Affinage

SRPK1

SRSF protein kinase 1 · UniProt Q96SB4

Length
655 aa
Mass
74.3 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    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

    PMID:8798720

    Open questions at the time
    • Did not define how site selection within the RS domain is achieved
    • Cellular consequences for splicing not addressed
  2. 1999 Medium

    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

    PMID:10049757

    Open questions at the time
    • Functional consequence of LBR phosphorylation not established here
    • In vivo relevance not tested
  3. 2001 Medium

    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

    PMID:11585720

    Open questions at the time
    • Molecular basis of the chemoresistance phenotype unresolved
    • Substrates mediating the effect not identified
  4. 2003 Medium

    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

    PMID:12660167

    Open questions at the time
    • Mechanism by which ICP27 alters SRPK1 catalysis unclear
    • Single-lab reciprocal interaction
  5. 2008 High

    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

    PMID:18155240 PMID:18342604 PMID:18687337

    Open questions at the time
    • Structure of full-length SRPK1 including disordered spacer not resolved
    • How chaperone binding modulates the catalytic cycle not addressed structurally
  6. 2009 High

    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

    PMID:19240134 PMID:19477182 PMID:19553338 PMID:19886675

    Open questions at the time
    • Identity of nuclear targeting/import machinery not defined
    • Quantitative stoichiometry of the chaperone complex unresolved
  7. 2011 High

    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

    PMID:21600902 PMID:21728354 PMID:22056509 PMID:22172722

    Open questions at the time
    • How the disordered spacer mechanically couples to the kinase domain remains incompletely defined
    • Other SRPK1-controlled angiogenic targets not yet mapped at this stage
  8. 2014 High

    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

    PMID:22839969 PMID:24074032 PMID:24550521 PMID:24703948

    Open questions at the time
    • Whether PHLPP1 scaffolding is direct and how it is regulated not fully resolved
    • Balance between kinase-dependent and scaffolding roles in vivo unclear
  9. 2016 High

    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

    PMID:27397683

    Open questions at the time
    • Cellular dynamics of the SRPK1-CLK1 handoff not quantified
    • Single rigorous study
  10. 2017 Medium

    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

    PMID:28166275

    Open questions at the time
    • Direct demonstration of disulfide formation in cells limited
    • Upstream oxidative signal not defined
  11. 2018 High

    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

    PMID:29478907 PMID:30568163

    Open questions at the time
    • Selectivity over SRPK2 and off-target effects need fuller delineation
    • BRD4 mechanism is single-lab
  12. 2020 High

    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

    PMID:32169215 PMID:32461560 PMID:32859889 PMID:33017668 PMID:33315986

    Open questions at the time
    • Interplay among acetylation, phosphorylation, and chaperone control not integrated
    • In vivo significance of LBR/protamine activities in mammals beyond model systems not established
  13. 2024 Medium

