{"gene":"SRPK1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1996,"finding":"SRPK1 phosphorylates SR proteins (including ASF/SF2) in vitro with a strong preference for Ser-Arg sites, whereas Clk/Sty has broader substrate specificity (Ser-Arg, Ser-Lys, Ser-Pro). SRPK1 phosphorylates ASF/SF2 at sites also phosphorylated in vivo, as shown by tryptic peptide mapping.","method":"In vitro kinase assay, tryptic peptide mapping, comparison with in vivo phosphorylation sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with site-mapping and in vivo validation, replicated across multiple SR protein substrates","pmids":["8798720"],"is_preprint":false},{"year":2002,"finding":"SRPK1 (95 kDa) was purified from HuH-7 cell lysates and identified by mass spectrometry as a kinase that interacts with HBV core protein and phosphorylates its arginine-rich C-terminal domain on the same serine residues phosphorylated in vivo. SRPK2 (115 kDa) was identified as a related kinase with the same activity.","method":"Affinity purification, mass spectrometry, in vitro kinase assay, immunoblot","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — purification, MS identification, in vitro phosphorylation confirmed to match in vivo sites; CDK and PKC ruled out by biochemical controls","pmids":["12134018"],"is_preprint":false},{"year":2003,"finding":"HSV-1 protein ICP27 interacts with SRPK1 and relocalizes it to the nucleus; SRPK1 activity is altered in the presence of ICP27 in vitro, leading to hypophosphorylation of SR proteins and inhibition of spliceosome assembly at complex A stage.","method":"Co-immunoprecipitation, in vitro kinase assay, nuclear extract splicing assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown by Co-IP, in vitro kinase activity alteration demonstrated, single lab","pmids":["12660167"],"is_preprint":false},{"year":2005,"finding":"Mass spectrometric analysis showed SRPK1 preferentially phosphorylates a short stretch of amino acids in the N-terminal portion (RS1) of the RS domain of ASF/SF2, while Clk/Sty phosphorylates all available serines. Both kinases use fully processive catalytic mechanisms but with different extents of RS domain coverage.","method":"Mass spectrometry, in vitro kinase assay, kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — first MS-level mapping of phosphosites combined with kinetic mechanistic analysis, single rigorous study with multiple orthogonal methods","pmids":["16223727"],"is_preprint":false},{"year":2005,"finding":"SRPK1 and SRPK2 suppress HBV replication by reducing pgRNA packaging efficiency without affecting core particle formation, through a mechanism independent of their phosphorylation of HBV core protein (kinase-dead mutants still suppressed replication).","method":"Overexpression/dominant-negative in cell-based HBV replication assay, Western blot","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead mutant controls establish the phosphorylation-independent mechanism; single lab","pmids":["16122776"],"is_preprint":false},{"year":2007,"finding":"SRPK1 uses a 'grab-and-pull' directional mechanism: it docks near the C-terminus of the RS1 segment of ASF/SF2 and moves in an N-terminal direction during processive phosphorylation. Multiple Ser-to-Ala and deletion mutations did not disrupt phosphorylation at other sites regardless of position.","method":"Region-specific phosphorylation monitoring with lysyl endoproteinase cleavage, Arg-to-Lys mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with site-specific phosphorylation kinetics, single lab with multiple orthogonal experiments","pmids":["18155240"],"is_preprint":false},{"year":2007,"finding":"HPV1 E1^E4 protein binds SRPK1 through an arginine-rich domain and a region facilitating E1^E4 oligomerization; SRPK1 phosphorylates HPV1 E1^E4 in vitro, and E1^E4 modulates SRPK1 autophosphorylation. SRPK1 is sequestered into E4 inclusion bodies in terminally differentiated cells in HPV1 warts.","method":"In vitro kinase assay, co-immunoprecipitation, immunofluorescence colocalization, mutagenesis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding, phosphorylation, and localization demonstrated with multiple methods; single lab","pmids":["17360743"],"is_preprint":false},{"year":2008,"finding":"Crystal structure (2.9 Å) of SRPK1:ASF/SF2 complex reveals that the RS domain docks in an acidic groove distal to the active site. Phosphorylation at the C-terminal end of the RS domain generates a primed phosphoserine that binds a basic site in the kinase, facilitating directional sliding of the RS peptide through the docking groove to the active site and processive phosphorylation, ending with unfolding of a beta strand of RRM.","method":"X-ray crystallography, biochemical phosphorylation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.9 Å with biochemical validation of the sliding mechanism","pmids":["18342604"],"is_preprint":false},{"year":2008,"finding":"Efficient processive phosphorylation of ASF/SF2 by SRPK1 requires stable but flexible interactions: while recognition of the RS domain by the docking groove initiates the directional mechanism, continued processive phosphorylation requires fine-tuning of contacts with the RRM1-RRM2 module. An electropositive pocket in SRPK1 stabilizes newly phosphorylated serines.","method":"Single-turnover and multiturnover kinetics, deletion mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic kinetic analysis with mutagenesis, single rigorous study with multiple orthogonal methods","pmids":["18687337"],"is_preprint":false},{"year":2009,"finding":"SRPK1 directly binds cochaperones Hsp40/DNAJc8 and Aha1, which mediate dynamic interactions with Hsp70 and Hsp90, anchoring SRPK1 in the cytoplasm. Inhibition of Hsp90 ATPase activity or osmotic shock triggers dissociation of SRPK1 from chaperone complexes, causing nuclear translocation, differential SR protein phosphorylation, and altered splice site selection.","method":"Co-immunoprecipitation, Hsp90 ATPase inhibitor treatment, cellular fractionation, splicing reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple chaperones, translocation experiments, functional splicing readout; replicated with two independent stimuli (drug + stress)","pmids":["19240134"],"is_preprint":false},{"year":2009,"finding":"SRPK1 initiates phosphorylation in an 'initiation box' near the middle/C-terminal end of the RS1 segment of ASF/SF2 and proceeds in an N-terminal direction. This initiation requires both the docking groove of SRPK1 and RRM2 of ASF/SF2.","method":"Engineered footprinting, single-turnover kinetics, mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods; single lab","pmids":["19477182"],"is_preprint":false},{"year":2009,"finding":"RRM2 of ASF/SF2 does not bind SRPK1 efficiently unless the docking groove is occupied by the RS domain; this domain cross-talk enhances processive phosphorylation. RRM-SRPK1 contacts control the folding of a critical beta-strand in RRM2, whose unfolding drives N-terminal serines of the RS domain into the active site.","method":"Biochemical binding assays, mutagenesis, kinetic analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — allosteric mechanism established by mutagenesis and kinetics; single rigorous study","pmids":["19886675"],"is_preprint":false},{"year":2009,"finding":"Arginine methylation of the ICP27 RGG box regulates its interaction with SRPK1: hypomethylation of ICP27 (lysine substitutions or methylation inhibitor) decreased co-immunoprecipitation and colocalization with SRPK1.","method":"Co-immunoprecipitation, colocalization studies, methylation inhibitor (adenosine dialdehyde) treatment","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and colocalization with genetic and pharmacological controls; single lab","pmids":["19553338"],"is_preprint":false},{"year":2011,"finding":"WT1 binds the SRPK1 promoter at a specific WT1 binding site and transcriptionally represses SRPK1 expression. In WT1 mutant cells, de-repression of SRPK1 leads to SRSF1 hyperphosphorylation, switching VEGF splicing toward pro-angiogenic isoforms.","method":"ChIP, promoter reporter assay, siRNA knockdown, VEGF splicing RT-PCR, in vivo angiogenesis/tumor models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP of WT1 at SRPK1 promoter, reporter assay, siRNA rescue, in vivo validation; multiple labs/models","pmids":["22172722"],"is_preprint":false},{"year":2011,"finding":"The N-terminal extension of SRPK1 adopts a stable structure (stabilized by the spacer insert domain) that positively regulates SR protein binding by stabilizing the docking groove. The spacer insert domain (SID) is intrinsically disordered and mediates chaperone interactions. Both the N-terminus and SID equally enhance SR protein turnover by altering catalytic loop stability.","method":"Hydrogen-deuterium exchange, steady-state kinetics, deletion mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HDX and kinetic analysis define domain contributions; single rigorous study","pmids":["21600902"],"is_preprint":false},{"year":2011,"finding":"SRPK1-mediated phosphorylation of LBR on its RS domain occurs on the same sites phosphorylated in vivo. Phosphorylation by SRPK1 is necessary for LBR association with histone H3, as shown by GST pull-down and molecular dynamics simulations.","method":"GST pull-down, molecular dynamics simulations, synthetic peptide kinase assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical pulldown confirming phosphorylation-dependent histone H3 interaction, supported by MD simulations; single lab","pmids":["22056509"],"is_preprint":false},{"year":2011,"finding":"During extended multisite phosphorylation of SRSF1 by SRPK1, ADP release is the rate-limiting step. Phosphoryl transfer is fast (t1/2 = 0.1 s for first phosphate) but multisite phosphorylation is slower (t1/2 = 15 s). Binding affinity, phosphoryl transfer rate, and ADP exchange rate all decline as phosphorylation of the RS domain progresses.","method":"Rapid quench flow transient-state kinetics, mutagenesis, viscosometric experiments","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — transient-state kinetic mechanism established with multiple methods; single rigorous study","pmids":["21728354"],"is_preprint":false},{"year":2012,"finding":"Sequences outside the SRPK1 kinase domain (a segment of the spacer insert