knockdown, ACSL3 splicing assays, arachidonic acid and ferroptosis readouts in osteosarcoma in vitro and in vivo\",\n      \"pmids\": [\"37993451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BRD4-SRPK2 interaction interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how SRPK2 engages HBV capsid, with cryo-EM showing docking-groove binding to unphosphorylated core protein that blocks premature assembly until phosphorylation reactivates it.\",\n      \"evidence\": \"Cryo-EM of HBV capsid-SRPK2 complex, pull-downs, in vitro capsid assembly assays, docking-groove mutagenesis, SRPK2 KO in HepG2\",\n      \"pmids\": [\"38324561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of assembly inhibition to HBV infection not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SRPK2 substrate selectivity, signaling-gated localization, and tissue-specific phenotypes (lipogenesis, neurodegeneration, tumor invasion, viral assembly) are integrated into a unified regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of a docking-groove-substrate complex\", \"Mechanism linking SRPK2 to actin dynamics undefined\", \"Comprehensive map of physiological splicing targets across tissues lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 7, 10, 12, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 11, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 18]}\n    ],\n    \"complexes\": [\"U4/U6-U5 tri-snRNP\"],\n    \"partners\": [\"SRSF1\", \"U1-70K\", \"DDX23\", \"AKT1\", \"YWHAB\", \"CAST1/ERC2\", \"BRD4\", \"SRSF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}