    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

    PMID:33602301 PMID:34433435 PMID:37973660 PMID:39095708

    Open questions at the time
    • These splicing axes are individually single-lab
    • Direct SRPK1 phosphorylation events on each pathway not always demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 8 R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-4839726 Chromatin organization 1
Partners
AHA1CLK1GSK3ΒHNRNPA1LIMK2PHLPP1SRSF1USP39
Complex memberships
Hsp40(DNAJc8)/Aha1/Hsp70/Hsp90 chaperone complexWNK1/GSK3β/SRPK1 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. In vitro kinase assay, tryptic peptide mapping, comparison with in vivo phosphorylation sites The Journal of biological chemistry High 8798720
2002 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. Affinity purification, mass spectrometry, in vitro kinase assay, immunoblot Journal of virology High 12134018
2003 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. Co-immunoprecipitation, in vitro kinase assay, nuclear extract splicing assay The EMBO journal Medium 12660167
2005 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. Mass spectrometry, in vitro kinase assay, kinetic analysis The Journal of biological chemistry High 16223727
2005 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). Overexpression/dominant-negative in cell-based HBV replication assay, Western blot Virology Medium 16122776
2007 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. Region-specific phosphorylation monitoring with lysyl endoproteinase cleavage, Arg-to-Lys mutagenesis Journal of molecular biology High 18155240
2007 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. In vitro kinase assay, co-immunoprecipitation, immunofluorescence colocalization, mutagenesis Journal of virology Medium 17360743
2008 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. X-ray crystallography, biochemical phosphorylation assays Molecular cell High 18342604
2008 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. Single-turnover and multiturnover kinetics, deletion mutagenesis Journal of molecular biology High 18687337
2009 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. Co-immunoprecipitation, Hsp90 ATPase inhibitor treatment, cellular fractionation, splicing reporter assays Genes & development High 19240134
2009 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. Engineered footprinting, single-turnover kinetics, mutagenesis Journal of molecular biology High 19477182
2009 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. Biochemical binding assays, mutagenesis, kinetic analysis Biochemistry High 19886675
2009 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. Co-immunoprecipitation, colocalization studies, methylation inhibitor (adenosine dialdehyde) treatment Journal of virology Medium 19553338
2011 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. ChIP, promoter reporter assay, siRNA knockdown, VEGF splicing RT-PCR, in vivo angiogenesis/tumor models Cancer cell High 22172722
2011 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. Hydrogen-deuterium exchange, steady-state kinetics, deletion mutagenesis Journal of molecular biology High 21600902
2011 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. GST pull-down, molecular dynamics simulations, synthetic peptide kinase assays Biochimica et biophysica acta Medium 22056509
2011 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. Rapid quench flow transient-state kinetics, mutagenesis, viscosometric experiments Biochemistry High 21728354
2012 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. Deletion analysis, steady-state kinetics, nucleotide exchange assays Biochemistry High 22839969
2013 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. In vitro kinase assays, steady-state and transient kinetics, docking groove mutants Biochemistry High 24074032
2014 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. Mouse embryonic fibroblast transformation assay, genome-wide phosphoproteomics, co-immunoprecipitation, Western blot Molecular cell High 24703948
2014 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. siRNA knockdown, SRPK1 inhibitor, splicing RT-PCR, SRSF1 localization studies RNA (New York, N.Y.) Medium 24550521
2014 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. In vitro kinase assay, mutagenesis of E2 phosphoacceptor sites, immunofluorescence in primary keratinocytes Journal of virology Medium 25142587