domain and the N-terminal extension) function cooperatively as a nucleotide release factor, increasing ADP dissociation rate and thereby enhancing SR protein phosphorylation.","method":"Deletion analysis, steady-state kinetics, nucleotide exchange assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — deletion mutagenesis combined with kinetic analysis identifies specific sequences; single rigorous study","pmids":["22839969"],"is_preprint":false},{"year":2013,"finding":"SRPK1 uses a distributive mechanism for phosphorylating Tra2β(ΔN) (short RS repeats), contrasting with the processive mechanism used for SRSF1 (long RS repeats). The docking groove, required for SRSF1 phosphorylation, is dispensable for Tra2β(ΔN) phosphorylation.","method":"In vitro kinase assays, steady-state and transient kinetics, docking groove mutants","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic distinction established by kinetic analysis with docking groove mutants; single rigorous study","pmids":["24074032"],"is_preprint":false},{"year":2014,"finding":"SRPK1 ablation in mouse embryonic fibroblasts induces cell transformation linked to constitutive Akt activation. SRPK1 physically interacts with Akt phosphatase PHLPP1, and downregulated SRPK1 impairs recruitment of PHLPP1 to Akt, preventing Akt dephosphorylation. Conversely, SRPK1 overexpression sequesters PHLPP1 away from Akt, also causing constitutive Akt activation.","method":"Mouse embryonic fibroblast transformation assay, genome-wide phosphoproteomics, co-immunoprecipitation, Western blot","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide phosphoproteomics plus Co-IP establishing SRPK1-PHLPP1 interaction with KO phenotype; multiple orthogonal methods","pmids":["24703948"],"is_preprint":false},{"year":2014,"finding":"SRPK1 phosphorylation of SRSF1 regulates nuclear translocation of SRSF1, which promotes inclusion of alternative exon 3b into Rac1 pre-mRNA to generate Rac1b in colorectal cells. SRPK1 knockdown or inhibition of its catalytic activity reduces SRSF1 phosphorylation and nuclear translocation, decreasing Rac1b levels.","method":"siRNA knockdown, SRPK1 inhibitor, splicing RT-PCR, SRSF1 localization studies","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition with functional splicing readout; single lab","pmids":["24550521"],"is_preprint":false},{"year":2014,"finding":"HPV1 E1^E4 potently inhibits SRPK1 phosphorylation of host SR proteins and of the viral E2 protein (which contains SR/RS dipeptides in its hinge region). E1^E4-mediated inhibition of SRPK1 alters E2 nuclear localization in primary keratinocytes.","method":"In vitro kinase assay, mutagenesis of E2 phosphoacceptor sites, immunofluorescence in primary keratinocytes","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase inhibition demonstrated, functional consequence on E2 localization shown; single lab","pmids":["25142587"],"is_preprint":false},{"year":2015,"finding":"SRPK1 knockdown inhibits focal adhesion reorganization and suppresses metastasis of breast cancer cells to distant organs (lung, liver, spleen) in two independent murine models, establishing SRPK1 as a determinant of tumor cell migration and metastasis.","method":"shRNA knockdown, phagokinetic track assay, live cell migration assays, two murine metastasis models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent in vivo models, siRNA screen validated in live migration assays, focal adhesion phenotype; strong replication","pmids":["25774502"],"is_preprint":false},{"year":2016,"finding":"SRPK1 interacts with an RS-like domain in the N terminus of CLK1. SRPK1 facilitates the release of phosphorylated SR proteins from CLK1 (which lacks the ability to release them on its own), enabling efficient splice-site recognition and spliceosome assembly. The two kinases fulfill separate catalytic roles for SR protein phosphorylation control.","method":"Biochemical binding assays, SR protein phosphorylation/release assays, spliceosome assembly assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding mapped, functional release mechanism demonstrated biochemically with spliceosome assays; single rigorous study with multiple methods","pmids":["27397683"],"is_preprint":false},{"year":2016,"finding":"SRPK1 phosphorylates LBR on Ser residues in its RS domain (all RS serines are approximate equal acceptor sites), while Akt specifically targets Ser80 and Ser82. 3D modeling shows only Ser80/Ser82-containing peptides fit the Akt active site, distinguishing direct Akt phosphorylation from SRPK1 activity on the same domain.","method":"Synthetic peptide kinase assays, recombinant LBR RS domain mutants, 3D modeling with MD simulations","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis with in vitro kinase assays; single lab","pmids":["27105349"],"is_preprint":false},{"year":2017,"finding":"Cysteine residues in the SRPK1 spacer domain (Cys356, Cys386, Cys427, Cys455) and in the first catalytic domain (Cys188) form disulfide bonds required for kinase activity and nuclear translocation in response to genotoxic stress. Mutation of individual cysteines (except Cys414) impairs kinase activity and nuclear translocation.","method":"Systematic cysteine mutagenesis, kinase activity assays, nuclear localization assays, splicing reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with functional readouts (kinase activity, localization, splicing); single lab","pmids":["28166275"],"is_preprint":false},{"year":2018,"finding":"SRPK1 phosphorylates 7 of the 8 hydroxy amino acids in the HBV core protein (HBc) CTD as identified by combining Phos-tag gel electrophoresis, mass spectrometry, and mutagenesis. Phosphorylation of all seven sites drastically reduces nonspecific RNA encapsidation and alters CTD surface accessibility without major structural changes in the capsid shell.","method":"Bacterial coexpression with SRPK1, Phos-tag gel, mass spectrometry, mutagenesis, electron microscopy","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — site identification by MS with mutagenesis validation, functional RNA-binding consequences demonstrated; multiple orthogonal methods","pmids":["30566530"],"is_preprint":false},{"year":2018,"finding":"SRPK1 inhibition in AML leads to altered isoform usage of BRD4 (and other genes), causing a switch from the short to the long BRD4 isoform. This switch is associated with BRD4 eviction from BCL2 and MYC genomic loci and mediates anti-leukemic effects including cell cycle arrest and leukemic cell differentiation.","method":"RNA-seq, shRNA knockdown, pharmacological inhibition, xenograft survival assay, BRD4 isoform overexpression rescue","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus isoform-specific rescue experiments; single lab","pmids":["30568163"],"is_preprint":false},{"year":2018,"finding":"SRPKIN-1, the first covalent SRPK1/2 inhibitor, forms an irreversible bond with a tyrosine phenol group in the ATP-binding pocket and attenuates SR protein phosphorylation at submicromolar concentrations, converting pro-angiogenic VEGF-A165a to anti-angiogenic VEGF-A165b more potently than SRPIN340 or siRNA knockdown.","method":"Covalent inhibitor design, kinome-wide selectivity profiling, SR protein phosphorylation assay, VEGF splicing RT-PCR, laser-induced murine retinal neovascularization model","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — irreversible mechanism characterized structurally, kinome-wide selectivity profiled, functional VEGF splicing and in vivo efficacy demonstrated","pmids":["29478907"],"is_preprint":false},{"year":2020,"finding":"SRPK1 catalyzes site-specific phosphorylation of protamine in the fertilized oocyte, initiating protamine-to-histone exchange (parental genome reprogramming). Protamine undergoes DNA-dependent phase transition to gel-like condensates; SRPK1-mediated phosphorylation opens these structures, enabling protamine dismissal by NPM2 and HIRA-mediated H3.3 deposition. ATAC-seq shows chromatin accessibility is erased in early pronuclei in a protamine phosphorylation-dependent manner.","method":"In vitro SRPK1 kinase assay on protamine, ATAC-seq, phase condensate experiments, NPM2/HIRA recruitment assays in fertilized oocytes","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation plus genome-wide ATAC-seq with rescue experiments; multiple orthogonal methods in single rigorous study","pmids":["32169215"],"is_preprint":false},{"year":2020,"finding":"Tip60 mediates acetylation of SRPK1, which is associated with chemotherapy sensitivity. In cisplatin-resistant breast cancer cells, SRPK1 acetylation is reduced while phosphorylation and kinase activity are increased, favoring anti-apoptotic splice variants. Re-sensitization was achieved by enhancing SRPK1 acetylation or inhibiting its kinase activity.","method":"Western blot with acetylation/phosphorylation antibodies, Tip60 overexpression/knockdown, drug resistance assays, splicing analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Tip60-mediated acetylation identified with functional resistance phenotype; single lab, limited mechanistic detail in abstract","pmids":["32461560"],"is_preprint":false},{"year":2020,"finding":"LIMK2 promotes phosphorylation and activation of SRPK1. LIMK2 inhibition blocks SRPK1 phosphorylation and its activity. SRPK1 genetic or pharmacological inhibition blocks metastatic attributes of TNBC cells similarly to LIMK2 inhibition, placing SRPK1 downstream of LIMK2 in a metastasis pathway.","method":"SILAC-based phosphoproteomics, shRNA knockdown, pharmacological inhibition, in vitro metastasis assays, in vivo metastasis model","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics identifies SRPK1 as LIMK2 substrate, epistasis confirmed with genetic/pharmacological tools; single lab","pmids":["32859889"],"is_preprint":false},{"year":2020,"finding":"In cancer cells (PC3 prostate, K562 leukemia), WT1 activates SRPK1 transcription through a canonical WT1 binding site adjacent to the transcription start site. The transcriptional corepressor BASP1 reverses WT1-mediated SRPK1 activation; both WT1 and BASP1 co-precipitate with the SRPK1 promoter by ChIP.","method":"siRNA knockdown, promoter reporter assay, ChIP, site-directed mutagenesis of WT1 binding site","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with mutant controls; single lab","pmids":["33017668"],"is_preprint":false},{"year":2020,"finding":"Ibuprofen prevents SRPK1 nuclear translocation by promoting disassembly of a WNK1/GSK3β/SRPK1 protein kinase complex, which exposes GSK3β Ser9 to inhibitory phosphorylation by AKT, resulting in cytoplasmic retention of SRPK1, SRSF1 hypophosphorylation, and inhibition of RAC1B alternative splicing in BRAF-mutant CRC cells.","method":"Co-immunoprecipitation (WNK1/GSK3β/SRPK1 complex), subcellular fractionation, phosphorylation assays, splicing RT-PCR","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex plus phosphorylation and localization readouts; single lab","pmids":["33315986"],"is_preprint":false},{"year":2021,"finding":"FGF-2 promotes angiogenesis by activating a SRSF1/SRSF3/SRPK1-dependent axis in endothelial cells that controls VEGFR1 pre-mRNA alternative splicing to generate soluble VEGFR1 splice variants (sVEGFR1-ex12).","method":"2D/3D endothelial cell cultures, siRNA knockdown, 3D collagen sprouting assay, in vivo sponge/zebrafish angiogenesis models, VEGFR1 splicing RT-PCR","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo models with SRPK1 knockdown and splicing readout; single lab","pmids":["34433435"],"is_preprint":false},{"year":2021,"finding":"SRPK1/2 enhance phosphorylation and nuclear translocation of SRSF1 (counteracted by PP1α), which promotes MKNK2 alternative splicing toward the MKNK2b isoform in colon adenocarcinoma cells.","method":"Western blot, PCR, siRNA knockdown, xenograft models","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with splicing and localization readouts; single lab","pmids":["33602301"],"is_preprint":false},{"year":2021,"finding":"USP39 directly binds SRSF1 and SRPK1 through its (101-565) fragment and promotes SRSF1 phosphorylation to regulate VEGF-A alternative splicing, suppressing VEGF-A165b in renal cell carcinoma cells.","method":"Affinity purification, mass spectrometry, co-immunoprecipitation, Western blot, splicing RT-PCR","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS and Co-IP establishing complex; functional splicing readout; single lab","pmids":["34544400"],"is_preprint":false},{"year":2023,"finding":"Phosphorylation of SRSF1 by SRPK1 promotes inclusion of full-length PD-1 (flPD1) over the soluble ΔEx3PD1 isoform. SRPK1 shRNA knockdown or pharmacological inhibition (SPHINX31) switches splicing toward ΔEx3PD1, which acts as a soluble antagonist preventing cancer cell-mediated T cell repression (equivalent to anti-PD1 antibody effect).","method":"shRNA knockdown, SPHINX31 inhibitor, PCR/Western blot in PBMCs and T cells, IL-2 ELISA, co-culture of cancer cells and T cells","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological SRPK1 inhibition with functional T cell readout; single lab","pmids":["37973660"],"is_preprint":false},{"year":2023,"finding":"SRPK1 promotes TKI (gefitinib) resistance in NSCLC independently of its kinase activity: the SRPK1 spacer domain binds GSK3β and enhances its autophosphorylation at Ser9, activating the Wnt pathway and increasing Bcl-X expression. SRPK1 also facilitates LEF1/β-catenin binding to the EGFR promoter to increase EGFR expression.","method":"In vitro and in vivo drug resistance assays, co-immunoprecipitation (SRPK1-GSK3β), Western blot, kinase-dead mutant controls, ChIP (LEF1/β-catenin at EGFR promoter)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing SRPK1-GSK3β interaction with kinase-dead mutant controls showing kinase-independent mechanism; single lab","pmids":["36869126"],"is_preprint":false},{"year":2024,"finding":"METTL3 directly methylates SRPK1 mRNA at m6A sites, which stabilizes SRPK1 mRNA in an IGF2BP2-dependent manner. Elevated SRPK1 then promotes glycolysis by interacting with hnRNPA1 and facilitating PKM alternative splicing to upregulate PKM2 in lung adenocarcinoma.","method":"m6A epitranscriptomic microarray, MeRIP, RIP, RNA stability assay, co-immunoprecipitation (SRPK1-hnRNPA1), metabolic quantification, Western blot","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA-biochemical methods (MeRIP, RIP, RNA stability) and Co-IP; single lab","pmids":["39095708"],"is_preprint":false},{"year":1999,"finding":"SRPK1 phosphorylates LBR (lamin B receptor) on the same RS repeat sites as the LBR kinase purified from turkey erythrocytes, and with similar kinetics, establishing SRPK1 as an LBR kinase in addition to its role in splicing factor phosphorylation.","method":"Synthetic peptide kinase assays, in vitro kinase assay with recombinant LBR fragments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay with site mapping on LBR; single lab","pmids":["10049757"],"is_preprint":false},{"year":2001,"finding":"Expression of human SRPK1 in yeast SKY1 deletion mutants restores cisplatin sensitivity, establishing functional conservation. Antisense-mediated downregulation of SRPK1 in human A2780 ovarian carcinoma cells conferred 4-fold cisplatin resistance.","method":"Heterologous complementation in yeast, antisense oligodeoxynucleotides in human cells, drug sensitivity assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species complementation plus human cell antisense; single lab with two model systems","pmids":["11585720"],"is_preprint":false},{"year":2015,"finding":"X-ray crystal structure of SRPK1 bound to SRPIN340 identified the compound's binding pocket in SRPK1. Novel inhibitors occupying a binding pocket created by the unique helical insert of SRPK1 and triggering a backbone flip in the hinge region achieve potent (<10 nM) and selective SRPK1 inhibition, SRSF1 hypophosphorylation, and VEGF-A splicing shift to anti-angiogenic isoforms in vitro and in vivo.","method":"X-ray crystallography, in vitro kinase assay, SRSF1 phosphorylation assay, VEGF splicing RT-PCR, choroidal angiogenesis in vivo model","journal":"ACS chemical biology / Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of SRPK1-inhibitor complex with functional VEGF splicing and in vivo validation","pmids":["28135068","25993998"],"is_preprint":false}],"current_model":"SRPK1 is a cytoplasmic SR protein-specific kinase anchored by an intrinsically disordered spacer domain to an Hsp70/Hsp90/Hsp40/Aha1 chaperone complex; upon stress or Hsp90 inhibition it translocates to the nucleus where it directionally and processively phosphorylates the RS domains of SR splicing factors (especially SRSF1/ASF/SF2) via a substrate-sliding mechanism that initiates at an 'initiation box' and proceeds N-terminally, releasing SR proteins for spliceosome assembly and splice-site selection—a process counterbalanced by CLK1 binding and regulated by Tip60-mediated acetylation; WT1 transcriptionally controls SRPK1 expression, while LIMK2 activates it by phosphorylation; downstream, SRPK1-driven SRSF1 phosphorylation controls alternative splicing of VEGF, RAC1B, PD-1, BRD4, and PKM2, and SRPK1 also modulates Akt activity by scaffolding the phosphatase PHLPP1, phosphorylates non-SR substrates including LBR and protamine (initiating parental genome reprogramming after fertilization), and is exploited or inhibited by viral proteins (HSV ICP27, HPV E1^E4, HBV core) to subvert host splicing."},"narrative":{"mechanistic_narrative":"SRPK1 is a serine/arginine protein kinase that controls pre-mRNA splicing by phosphorylating the arginine/serine (RS) domains of SR splicing factors, especially SRSF1/ASF-SF2, with strict specificity for Ser-Arg sites [PMID:8798720]. It engages substrates through a directional, processive mechanism: an acidic docking groove distal to the active site captures the RS domain, and an 'initiation box' near the C-terminal end of the RS1 segment seeds phosphorylation that then proceeds N-terminally by substrate sliding, a 'grab-and-pull' process driven by primed phosphoserine binding and coupled to controlled unfolding of an RRM2 beta-strand [PMID:18155240, PMID:18342604, PMID:19477182, PMID:19886675]; this processive mode applies to long-RS substrates such as SRSF1 while short-RS substrates like Tra2β are phosphorylated distributively without the docking groove [PMID:24074032]. SRPK1's intrinsically disordered spacer-insert domain and N-terminal extension act as a nucleotide-release factor and chaperone-binding module: SRPK1 is anchored in the cytoplasm by an Hsp40/Aha1/Hsp70/Hsp90 complex, and Hsp90 inhibition or osmotic/genotoxic stress dissociates it to drive nuclear translocation and altered SR-protein phosphorylation and splice-site selection [PMID:19240134, PMID:21600902, PMID:22839969, PMID:28166275]. SRPK1 cooperates with CLK1, releasing CLK1-bound phosphorylated SR proteins to enable spliceosome assembly [PMID:27397683]. Through SRSF1 phosphorylation and nuclear translocation, SRPK1 governs the alternative splicing of VEGF, RAC1B, BRD4, MKNK2, PKM, and PD-1, and is wired into oncogenic programs where it is transcriptionally repressed by WT1 and de-repression yields pro-angiogenic VEGF isoforms [PMID:22172722, PMID:24550521, PMID:30568163, PMID:33602301, PMID:37973660, PMID:39095708]. SRPK1 drives tumor cell migration, metastasis, and chemoresistance, acting downstream of LIMK2 and via both kinase-dependent splicing control and kinase-independent scaffolding of PHLPP1 (modulating Akt) and GSK3β/Wnt signaling [PMID:24703948, PMID:25774502, PMID:32859889, PMID:36869126]. Beyond splicing factors it phosphorylates the RS domain of the lamin B receptor [PMID:22056509, PMID:10049757] and phosphorylates protamine to initiate protamine-to-histone exchange and parental genome reprogramming after fertilization [PMID:32169215]. SRPK1 is also targeted by viral proteins (HBV core, HSV ICP27, HPV E1^E4) that exploit or inhibit its activity to subvert host splicing [PMID:12134018, PMID:12660167, PMID:17360743, PMID:30566530], and it is a validated drug target with selective and covalent ATP-pocket inhibitors that reverse pro-angiogenic VEGF splicing [PMID:29478907, PMID:28135068, PMID:25993998].","teleology":[{"year":1996,"claim":"Established SRPK1 as an SR-protein kinase with strict Ser-Arg specificity that targets the physiological phosphosites of ASF/SF2, defining its core substrate class distinct from the broader-specificity Clk/Sty.","evidence":"In vitro kinase assays with tryptic peptide mapping against in vivo phosphosites","pmids":["8798720"],"confidence":"High","gaps":["Did not define how site selection within the RS