2015 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. shRNA knockdown, phagokinetic track assay, live cell migration assays, two murine metastasis models The Journal of clinical investigation High 25774502
2016 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. Biochemical binding assays, SR protein phosphorylation/release assays, spliceosome assembly assays Molecular cell High 27397683
2016 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. Synthetic peptide kinase assays, recombinant LBR RS domain mutants, 3D modeling with MD simulations PloS one Medium 27105349
2017 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. Systematic cysteine mutagenesis, kinase activity assays, nuclear localization assays, splicing reporter assay PloS one Medium 28166275
2018 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. Bacterial coexpression with SRPK1, Phos-tag gel, mass spectrometry, mutagenesis, electron microscopy PLoS pathogens High 30566530
2018 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. RNA-seq, shRNA knockdown, pharmacological inhibition, xenograft survival assay, BRD4 isoform overexpression rescue Nature communications Medium 30568163
2018 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. Covalent inhibitor design, kinome-wide selectivity profiling, SR protein phosphorylation assay, VEGF splicing RT-PCR, laser-induced murine retinal neovascularization model Cell chemical biology High 29478907
2020 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. In vitro SRPK1 kinase assay on protamine, ATAC-seq, phase condensate experiments, NPM2/HIRA recruitment assays in fertilized oocytes Cell High 32169215
2020 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. Western blot with acetylation/phosphorylation antibodies, Tip60 overexpression/knockdown, drug resistance assays, splicing analysis Communications biology Medium 32461560
2020 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. SILAC-based phosphoproteomics, shRNA knockdown, pharmacological inhibition, in vitro metastasis assays, in vivo metastasis model Oncogenesis Medium 32859889
2020 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. siRNA knockdown, promoter reporter assay, ChIP, site-directed mutagenesis of WT1 binding site Biochimica et biophysica acta. Gene regulatory mechanisms Medium 33017668
2020 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. Co-immunoprecipitation (WNK1/GSK3β/SRPK1 complex), subcellular fractionation, phosphorylation assays, splicing RT-PCR Oncotarget Medium 33315986
2021 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). 2D/3D endothelial cell cultures, siRNA knockdown, 3D collagen sprouting assay, in vivo sponge/zebrafish angiogenesis models, VEGFR1 splicing RT-PCR BMC biology Medium 34433435
2021 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. Western blot, PCR, siRNA knockdown, xenograft models Journal of experimental & clinical cancer research Medium 33602301
2021 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. Affinity purification, mass spectrometry, co-immunoprecipitation, Western blot, splicing RT-PCR Cancer cell international Medium 34544400
2023 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). shRNA knockdown, SPHINX31 inhibitor, PCR/Western blot in PBMCs and T cells, IL-2 ELISA, co-culture of cancer cells and T cells Cancer immunology, immunotherapy Medium 37973660
2023 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. 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) Oncogene Medium 36869126
2024 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. m6A epitranscriptomic microarray, MeRIP, RIP, RNA stability assay, co-immunoprecipitation (SRPK1-hnRNPA1), metabolic quantification, Western blot Cellular & molecular biology letters Medium 39095708
1999 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. Synthetic peptide kinase assays, in vitro kinase assay with recombinant LBR fragments Biochemical and biophysical research communications Medium 10049757
2001 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. Heterologous complementation in yeast, antisense oligodeoxynucleotides in human cells, drug sensitivity assays Cancer research Medium 11585720
2015 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. X-ray crystallography, in vitro kinase assay, SRSF1 phosphorylation assay, VEGF splicing RT-PCR, choroidal angiogenesis in vivo model ACS chemical biology / Molecular pharmacology High 25993998 28135068