domain is achieved","Cellular consequences for splicing not addressed"]},{"year":1999,"claim":"Extended SRPK1's substrate range beyond splicing factors by showing it phosphorylates the lamin B receptor RS domain at authentic sites with kinetics matching the native LBR kinase.","evidence":"Synthetic peptide and recombinant LBR fragment kinase assays","pmids":["10049757"],"confidence":"Medium","gaps":["Functional consequence of LBR phosphorylation not established here","In vivo relevance not tested"]},{"year":2001,"claim":"Linked SRPK1 levels to cisplatin sensitivity, providing the first functional/cancer-relevant phenotype and demonstrating cross-species conservation of function.","evidence":"Yeast SKY1-deletion complementation and antisense knockdown in ovarian carcinoma cells with drug-sensitivity assays","pmids":["11585720"],"confidence":"Medium","gaps":["Molecular basis of the chemoresistance phenotype unresolved","Substrates mediating the effect not identified"]},{"year":2003,"claim":"Showed that viral and stress-responsive control of SRPK1 occurs partly through relocalization, as HSV-1 ICP27 binds SRPK1, drives it to the nucleus, and alters SR-protein phosphorylation to block spliceosome assembly.","evidence":"Co-IP, in vitro kinase assays, and nuclear-extract splicing assays","pmids":["12660167"],"confidence":"Medium","gaps":["Mechanism by which ICP27 alters SRPK1 catalysis unclear","Single-lab reciprocal interaction"]},{"year":2008,"claim":"Defined the structural and kinetic basis of processive RS-domain phosphorylation, resolving how SRPK1 achieves directional, ordered modification of SR proteins.","evidence":"2.9 Å crystal structure of SRPK1:ASF/SF2 plus single/multiturnover kinetics and docking-groove mutagenesis","pmids":["18342604","18687337","18155240"],"confidence":"High","gaps":["Structure of full-length SRPK1 including disordered spacer not resolved","How chaperone binding modulates the catalytic cycle not addressed structurally"]},{"year":2009,"claim":"Established cytoplasmic chaperone anchoring as the switch governing SRPK1 nuclear access, and refined the initiation site and allosteric RRM cross-talk underlying processivity.","evidence":"Reciprocal Co-IP with Hsp40/Aha1/Hsp70/Hsp90, Hsp90-inhibitor and osmotic-shock translocation assays, plus footprinting and binding/kinetic analyses","pmids":["19240134","19477182","19886675","19553338"],"confidence":"High","gaps":["Identity of nuclear targeting/import machinery not defined","Quantitative stoichiometry of the chaperone complex unresolved"]},{"year":2011,"claim":"Identified the spacer-insert and N-terminal extension as regulatory modules controlling catalysis and chaperone binding, and placed SRPK1 in an oncogenic transcriptional circuit with WT1 governing VEGF splicing.","evidence":"HDX and steady/transient kinetics on truncations; ChIP, promoter reporter, siRNA rescue, and in vivo tumor/angiogenesis models for WT1 regulation; GST pull-down for LBR-H3","pmids":["21600902","21728354","22172722","22056509"],"confidence":"High","gaps":["How the disordered spacer mechanically couples to the kinase domain remains incompletely defined","Other SRPK1-controlled angiogenic targets not yet mapped at this stage"]},{"year":2014,"claim":"Revealed kinase-independent scaffolding functions and cancer-driving splicing outputs, broadening SRPK1 from a splicing kinase to a signaling hub controlling Akt and oncogenic isoform switches.","evidence":"MEF transformation assay with phosphoproteomics and Co-IP for the SRPK1-PHLPP1-Akt axis; siRNA/inhibitor with splicing RT-PCR for RAC1B; nucleotide-release and distributive-mechanism kinetics","pmids":["24703948","24550521","22839969","24074032"],"confidence":"High","gaps":["Whether PHLPP1 scaffolding is direct and how it is regulated not fully resolved","Balance between kinase-dependent and scaffolding roles in vivo unclear"]},{"year":2016,"claim":"Clarified the division of labor between SRPK1 and CLK1, showing SRPK1 enables release of CLK1-bound phosphorylated SR proteins to permit spliceosome assembly.","evidence":"Biochemical binding mapping, SR-protein phosphorylation/release assays, and spliceosome assembly assays","pmids":["27397683"],"confidence":"High","gaps":["Cellular dynamics of the SRPK1-CLK1 handoff not quantified","Single rigorous study"]},{"year":2017,"claim":"Connected redox/genotoxic stress to SRPK1 activation by identifying disulfide-forming cysteines required for kinase activity and nuclear translocation.","evidence":"Systematic cysteine mutagenesis with kinase, localization, and splicing reporter readouts","pmids":["28166275"],"confidence":"Medium","gaps":["Direct demonstration of disulfide formation in cells limited","Upstream oxidative signal not defined"]},{"year":2018,"claim":"Validated SRPK1 as a druggable therapeutic target and expanded its disease-relevant splicing repertoire to BRD4 in leukemia.","evidence":"Covalent inhibitor SRPKIN-1 with kinome-wide profiling, VEGF splicing and retinal neovascularization model; RNA-seq and isoform-rescue for BRD4 in AML","pmids":["29478907","30568163"],"confidence":"High","gaps":["Selectivity over SRPK2 and off-target effects need fuller delineation","BRD4 mechanism is single-lab"]},{"year":2020,"claim":"Established a developmental role in genome reprogramming and multiple upstream regulators (LIMK2, Tip60, WT1/BASP1, WNK1/GSK3β) that set SRPK1 activity and localization.","evidence":"In vitro protamine kinase assay with ATAC-seq, condensate, and NPM2/HIRA recruitment in oocytes; phosphoproteomics/epistasis for LIMK2; acetylation Westerns for Tip60; ChIP/reporter for WT1/BASP1; Co-IP/fractionation for the WNK1/GSK3β complex","pmids":["32169215","32859889","32461560","33017668","33315986"],"confidence":"High","gaps":["Interplay among acetylation, phosphorylation, and chaperone control not integrated","In vivo significance of LBR/protamine activities in mammals beyond model systems not established"]},{"year":2024,"claim":"Showed SRPK1 itself is post-transcriptionally regulated by m6A and feeds metabolic and immune programs through additional splicing targets.","evidence":"MeRIP/RIP/RNA-stability and Co-IP for METTL3-IGF2BP2-SRPK1-hnRNPA1-PKM2 (2024); shRNA/SPHINX31 with T-cell co-culture for PD-1 splicing (2023); FGF-2/VEGFR1 and MKNK2 splicing models","pmids":["39095708","37973660","34433435","33602301"],"confidence":"Medium","gaps":["These splicing axes are individually single-lab","Direct SRPK1 phosphorylation events on each pathway not always demonstrated"]},{"year":null,"claim":"How the chaperone-anchored cytoplasmic pool, acetylation/phosphorylation/redox switches, and upstream kinases are integrated to set SRPK1 nuclear timing and substrate choice in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking all regulatory inputs to nuclear translocation","Structure of full-length SRPK1 with the disordered spacer unsolved","Selectivity of substrate engagement (SR proteins vs LBR vs protamine) in cells not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,5,7,15,26,29,40]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,16,17]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[16,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[19,23,38]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,33]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,9,25]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,9,20,23,27,35,37,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[13,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,31,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,6,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[29]}],"complexes":["Hsp40(DNAJc8)/Aha1/Hsp70/Hsp90 chaperone complex","WNK1/GSK3β/SRPK1 complex"],"partners":["SRSF1","CLK1","PHLPP1","GSK3Β","AHA1","HNRNPA1","LIMK2","USP39"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96SB4","full_name":"SRSF protein kinase 1","aliases":["SFRS protein kinase 1","Serine/arginine-rich protein-specific kinase 1","SR-protein-specific kinase 1"],"length_aa":655,"mass_kda":74.3,"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. Plays a central role in the regulatory network for splicing, controlling the intranuclear distribution of splicing factors in interphase cells and the reorganization of nuclear speckles during mitosis. Can influence additional steps of mRNA maturation, as well as other cellular activities, such as chromatin reorganization in somatic and sperm cells and cell cycle progression. Isoform 2 phosphorylates SFRS2, ZRSR2, LBR and PRM1. Isoform 2 phosphorylates SRSF1 using a directional (C-terminal to N-terminal) and a dual-track mechanism incorporating both processive phosphorylation (in which the kinase stays attached to the substrate after each round of phosphorylation) and distributive phosphorylation steps (in which the kinase and substrate dissociate after each phosphorylation event). The RS domain of SRSF1 binds first to a docking groove in the large lobe of the kinase domain of SRPK1. This induces certain structural changes in SRPK1 and/or RRM2 domain of SRSF1, allowing RRM2 to bind the kinase and initiate phosphorylation. The cycles continue for several phosphorylation steps in a processive manner (steps 1-8) until the last few phosphorylation steps (approximately steps 9-12). During that time, a mechanical stress induces the unfolding of the beta-4 motif in RRM2, which then docks at the docking groove of SRPK1. This also signals RRM2 to begin to dissociate, which facilitates SRSF1 dissociation after phosphorylation is completed. Isoform 2 can mediate hepatitis B virus (HBV) core protein phosphorylation. It 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. Isoform 1 and isoform 2 can induce splicing of exon 10 in MAPT/TAU. The ratio of isoform 1/isoform 2 plays a decisive role in determining cell fate in K-562 leukemic cell line: isoform 2 favors proliferation where as isoform 1 favors differentiation. Phosphorylates the N-terminus of ERC1 (PubMed:30745339)","subcellular_location":"Cytoplasm; Nucleus, nucleoplasm; Nucleus speckle; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96SB4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRPK1","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SRPK1","total_profiled":1310},"omim":[{"mim_id":"612172","title":"DEAD-BOX HELICASE 23; DDX23","url":"https://www.omim.org/entry/612172"},{"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"},{"mim_id":"601951","title":"CDC-LIKE KINASE 1; CLK1","url":"https://www.omim.org/entry/601951"},{"mim_id":"601939","title":"SRSF PROTEIN KINASE 1; SRPK1","url":"https://www.omim.org/entry/601939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRPK1"},"hgnc":{"alias_symbol":["SFRSK1"],"prev_symbol":[]},"alphafold":{"accession":"Q96SB4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SB4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SB4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SB4-F1-predicted_aligned_error_v6.png","plddt_mean":70.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRPK1","jax_strain_url":"https://www.jax.org/strain/search?query=SRPK1"},"sequence":{"accession":"Q96SB4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96SB4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96SB4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SB4"}},"corpus_meta":[{"pmid":"22172722","id":"PMC_22172722","title":"WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.","date":"2011","source":"Cancer 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SRPK1 phosphorylates ASF/SF2 at sites also phosphorylated in vivo, as shown by tryptic peptide mapping.\",\n      \"method\": \"In vitro kinase assay, tryptic peptide mapping, comparison with in vivo phosphorylation sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with site-mapping and in vivo validation, replicated across multiple SR protein substrates\",\n      \"pmids\": [\"8798720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRPK1 (95 kDa) was purified from HuH-7 cell lysates and identified by mass spectrometry as a kinase that interacts with HBV core protein and phosphorylates its arginine-rich C-terminal domain on the same serine residues phosphorylated in vivo. SRPK2 (115 kDa) was identified as a related kinase with the same activity.\",\n      \"method\": \"Affinity purification, mass spectrometry, in vitro kinase assay, immunoblot\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purification, MS identification, in vitro phosphorylation confirmed to match in vivo sites; CDK and PKC ruled out by biochemical controls\",\n      \"pmids\": [\"12134018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HSV-1 protein ICP27 interacts with SRPK1 and relocalizes it to the nucleus; SRPK1 activity is altered in the presence of ICP27 in vitro, leading to hypophosphorylation of SR proteins and inhibition of spliceosome assembly at complex A stage.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, nuclear extract splicing assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown by Co-IP, in vitro kinase activity alteration demonstrated, single lab\",\n      \"pmids\": [\"12660167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mass spectrometric analysis showed SRPK1 preferentially phosphorylates a short stretch of amino acids in the N-terminal portion (RS1) of the RS domain of ASF/SF2, while Clk/Sty phosphorylates all available serines. Both kinases use fully processive catalytic mechanisms but with different extents of RS domain coverage.\",\n      \"method\": \"Mass spectrometry, in vitro kinase assay, kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — first MS-level mapping of phosphosites combined with kinetic mechanistic analysis, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"16223727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SRPK1 and SRPK2 suppress HBV replication by reducing pgRNA packaging efficiency without affecting core particle formation, through a mechanism independent of their phosphorylation of HBV core protein (kinase-dead mutants still suppressed replication).\",\n      \"method\": \"Overexpression/dominant-negative in cell-based HBV replication assay, Western blot\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead mutant controls establish the phosphorylation-independent mechanism; single lab\",\n      \"pmids\": [\"16122776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SRPK1 uses a 'grab-and-pull' directional mechanism: it docks near the C-terminus of the RS1 segment of ASF/SF2 and moves in an N-terminal direction during processive phosphorylation. Multiple Ser-to-Ala and deletion mutations did not disrupt phosphorylation at other sites regardless of position.\",\n      \"method\": \"Region-specific phosphorylation monitoring with lysyl endoproteinase cleavage, Arg-to-Lys mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with site-specific phosphorylation kinetics, single lab with multiple orthogonal experiments\",\n      \"pmids\": [\"18155240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HPV1 E1^E4 protein binds SRPK1 through an arginine-rich domain and a region facilitating E1^E4 oligomerization; SRPK1 phosphorylates HPV1 E1^E4 in vitro, and E1^E4 modulates SRPK1 autophosphorylation. SRPK1 is sequestered into E4 inclusion bodies in terminally differentiated cells in HPV1 warts.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, immunofluorescence colocalization, mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding, phosphorylation, and localization demonstrated with multiple methods; single lab\",\n      \"pmids\": [\"17360743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure (2.9 Å) of SRPK1:ASF/SF2 complex reveals that the RS domain docks in an acidic groove distal to the active site. Phosphorylation at the C-terminal end of the RS domain generates a primed phosphoserine that binds a basic site in the kinase, facilitating directional sliding of the RS peptide through the docking groove to the active site and processive phosphorylation, ending with unfolding of a beta strand of RRM.\",\n      \"method\": \"X-ray crystallography, biochemical phosphorylation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.9 Å with biochemical validation of the sliding mechanism\",\n      \"pmids\": [\"18342604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Efficient processive phosphorylation of ASF/SF2 by SRPK1 requires stable but flexible interactions: while recognition of the RS domain by the docking groove initiates the directional mechanism, continued processive phosphorylation requires fine-tuning of contacts with the RRM1-RRM2 module. An electropositive pocket in SRPK1 stabilizes newly phosphorylated serines.\",\n      \"method\": \"Single-turnover and multiturnover kinetics, deletion mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic kinetic analysis with mutagenesis, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"18687337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRPK1 directly binds cochaperones Hsp40/DNAJc8 and Aha1, which mediate dynamic interactions with Hsp70 and Hsp90, anchoring SRPK1 in the cytoplasm. Inhibition of Hsp90 ATPase activity or osmotic shock triggers dissociation of SRPK1 from chaperone complexes, causing nuclear translocation, differential SR protein phosphorylation, and altered splice site selection.\",\n      \"method\": \"Co-immunoprecipitation, Hsp90 ATPase inhibitor treatment, cellular fractionation, splicing reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple chaperones, translocation experiments, functional splicing readout; replicated with two independent stimuli (drug + stress)\",\n      \"pmids\": [\"19240134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SRPK1 initiates phosphorylation in an 'initiation box' near the middle/C-terminal end of the RS1 segment of ASF/SF2 and proceeds in an N-terminal direction. This initiation requires both the docking groove of SRPK1 and RRM2 of ASF/SF2.\",\n      \"method\": \"Engineered footprinting, single-turnover kinetics, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods; single lab\",\n      \"pmids\": [\"19477182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RRM2 of ASF/SF2 does not bind SRPK1 efficiently unless the docking groove is occupied by the RS domain; this domain cross-talk enhances processive phosphorylation. RRM-SRPK1 contacts control the folding of a critical beta-strand in RRM2, whose unfolding drives N-terminal serines of the RS domain into the active site.\",\n      \"method\": \"Biochemical binding assays, mutagenesis, kinetic analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — allosteric mechanism established by mutagenesis and kinetics; single rigorous study\",\n      \"pmids\": [\"19886675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Arginine methylation of the ICP27 RGG box regulates its interaction with SRPK1: hypomethylation of ICP27 (lysine substitutions or methylation inhibitor) decreased co-immunoprecipitation and colocalization with SRPK1.\",\n      \"method\": \"Co-immunoprecipitation, colocalization studies, methylation inhibitor (adenosine dialdehyde) treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and colocalization with genetic and pharmacological controls; single lab\",\n      \"pmids\": [\"19553338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WT1 binds the SRPK1 promoter at a specific WT1 binding site and transcriptionally represses SRPK1 expression. In WT1 mutant cells, de-repression of SRPK1 leads to SRSF1 hyperphosphorylation, switching VEGF splicing toward pro-angiogenic isoforms.\",\n      \"method\": \"ChIP, promoter reporter assay, siRNA knockdown, VEGF splicing RT-PCR, in vivo angiogenesis/tumor models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP of WT1 at SRPK1 promoter, reporter assay, siRNA rescue, in vivo validation; multiple labs/models\",\n      \"pmids\": [\"22172722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The N-terminal extension of SRPK1 adopts a stable structure (stabilized by the spacer insert domain) that positively regulates SR protein binding by stabilizing the docking groove. The spacer insert domain (SID) is intrinsically disordered and mediates chaperone interactions. Both the N-terminus and SID equally enhance SR protein turnover by altering catalytic loop stability.\",\n      \"method\": \"Hydrogen-deuterium exchange, steady-state kinetics, deletion mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HDX and kinetic analysis define domain contributions; single rigorous study\",\n      \"pmids\": [\"21600902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRPK1-mediated phosphorylation of LBR on its RS domain occurs on the same sites phosphorylated in vivo. Phosphorylation by SRPK1 is necessary for LBR association with histone H3, as shown by GST pull-down and molecular dynamics simulations.