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer cell 212 22172722
1996 SRPK1 and Clk/Sty protein kinases show distinct substrate specificities for serine/arginine-rich splicing factors. The Journal of biological chemistry 175 8798720
2009 Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperones. Genes & development 162 19240134
2003 ICP27 interacts with SRPK1 to mediate HSV splicing inhibition by altering SR protein phosphorylation. The EMBO journal 152 12660167
2017 MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway. Molecular cancer 150 28606154
2012 Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma. PloS one 128 23071587
2014 Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer. Oncogene 127 25381816
2002 Identification of SRPK1 and SRPK2 as the major cellular protein kinases phosphorylating hepatitis B virus core protein. Journal of virology 124 12134018
2014 Both decreased and increased SRPK1 levels promote cancer by interfering with PHLPP-mediated dephosphorylation of Akt. Molecular cell 112 24703948
2015 Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant. The Journal of clinical investigation 109 25774502
2018 SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform. Cell chemical biology 106 29478907
2014 Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma. British journal of cancer 103 25010863
2021 FGF-2 promotes angiogenesis through a SRSF1/SRSF3/SRPK1-dependent axis that controls VEGFR1 splicing in endothelial cells. BMC biology 100 34433435
2008 A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1. Molecular cell 97 18342604
2014 Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells. RNA (New York, N.Y.) 93 24550521
2017 Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease. ACS chemical biology 86 28135068
2015 Involvement of SRPK1 in cisplatin resistance related to long non-coding RNA UCA1 in human ovarian cancer cells. Neoplasma 84 25866223
2015 Involvement of SRPK1 in cisplatin resistance related to long non-coding RNA UCA1 in human ovarian cancer cells. Neoplasma 84 25967360
2016 Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing. Molecular cell 81 27397683
2020 Initiation of Parental Genome Reprogramming in Fertilized Oocyte by Splicing Kinase SRPK1-Catalyzed Protamine Phosphorylation. Cell 80 32169215
2005 Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty. The Journal of biological chemistry 80 16223727
2018 SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nature communications 71 30568163
2021 SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma. Journal of experimental & clinical cancer research : CR 70 33602301
2014 Elevated SRPK1 lessens apoptosis in breast cancer cells through RBM4-regulated splicing events. RNA (New York, N.Y.) 70 25140042
2018 Hepatitis B virus core protein phosphorylation: Identification of the SRPK1 target sites and impact of their occupancy on RNA binding and capsid structure. PLoS pathogens 68 30566530
2013 Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Investigative ophthalmology & visual science 61 23887803
2016 Long non-coding RNA MALAT1 increases AKAP-9 expression by promoting SRPK1-catalyzed SRSF1 phosphorylation in colorectal cancer cells. Oncotarget 56 26887056
2001 SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line. Cancer research 53 11585720
2017 The many faces of SRPK1. The Journal of pathology 47 27859253
2014 Human papillomavirus type 1 E1^E4 protein is a potent inhibitor of the serine-arginine (SR) protein kinase SRPK1 and inhibits phosphorylation of host SR proteins and of the viral transcription and replication regulator E2. Journal of virology 47 25142587
2007 Ordered multi-site phosphorylation of the splicing factor ASF/SF2 by SRPK1. Journal of molecular biology 46 18155240
2005 Suppression of hepatitis B virus replication by SRPK1 and SRPK2 via a pathway independent of the phosphorylation of the viral core protein. Virology 46 16122776
2018 SRPK1 gene silencing promotes vascular smooth muscle cell proliferation and vascular remodeling via inhibition of the PI3K/Akt signaling pathway in a rat model of intracranial aneurysms. CNS neuroscience & therapeutics 45 30101479
2012 SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases. Biochemical Society transactions 45 22817743
2008 Adaptable molecular interactions guide phosphorylation of the SR protein ASF/SF2 by SRPK1. Journal of molecular biology 44 18687337
2004 Resistance to platinum-containing chemotherapy in testicular germ cell tumors is associated with downregulation of the protein kinase SRPK1. Neoplasia (New York, N.Y.) 44 15256051