\",\n      \"method\": \"GST pull-down, molecular dynamics simulations, synthetic peptide kinase assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical pulldown confirming phosphorylation-dependent histone H3 interaction, supported by MD simulations; single lab\",\n      \"pmids\": [\"22056509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"During extended multisite phosphorylation of SRSF1 by SRPK1, ADP release is the rate-limiting step. Phosphoryl transfer is fast (t1/2 = 0.1 s for first phosphate) but multisite phosphorylation is slower (t1/2 = 15 s). Binding affinity, phosphoryl transfer rate, and ADP exchange rate all decline as phosphorylation of the RS domain progresses.\",\n      \"method\": \"Rapid quench flow transient-state kinetics, mutagenesis, viscosometric experiments\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — transient-state kinetic mechanism established with multiple methods; single rigorous study\",\n      \"pmids\": [\"21728354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sequences outside the SRPK1 kinase domain (a segment of the spacer insert domain and the N-terminal extension) function cooperatively as a nucleotide release factor, increasing ADP dissociation rate and thereby enhancing SR protein phosphorylation.\",\n      \"method\": \"Deletion analysis, steady-state kinetics, nucleotide exchange assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — deletion mutagenesis combined with kinetic analysis identifies specific sequences; single rigorous study\",\n      \"pmids\": [\"22839969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SRPK1 uses a distributive mechanism for phosphorylating Tra2β(ΔN) (short RS repeats), contrasting with the processive mechanism used for SRSF1 (long RS repeats). The docking groove, required for SRSF1 phosphorylation, is dispensable for Tra2β(ΔN) phosphorylation.\",\n      \"method\": \"In vitro kinase assays, steady-state and transient kinetics, docking groove mutants\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic distinction established by kinetic analysis with docking groove mutants; single rigorous study\",\n      \"pmids\": [\"24074032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRPK1 ablation in mouse embryonic fibroblasts induces cell transformation linked to constitutive Akt activation. SRPK1 physically interacts with Akt phosphatase PHLPP1, and downregulated SRPK1 impairs recruitment of PHLPP1 to Akt, preventing Akt dephosphorylation. Conversely, SRPK1 overexpression sequesters PHLPP1 away from Akt, also causing constitutive Akt activation.\",\n      \"method\": \"Mouse embryonic fibroblast transformation assay, genome-wide phosphoproteomics, co-immunoprecipitation, Western blot\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide phosphoproteomics plus Co-IP establishing SRPK1-PHLPP1 interaction with KO phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"24703948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SRPK1 phosphorylation of SRSF1 regulates nuclear translocation of SRSF1, which promotes inclusion of alternative exon 3b into Rac1 pre-mRNA to generate Rac1b in colorectal cells. SRPK1 knockdown or inhibition of its catalytic activity reduces SRSF1 phosphorylation and nuclear translocation, decreasing Rac1b levels.\",\n      \"method\": \"siRNA knockdown, SRPK1 inhibitor, splicing RT-PCR, SRSF1 localization studies\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition with functional splicing readout; single lab\",\n      \"pmids\": [\"24550521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HPV1 E1^E4 potently inhibits SRPK1 phosphorylation of host SR proteins and of the viral E2 protein (which contains SR/RS dipeptides in its hinge region). E1^E4-mediated inhibition of SRPK1 alters E2 nuclear localization in primary keratinocytes.\",\n      \"method\": \"In vitro kinase assay, mutagenesis of E2 phosphoacceptor sites, immunofluorescence in primary keratinocytes\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase inhibition demonstrated, functional consequence on E2 localization shown; single lab\",\n      \"pmids\": [\"25142587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SRPK1 knockdown inhibits focal adhesion reorganization and suppresses metastasis of breast cancer cells to distant organs (lung, liver, spleen) in two independent murine models, establishing SRPK1 as a determinant of tumor cell migration and metastasis.\",\n      \"method\": \"shRNA knockdown, phagokinetic track assay, live cell migration assays, two murine metastasis models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent in vivo models, siRNA screen validated in live migration assays, focal adhesion phenotype; strong replication\",\n      \"pmids\": [\"25774502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SRPK1 interacts with an RS-like domain in the N terminus of CLK1. SRPK1 facilitates the release of phosphorylated SR proteins from CLK1 (which lacks the ability to release them on its own), enabling efficient splice-site recognition and spliceosome assembly. The two kinases fulfill separate catalytic roles for SR protein phosphorylation control.\",\n      \"method\": \"Biochemical binding assays, SR protein phosphorylation/release assays, spliceosome assembly assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding mapped, functional release mechanism demonstrated biochemically with spliceosome assays; single rigorous study with multiple methods\",\n      \"pmids\": [\"27397683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SRPK1 phosphorylates LBR on Ser residues in its RS domain (all RS serines are approximate equal acceptor sites), while Akt specifically targets Ser80 and Ser82. 3D modeling shows only Ser80/Ser82-containing peptides fit the Akt active site, distinguishing direct Akt phosphorylation from SRPK1 activity on the same domain.\",\n      \"method\": \"Synthetic peptide kinase assays, recombinant LBR RS domain mutants, 3D modeling with MD simulations\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis with in vitro kinase assays; single lab\",\n      \"pmids\": [\"27105349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cysteine residues in the SRPK1 spacer domain (Cys356, Cys386, Cys427, Cys455) and in the first catalytic domain (Cys188) form disulfide bonds required for kinase activity and nuclear translocation in response to genotoxic stress. Mutation of individual cysteines (except Cys414) impairs kinase activity and nuclear translocation.\",\n      \"method\": \"Systematic cysteine mutagenesis, kinase activity assays, nuclear localization assays, splicing reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with functional readouts (kinase activity, localization, splicing); single lab\",\n      \"pmids\": [\"28166275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRPK1 phosphorylates 7 of the 8 hydroxy amino acids in the HBV core protein (HBc) CTD as identified by combining Phos-tag gel electrophoresis, mass spectrometry, and mutagenesis. Phosphorylation of all seven sites drastically reduces nonspecific RNA encapsidation and alters CTD surface accessibility without major structural changes in the capsid shell.\",\n      \"method\": \"Bacterial coexpression with SRPK1, Phos-tag gel, mass spectrometry, mutagenesis, electron microscopy\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site identification by MS with mutagenesis validation, functional RNA-binding consequences demonstrated; multiple orthogonal methods\",\n      \"pmids\": [\"30566530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRPK1 inhibition in AML leads to altered isoform usage of BRD4 (and other genes), causing a switch from the short to the long BRD4 isoform. This switch is associated with BRD4 eviction from BCL2 and MYC genomic loci and mediates anti-leukemic effects including cell cycle arrest and leukemic cell differentiation.\",\n      \"method\": \"RNA-seq, shRNA knockdown, pharmacological inhibition, xenograft survival assay, BRD4 isoform overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus isoform-specific rescue experiments; single lab\",\n      \"pmids\": [\"30568163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRPKIN-1, the first covalent SRPK1/2 inhibitor, forms an irreversible bond with a tyrosine phenol group in the ATP-binding pocket and attenuates SR protein phosphorylation at submicromolar concentrations, converting pro-angiogenic VEGF-A165a to anti-angiogenic VEGF-A165b more potently than SRPIN340 or siRNA knockdown.\",\n      \"method\": \"Covalent inhibitor design, kinome-wide selectivity profiling, SR protein phosphorylation assay, VEGF splicing RT-PCR, laser-induced murine retinal neovascularization model\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — irreversible mechanism characterized structurally, kinome-wide selectivity profiled, functional VEGF splicing and in vivo efficacy demonstrated\",\n      \"pmids\": [\"29478907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRPK1 catalyzes site-specific phosphorylation of protamine in the fertilized oocyte, initiating protamine-to-histone exchange (parental genome reprogramming). Protamine undergoes DNA-dependent phase transition to gel-like condensates; SRPK1-mediated phosphorylation opens these structures, enabling protamine dismissal by NPM2 and HIRA-mediated H3.3 deposition. ATAC-seq shows chromatin accessibility is erased in early pronuclei in a protamine phosphorylation-dependent manner.\",\n      \"method\": \"In vitro SRPK1 kinase assay on protamine, ATAC-seq, phase condensate experiments, NPM2/HIRA recruitment assays in fertilized oocytes\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation plus genome-wide ATAC-seq with rescue experiments; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"32169215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tip60 mediates acetylation of SRPK1, which is associated with chemotherapy sensitivity. In cisplatin-resistant breast cancer cells, SRPK1 acetylation is reduced while phosphorylation and kinase activity are increased, favoring anti-apoptotic splice variants. Re-sensitization was achieved by enhancing SRPK1 acetylation or inhibiting its kinase activity.