2020 SRPK1 acetylation modulates alternative splicing to regulate cisplatin resistance in breast cancer cells. Communications biology 43 32461560
2013 SRPK1 contributes to malignancy of hepatocellular carcinoma through a possible mechanism involving PI3K/Akt. Molecular and cellular biochemistry 42 23644876
2013 SRPK1 inhibition modulates VEGF splicing to reduce pathological neovascularization in a rat model of retinopathy of prematurity. Investigative ophthalmology & visual science 42 23761094
2019 Altered VEGF Splicing Isoform Balance in Tumor Endothelium Involves Activation of Splicing Factors Srpk1 and Srsf1 by the Wilms' Tumor Suppressor Wt1. Cells 40 30641926
2015 The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 25833691
2023 Pathogenic fungi neutralize plant-derived ROS via Srpk1 deacetylation. The EMBO journal 39 36891678
2015 Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice. Molecular pharmacology 39 25993998
2021 SRPK1/AKT axis promotes oxaliplatin-induced anti-apoptosis via NF-κB activation in colon cancer. Journal of translational medicine 38 34193174
2015 Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion. Journal of clinical pathology 37 26500332
2018 Serine arginine protein kinase 1 (SRPK1): a moonlighting protein with theranostic ability in cancer prevention. Molecular biology reports 36 30535769
2020 LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1. Oncogenesis 35 32859889
1999 SRPK1 and LBR protein kinases show identical substrate specificities. Biochemical and biophysical research communications 35 10049757
2008 SRPK1: a cisplatin sensitive protein expressed in retinoblastoma. Pediatric blood & cancer 34 17091485
2013 SRPK1 Dissimilarly Impacts on the Growth, Metastasis, Chemosensitivity and Angiogenesis of Glioma in Normoxic and Hypoxic Conditions. Journal of Cancer 33 24312143
2011 Phosphorylation of the arginine/serine repeats of lamin B receptor by SRPK1-insights from molecular dynamics simulations. Biochimica et biophysica acta 33 22056509
2007 The E1circumflexE4 protein of human papillomavirus interacts with the serine-arginine-specific protein kinase SRPK1. Journal of virology 32 17360743
2020 Human papillomavirus type 16 infection activates the host serine arginine protein kinase 1 (SRPK1) - splicing factor axis. The Journal of general virology 31 32182205
2009 Arginine methylation of the ICP27 RGG box regulates the functional interactions of ICP27 with SRPK1 and Aly/REF during herpes simplex virus 1 infection. Journal of virology 31 19553338
2021 USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1. Cancer cell international 29 34544400
2009 Regiospecific phosphorylation control of the SR protein ASF/SF2 by SRPK1. Journal of molecular biology 29 19477182
2022 Serine-Arginine Protein Kinase 1 (SRPK1): a systematic review of its multimodal role in oncogenesis. Molecular and cellular biochemistry 27 35583632
2021 LncRNA Neat1/miR-298-5p/Srpk1 Contributes to Sevoflurane-Induced Neurotoxicity. Neurochemical research 27 34524595
2015 Up-regulation of SRPK1 in non-small cell lung cancer promotes the growth and migration of cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 26666824
2000 Functional coexpression of serine protein kinase SRPK1 and its substrate ASF/SF2 in Escherichia coli. Nucleic acids research 26 10666475
2017 SRPK1‑siRNA suppresses K562 cell growth and induces apoptosis via the PARP‑caspase3 pathway. Molecular medicine reports 24 29138847
2015 The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas. Medical oncology (Northwood, London, England) 24 26099172
2020 Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target. Molecular & cellular proteomics : MCP 23 32994315
2023 Targeting alternative splicing as a new cancer immunotherapy-phosphorylation of serine arginine-rich splicing factor (SRSF1) by SR protein kinase 1 (SRPK1) regulates alternative splicing of PD1 to generate a soluble antagonistic isoform that prevents T cell exhaustion. Cancer immunology, immunotherapy : CII 22 37973660
2014 MiR-9 regulates the post-transcriptional level of VEGF165a by targeting SRPK-1 in ARPE-19 cells. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 22 25007957
2023 Serine-arginine protein kinase 1 (SRPK1) promotes EGFR-TKI resistance by enhancing GSK3β Ser9 autophosphorylation independent of its kinase activity in non-small-cell lung cancer. Oncogene 21 36869126
2019 SRPK1 facilitates tumor cell growth via modulating the small nucleolar RNA expression in gastric cancer. Journal of cellular physiology 21 30633341