\",\n      \"method\": \"Western blot with acetylation/phosphorylation antibodies, Tip60 overexpression/knockdown, drug resistance assays, splicing analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Tip60-mediated acetylation identified with functional resistance phenotype; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"32461560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LIMK2 promotes phosphorylation and activation of SRPK1. LIMK2 inhibition blocks SRPK1 phosphorylation and its activity. SRPK1 genetic or pharmacological inhibition blocks metastatic attributes of TNBC cells similarly to LIMK2 inhibition, placing SRPK1 downstream of LIMK2 in a metastasis pathway.\",\n      \"method\": \"SILAC-based phosphoproteomics, shRNA knockdown, pharmacological inhibition, in vitro metastasis assays, in vivo metastasis model\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics identifies SRPK1 as LIMK2 substrate, epistasis confirmed with genetic/pharmacological tools; single lab\",\n      \"pmids\": [\"32859889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In cancer cells (PC3 prostate, K562 leukemia), WT1 activates SRPK1 transcription through a canonical WT1 binding site adjacent to the transcription start site. The transcriptional corepressor BASP1 reverses WT1-mediated SRPK1 activation; both WT1 and BASP1 co-precipitate with the SRPK1 promoter by ChIP.\",\n      \"method\": \"siRNA knockdown, promoter reporter assay, ChIP, site-directed mutagenesis of WT1 binding site\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with mutant controls; single lab\",\n      \"pmids\": [\"33017668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ibuprofen prevents SRPK1 nuclear translocation by promoting disassembly of a WNK1/GSK3β/SRPK1 protein kinase complex, which exposes GSK3β Ser9 to inhibitory phosphorylation by AKT, resulting in cytoplasmic retention of SRPK1, SRSF1 hypophosphorylation, and inhibition of RAC1B alternative splicing in BRAF-mutant CRC cells.\",\n      \"method\": \"Co-immunoprecipitation (WNK1/GSK3β/SRPK1 complex), subcellular fractionation, phosphorylation assays, splicing RT-PCR\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex plus phosphorylation and localization readouts; single lab\",\n      \"pmids\": [\"33315986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF-2 promotes angiogenesis by activating a SRSF1/SRSF3/SRPK1-dependent axis in endothelial cells that controls VEGFR1 pre-mRNA alternative splicing to generate soluble VEGFR1 splice variants (sVEGFR1-ex12).\",\n      \"method\": \"2D/3D endothelial cell cultures, siRNA knockdown, 3D collagen sprouting assay, in vivo sponge/zebrafish angiogenesis models, VEGFR1 splicing RT-PCR\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo models with SRPK1 knockdown and splicing readout; single lab\",\n      \"pmids\": [\"34433435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRPK1/2 enhance phosphorylation and nuclear translocation of SRSF1 (counteracted by PP1α), which promotes MKNK2 alternative splicing toward the MKNK2b isoform in colon adenocarcinoma cells.\",\n      \"method\": \"Western blot, PCR, siRNA knockdown, xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with splicing and localization readouts; single lab\",\n      \"pmids\": [\"33602301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 directly binds SRSF1 and SRPK1 through its (101-565) fragment and promotes SRSF1 phosphorylation to regulate VEGF-A alternative splicing, suppressing VEGF-A165b in renal cell carcinoma cells.\",\n      \"method\": \"Affinity purification, mass spectrometry, co-immunoprecipitation, Western blot, splicing RT-PCR\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS and Co-IP establishing complex; functional splicing readout; single lab\",\n      \"pmids\": [\"34544400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Phosphorylation of SRSF1 by SRPK1 promotes inclusion of full-length PD-1 (flPD1) over the soluble ΔEx3PD1 isoform. SRPK1 shRNA knockdown or pharmacological inhibition (SPHINX31) switches splicing toward ΔEx3PD1, which acts as a soluble antagonist preventing cancer cell-mediated T cell repression (equivalent to anti-PD1 antibody effect).\",\n      \"method\": \"shRNA knockdown, SPHINX31 inhibitor, PCR/Western blot in PBMCs and T cells, IL-2 ELISA, co-culture of cancer cells and T cells\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological SRPK1 inhibition with functional T cell readout; single lab\",\n      \"pmids\": [\"37973660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRPK1 promotes TKI (gefitinib) resistance in NSCLC independently of its kinase activity: the SRPK1 spacer domain binds GSK3β and enhances its autophosphorylation at Ser9, activating the Wnt pathway and increasing Bcl-X expression. SRPK1 also facilitates LEF1/β-catenin binding to the EGFR promoter to increase EGFR expression.\",\n      \"method\": \"In vitro and in vivo drug resistance assays, co-immunoprecipitation (SRPK1-GSK3β), Western blot, kinase-dead mutant controls, ChIP (LEF1/β-catenin at EGFR promoter)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing SRPK1-GSK3β interaction with kinase-dead mutant controls showing kinase-independent mechanism; single lab\",\n      \"pmids\": [\"36869126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 directly methylates SRPK1 mRNA at m6A sites, which stabilizes SRPK1 mRNA in an IGF2BP2-dependent manner. Elevated SRPK1 then promotes glycolysis by interacting with hnRNPA1 and facilitating PKM alternative splicing to upregulate PKM2 in lung adenocarcinoma.\",\n      \"method\": \"m6A epitranscriptomic microarray, MeRIP, RIP, RNA stability assay, co-immunoprecipitation (SRPK1-hnRNPA1), metabolic quantification, Western blot\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA-biochemical methods (MeRIP, RIP, RNA stability) and Co-IP; single lab\",\n      \"pmids\": [\"39095708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SRPK1 phosphorylates LBR (lamin B receptor) on the same RS repeat sites as the LBR kinase purified from turkey erythrocytes, and with similar kinetics, establishing SRPK1 as an LBR kinase in addition to its role in splicing factor phosphorylation.\",\n      \"method\": \"Synthetic peptide kinase assays, in vitro kinase assay with recombinant LBR fragments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay with site mapping on LBR; single lab\",\n      \"pmids\": [\"10049757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Expression of human SRPK1 in yeast SKY1 deletion mutants restores cisplatin sensitivity, establishing functional conservation. Antisense-mediated downregulation of SRPK1 in human A2780 ovarian carcinoma cells conferred 4-fold cisplatin resistance.\",\n      \"method\": \"Heterologous complementation in yeast, antisense oligodeoxynucleotides in human cells, drug sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species complementation plus human cell antisense; single lab with two model systems\",\n      \"pmids\": [\"11585720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"X-ray crystal structure of SRPK1 bound to SRPIN340 identified the compound's binding pocket in SRPK1. Novel inhibitors occupying a binding pocket created by the unique helical insert of SRPK1 and triggering a backbone flip in the hinge region achieve potent (<10 nM) and selective SRPK1 inhibition, SRSF1 hypophosphorylation, and VEGF-A splicing shift to anti-angiogenic isoforms in vitro and in vivo.\",\n      \"method\": \"X-ray crystallography, in vitro kinase assay, SRSF1 phosphorylation assay, VEGF splicing RT-PCR, choroidal angiogenesis in vivo model\",\n      \"journal\": \"ACS chemical biology / Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of SRPK1-inhibitor complex with functional VEGF splicing and in vivo validation\",\n      \"pmids\": [\"28135068\", \"25993998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRPK1 is a cytoplasmic SR protein-specific kinase anchored by an intrinsically disordered spacer domain to an Hsp70/Hsp90/Hsp40/Aha1 chaperone complex; upon stress or Hsp90 inhibition it translocates to the nucleus where it directionally and processively phosphorylates the RS domains of SR splicing factors (especially SRSF1/ASF/SF2) via a substrate-sliding mechanism that initiates at an 'initiation box' and proceeds N-terminally, releasing SR proteins for spliceosome assembly and splice-site selection—a process counterbalanced by CLK1 binding and regulated by Tip60-mediated acetylation; WT1 transcriptionally controls SRPK1 expression, while LIMK2 activates it by phosphorylation; downstream, SRPK1-driven SRSF1 phosphorylation controls alternative splicing of VEGF, RAC1B, PD-1, BRD4, and PKM2, and SRPK1 also modulates Akt activity by scaffolding the phosphatase PHLPP1, phosphorylates non-SR substrates including LBR and protamine (initiating parental genome reprogramming after fertilization), and is exploited or inhibited by viral proteins (HSV ICP27, HPV E1^E4, HBV core) to subvert host splicing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SRPK1 is a serine/arginine protein kinase that controls pre-mRNA splicing by phosphorylating the arginine/serine (RS) domains of SR splicing factors, especially SRSF1/ASF-SF2, with strict specificity for Ser-Arg sites [#0]. It engages substrates through a directional, processive mechanism: an acidic docking groove distal to the active site captures the RS domain, and an 'initiation box' near the C-terminal end of the RS1 segment seeds phosphorylation that then proceeds N-terminally by substrate sliding, a 'grab-and-pull' process driven by primed phosphoserine binding and coupled to controlled unfolding of an RRM2 beta-strand [#5, #7, #10, #11]; this processive mode applies to long-RS substrates such as SRSF1 while short-RS substrates like Tra2\\u03b2 are phosphorylated distributively without the docking groove [#18]. SRPK1's intrinsically disordered spacer-insert domain and N-terminal extension act as a nucleotide-release factor and chaperone-binding module: SRPK1 is anchored in the cytoplasm by an Hsp40/Aha1/Hsp70/Hsp90 complex, and Hsp90 inhibition or osmotic/genotoxic stress dissociates it to drive nuclear translocation and altered SR-protein phosphorylation and splice-site selection [#9, #14, #17, #25]. SRPK1 cooperates with CLK1, releasing CLK1-bound phosphorylated SR proteins to enable spliceosome assembly [#23]. Through SRSF1 phosphorylation and nuclear translocation, SRPK1 governs the alternative splicing of VEGF, RAC1B, BRD4, MKNK2, PKM, and PD-1, and is wired into oncogenic programs where it is transcriptionally repressed by WT1 and de-repression yields pro-angiogenic VEGF isoforms [#13, #20, #27, #35, #37, #39]. SRPK1 drives tumor cell migration, metastasis, and chemoresistance, acting downstream of LIMK2 and via both kinase-dependent splicing control and kinase-independent scaffolding of PHLPP1 (modulating Akt) and GSK3\\u03b2/Wnt signaling [#19, #22, #31, #38]. Beyond splicing factors it phosphorylates the RS domain of the lamin B receptor [#15, #40] and phosphorylates protamine to initiate protamine-to-histone exchange and parental genome reprogramming after fertilization [#29]. SRPK1 is also targeted by viral proteins (HBV core, HSV ICP27, HPV E1^E4) that exploit or inhibit its activity to subvert host splicing [#1, #2, #6, #26], and it is a validated drug target with selective and covalent ATP-pocket inhibitors that reverse pro-angiogenic VEGF splicing [#28, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established SRPK1 as an SR-protein kinase with strict Ser-Arg specificity that targets the physiological phosphosites of ASF/SF2, defining its core substrate class distinct from the broader-specificity Clk/Sty.\",\n      \"evidence\": \"In vitro kinase assays with tryptic peptide mapping against in vivo phosphosites\",\n      \"pmids\": [\"8798720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how site selection within the RS domain is achieved\", \"Cellular consequences for splicing not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended SRPK1's substrate range beyond splicing factors by showing it phosphorylates the lamin B receptor RS domain at authentic sites with kinetics matching the native LBR kinase.\",\n      \"evidence\": \"Synthetic peptide and recombinant LBR fragment kinase assays\",\n      \"pmids\": [\"10049757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of LBR phosphorylation not established here\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked SRPK1 levels to cisplatin sensitivity, providing the first functional/cancer-relevant phenotype and demonstrating cross-species conservation of function.\",\n      \"evidence\": \"Yeast SKY1-deletion complementation and antisense knockdown in ovarian carcinoma cells with drug-sensitivity assays\",\n      \"pmids\": [\"11585720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the chemoresistance phenotype unresolved\", \"Substrates mediating the effect not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that viral and stress-responsive control of SRPK1 occurs partly through relocalization, as HSV-1 ICP27 binds SRPK1, drives it to the nucleus, and alters SR-protein phosphorylation to block spliceosome assembly.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, and nuclear-extract splicing assays\",\n      \"pmids\": [\"12660167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ICP27 alters SRPK1 catalysis unclear\", \"Single-lab reciprocal interaction\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the structural and kinetic basis of processive RS-domain phosphorylation, resolving how SRPK1 achieves directional, ordered modification of SR proteins.\",\n      \"evidence\": \"2.9 \\u00c5 crystal structure of SRPK1:ASF/SF2 plus single/multiturnover kinetics and docking-groove mutagenesis\",\n      \"pmids\": [\"18342604\", \"18687337\", \"18155240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length SRPK1 including disordered spacer not resolved\", \"How chaperone binding modulates the catalytic cycle not addressed structurally\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established cytoplasmic chaperone anchoring as the switch governing SRPK1 nuclear access, and refined the initiation site and allosteric RRM cross-talk underlying processivity.\",\n      \"evidence\": \"Reciprocal Co-IP with Hsp40/Aha1/Hsp70/Hsp90, Hsp90-inhibitor and osmotic-shock translocation assays, plus footprinting and binding/kinetic analyses\",\n      \"pmids\": [\"19240134\", \"19477182\", \"19886675\", \"19553338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of nuclear targeting/import machinery not defined\", \"Quantitative stoichiometry of the chaperone complex unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the spacer-insert and N-terminal extension as regulatory modules controlling catalysis and chaperone binding, and placed SRPK1 in an oncogenic transcriptional circuit with WT1 governing VEGF splicing.\",\n      \"evidence\": \"HDX and steady/transient kinetics on truncations; ChIP, promoter reporter, siRNA rescue, and in vivo tumor/angiogenesis models for WT1 regulation; GST pull-down for LBR-H3\",\n      \"pmids\": [\"21600902\", \"21728354\", \"22172722\", \"22056509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the disordered spacer mechanically couples to the kinase domain remains incompletely defined\", \"Other SRPK1-controlled angiogenic targets not yet mapped at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed kinase-independent scaffolding functions and cancer-driving splicing outputs, broadening SRPK1 from a splicing kinase to a signaling hub controlling Akt and oncogenic isoform switches.\",\n      \"evidence\": \"MEF transformation assay with phosphoproteomics and Co-IP for the SRPK1-PHLPP1-Akt axis; siRNA/inhibitor with splicing RT-PCR for RAC1B; nucleotide-release and distributive-mechanism kinetics\",\n      \"pmids\": [\"24703948\", \"24550521\", \"22839969\", \"24074032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PHLPP1 scaffolding is direct and how it is regulated not fully resolved\", \"Balance between kinase-dependent and scaffolding roles in vivo unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clarified the division of labor between SRPK1 and CLK1, showing SRPK1 enables release of CLK1-bound phosphorylated SR proteins to permit spliceosome assembly.\",\n      \"evidence\": \"Biochemical binding mapping, SR-protein phosphorylation/release assays, and spliceosome assembly assays\",\n      \"pmids\": [\"27397683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular dynamics of the SRPK1-CLK1 handoff not quantified\", \"Single rigorous study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected redox/genotoxic stress to SRPK1 activation by identifying disulfide-forming cysteines required for kinase activity and nuclear translocation.\",\n      \"evidence\": \"Systematic cysteine mutagenesis with kinase, localization, and splicing reporter readouts\",\n      \"pmids\": [\"28166275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of disulfide formation in cells limited\", \"Upstream oxidative signal not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Validated SRPK1 as a druggable therapeutic target and expanded its disease-relevant splicing repertoire to BRD4 in leukemia.\",\n      \"evidence\": \"Covalent inhibitor SRPKIN-1 with kinome-wide profiling, VEGF splicing and retinal neovascularization model; RNA-seq and isoform-rescue for BRD4 in AML\",\n      \"pmids\": [\"29478907\", \"30568163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over SRPK2 and off-target effects need fuller delineation\", \"BRD4 mechanism is single-lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a developmental role in genome reprogramming and multiple upstream regulators (LIMK2, Tip60, WT1/BASP1, WNK1/GSK3\\u03b2) that set SRPK1 activity and localization.\",\n      \"evidence\": \"In vitro protamine kinase assay with ATAC-seq, condensate, and NPM2/HIRA recruitment in oocytes; phosphoproteomics/epistasis for LIMK2; acetylation Westerns for Tip60; ChIP/reporter for WT1/BASP1; Co-IP/fractionation for the WNK1/GSK3\\u03b2 complex\",\n      \"pmids\": [\"32169215\", \"32859889\", \"32461560\", \"33017668\", \"33315986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay among acetylation, phosphorylation, and chaperone control not integrated\", \"In vivo significance of LBR/protamine activities in mammals beyond model systems not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SRPK1 itself is post-transcriptionally regulated by m6A and feeds metabolic and immune programs through additional splicing targets.\",\n      \"evidence\": \"MeRIP/RIP/RNA-stability and Co-IP for METTL3-IGF2BP2-SRPK1-hnRNPA1-PKM2 (2024); shRNA/SPHINX31 with T-cell co-culture for PD-1 splicing (2023); FGF-2/VEGFR1 and MKNK2 splicing models\",\n      \"pmids\": [\"39095708\", \"37973660\", \"34433435\", \"33602301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These splicing axes are individually single-lab\", \"Direct SRPK1 phosphorylation events on each pathway not always demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the chaperone-anchored cytoplasmic pool, acetylation/phosphorylation/redox switches, and upstream kinases are integrated to set SRPK1 nuclear timing and substrate choice in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking all regulatory inputs to nuclear translocation\", \"Structure of full-length SRPK1 with the disordered spacer unsolved\", \"Selectivity of substrate engagement (SR proteins vs LBR vs protamine) in cells not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 5, 7, 15, 26, 29, 40]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 16, 17]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [19, 23, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 33]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 9, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 9, 20, 23, 27, 35, 37, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [13, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 31, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 6, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"complexes\": [\n      \"Hsp40(DNAJc8)/Aha1/Hsp70/Hsp90 chaperone complex\",\n      \"WNK1/GSK3\\u03b2/SRPK1 complex\"\n    ],\n    \"partners\": [\n      \"SRSF1\",\n      \"CLK1\",\n      \"PHLPP1\",\n      \"GSK3\\u03b2\",\n      \"Aha1\",\n      \"hnRNPA1\",\n      \"LIMK2\",\n      \"USP39\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}