2017 The crucial role of SRPK1 in IGF-1-induced EMT of human gastric cancer. Oncotarget 20 29069776
2016 Expression of SRPK1 in gliomas and its role in glioma cell lines viability. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 26738865
2011 Regulating SR protein phosphorylation through regions outside the kinase domain of SRPK1. Journal of molecular biology 20 21600902
2020 Downregulation of long noncoding RNA DLEU1 attenuates hypersensitivity in chronic constriction injury-induced neuropathic pain in rats by targeting miR-133a-3p/SRPK1 axis. Molecular medicine (Cambridge, Mass.) 19 33167866
2016 SRPK1 and Akt Protein Kinases Phosphorylate the RS Domain of Lamin B Receptor with Distinct Specificity: A Combined Biochemical and In Silico Approach. PloS one 18 27105349
2002 Bleomycin resistance in mammalian cells expressing a genetic suppressor element derived from the SRPK1 gene. Cancer research 18 12154054
2020 WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1. Biochimica et biophysica acta. Gene regulatory mechanisms 17 33017668
2018 MiR-216b suppresses colorectal cancer proliferation, migration, and invasion by targeting SRPK1. OncoTargets and therapy 17 29615842
2017 Serine-arginine protein kinase 1 (SRPK1) is elevated in gastric cancer and plays oncogenic functions. Oncotarget 17 28977917
2011 Applying the brakes to multisite SR protein phosphorylation: substrate-induced effects on the splicing kinase SRPK1. Biochemistry 17 21728354
2009 Allosteric interactions direct binding and phosphorylation of ASF/SF2 by SRPK1. Biochemistry 17 19886675
1999 Localization of serine kinases, SRPK1 (SFRSK1) and SRPK2 (SFRSK2), specific for the SR family of splicing factors in mouse and human chromosomes. Genomics 17 10198174
2020 Identification of a novel and potent small molecule inhibitor of SRPK1: mechanism of dual inhibition of SRPK1 for the inhibition of cancer progression. Aging 16 33291073
2013 Splicing kinase SRPK1 conforms to the landscape of its SR protein substrate. Biochemistry 16 24074032
2012 Nucleotide release sequences in the protein kinase SRPK1 accelerate substrate phosphorylation. Biochemistry 16 22839969
2024 N6-methyladenosine-modified SRPK1 promotes aerobic glycolysis of lung adenocarcinoma via PKM splicing. Cellular & molecular biology letters 15 39095708
2022 Icariside Ⅱ Attenuates Palmitic Acid-Induced Endothelial Dysfunction Through SRPK1-Akt-eNOS Signaling Pathway. Frontiers in pharmacology 15 35846993
2021 miR-150 and SRPK1 regulate AKT3 expression to participate in LPS-induced inflammatory response. Innate immunity 15 34092081
2018 miR-126 Functions as a Tumor Suppressor by Targeting SRPK1 in Human Gastric Cancer. Oncology research 15 29510776
2018 SOX2 knockdown inhibits the migration and invasion of basal cell carcinoma cells by targeting the SRPK1-mediated PI3K/AKT signaling pathway. Oncology letters 15 30675221
2017 Evidence for disulfide bonds in SR Protein Kinase 1 (SRPK1) that are required for activity and nuclear localization. PloS one 15 28166275
2017 Chimeric antibody targeting SRPK-1 in the treatment of non-small cell lung cancer by inhibiting growth, migration and invasion. Molecular medicine reports 15 28656224
2022 SRPK1 promotes sepsis-induced acute lung injury via regulating PI3K/AKT/FOXO3 signaling. Immunopharmacology and immunotoxicology 14 36226860
2014 Akt-ing up on SRPK1: oncogene or tumor suppressor? Molecular cell 14 24813709
2010 The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells. Biochimica et biophysica acta 14 20708644
2005 Synthesis of selective SRPK-1 inhibitors: novel tricyclic quinoxaline derivatives. Bioorganic & medicinal chemistry letters 14 15925511
2021 A HIF1A/miR-485-5p/SRPK1 axis modulates the aggressiveness of glioma cells upon hypoxia. Experimental cell research 13 33722639
2021 MiR-155 Inhibits Malignant Biological Behavior of Human Liver Cancer Cells by Regulating SRPK1. Technology in cancer research & treatment 13 33827350
2021 Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene. BMC cancer 13 34051734
2016 Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/αvβ3 signaling pathway and SRPK1. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 26944058
2011 Distribution of SRPK1 in human brain. Journal of chemical neuroanatomy 12 22019390
2020 Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells. Oncotarget 10 33315986
2018 Multi-posttranscriptional regulations lessen the repressive effect of SRPK1 on brown adipogenesis. Biochimica et biophysica acta. Molecular and cell biology of lipids 10 29474929

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