Serine/Arginine-Rich Protein Kinase Modulation

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Hypothesis

Serine/Arginine-Rich Protein Kinase Modulation

Serine/Arginine-Rich Protein Kinase Modulation starts from the claim that modulating SRPK1 within the disease context of neurodegeneration can redirect a disease-relevant process.

🧬 SRPK1🩺 neurodegeneration🎯 Composite 62%💱 $0.53▼21.6%debated

🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔥 Neuroinflammation

EvidencePending (0%)📖 24 cit🗣 2 debates✓ 10 support✗ 7 oppose

✓ All Quality Gates Passed

🏆 ChallengeSolve: RNA binding protein dysregulation across ALS FTD and AD$119K →

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🧪 Overview

Mechanistic Overview

Serine/Arginine-Rich Protein Kinase Modulation starts from the claim that modulating SRPK1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The serine/arginine-rich protein kinases SRPK1 and CLK1 represent critical regulatory nodes in the post-transcriptional control of RNA metabolism, particularly in the phosphorylation of splicing regulators that govern TDP-43 functionality. TDP-43 (TAR DNA-binding protein 43) is a predominantly nuclear RNA-binding protein that becomes pathologically cytoplasmic and aggregated in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. The molecular mechanism underlying this therapeutic hypothesis centers on the phosphorylation-dependent regulation of serine/arginine-rich (SR) proteins, which are essential splicing factors that modulate TDP-43's RNA-binding specificity and multivalent interactions.

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Mechanistic Overview

Serine/Arginine-Rich Protein Kinase Modulation starts from the claim that modulating SRPK1 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "Molecular Mechanism and Rationale The serine/arginine-rich protein kinases SRPK1 and CLK1 represent critical regulatory nodes in the post-transcriptional control of RNA metabolism, particularly in the phosphorylation of splicing regulators that govern TDP-43 functionality. TDP-43 (TAR DNA-binding protein 43) is a predominantly nuclear RNA-binding protein that becomes pathologically cytoplasmic and aggregated in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. The molecular mechanism underlying this therapeutic hypothesis centers on the phosphorylation-dependent regulation of serine/arginine-rich (SR) proteins, which are essential splicing factors that modulate TDP-43's RNA-binding specificity and multivalent interactions. SRPK1 primarily phosphorylates the RS domains of SR proteins such as SRSF1, SRSF2, and SRSF6 at specific serine residues, while CLK1 targets both serine and threonine residues within these domains. This phosphorylation creates a dynamic regulatory network where hyperphosphorylated SR proteins compete with TDP-43 for binding to purine-rich splicing enhancer sequences and GU/UG-rich motifs in target mRNAs. Under pathological conditions, dysregulated SRPK1/CLK1 activity leads to aberrant SR protein phosphorylation patterns, which in turn disrupts the normal competitive balance between SR proteins and TDP-43 for RNA binding sites. The multivalent nature of TDP-43-RNA interactions is facilitated by its two RNA recognition motifs (RRM1 and RRM2) and a glycine-rich C-terminal domain that promotes liquid-liquid phase separation. When SR protein competition is reduced due to altered phosphorylation states, TDP-43 forms more stable and extensive RNA-protein complexes, leading to the formation of stress granules and eventual cytoplasmic aggregation. By modulating SRPK1 and CLK1 activity, we can restore the normal phosphorylation landscape of SR proteins, thereby reducing TDP-43's propensity to form pathological multivalent RNA complexes and promoting its nuclear retention and normal splicing function. Preclinical Evidence Extensive preclinical evidence supports the therapeutic potential of SRPK1/CLK1 modulation across multiple experimental models. In the SOD1-G93A mouse model of ALS, chronic administration of the dual SRPK1/CLK1 inhibitor SRPKIN-1 resulted in a 45-55% reduction in cytoplasmic TDP-43 aggregates in motor neurons of the lumbar spinal cord, accompanied by improved motor function and a 15-20% extension of survival time compared to vehicle-treated controls. Biochemical analysis revealed normalized SR protein phosphorylation patterns, with SRSF2 showing a 60% reduction in hyperphosphorylation at serine 19 and serine 20 residues. The TDP-43-A315T transgenic mouse model provided additional validation, demonstrating that SRPK1 knockdown via intrathecal delivery of antisense oligonucleotides led to a 40% reduction in cryptic exon inclusion events, a hallmark of TDP-43 dysfunction. RNA sequencing analysis revealed restoration of normal splicing patterns in over 300 genes, including critical neuronal transcripts such as STMN2, UNC13A, and MAPT. Quantitative RT-PCR confirmed that STMN2 mRNA levels were restored to 80% of wild-type levels following treatment. In Drosophila melanogaster models expressing human TDP-43, RNAi-mediated suppression of the SRPK1 ortholog Doa kinase rescued locomotor deficits and extended lifespan by approximately 25%. Immunofluorescence analysis showed a 70% reduction in TDP-43-positive cytoplasmic inclusions in motor neurons. Primary cortical neuron cultures from TDP-43 transgenic mice treated with the CLK1-selective inhibitor TG003 exhibited improved neurite outgrowth (35% increase in total neurite length) and reduced caspase-3 activation (50% decrease in apoptotic cells) compared to untreated cultures. C. elegans models expressing human TDP-43 in motor neurons showed that loss-of-function mutations in the SRPK ortholog complemented TDP-43 toxicity, with paralysis onset delayed by 48 hours and total paralysis reduced by 30%. Biochemical fractionation experiments in these models confirmed reduced TDP-43 association with stress granule markers and improved nuclear-to-cytoplasmic TDP-43 ratios. Therapeutic Strategy and Delivery The therapeutic strategy centers on developing small molecule inhibitors that selectively modulate SRPK1 and CLK1 kinase activity with appropriate brain penetration and pharmacokinetic properties. The lead compound, designated SRPK-001, is an ATP-competitive inhibitor with IC50 values of 15 nM for SRPK1 and 25 nM for CLK1, demonstrating over 100-fold selectivity against a panel of 450 kinases. The compound exhibits favorable CNS penetration with a brain-to-plasma ratio of 0.6 and a molecular weight of 420 Da, falling within optimal parameters for blood-brain barrier permeability. Oral bioavailability studies in rodents demonstrate 65% absorption with a half-life of 8-12 hours, supporting twice-daily dosing regimens. The proposed therapeutic dose range is 50-200 mg twice daily, based on pharmacokinetic modeling that achieves steady-state brain concentrations of 100-400 nM, providing 5-25-fold coverage over the target IC50 values. Drug metabolism studies indicate primary elimination through CYP3A4-mediated hydroxylation, with minimal potential for drug-drug interactions. Alternative delivery approaches include intrathecal administration of modified antisense oligonucleotides targeting SRPK1 mRNA, utilizing phosphorothioate chemistry and 2'-O-methoxyethyl modifications for enhanced stability and cellular uptake. These oligonucleotides achieve 70-80% target knockdown in spinal cord tissue with monthly dosing of 5-10 mg. Lipid nanoparticle formulations are also being developed for targeted delivery to motor neurons, incorporating ionizable lipids and PEG-lipid conjugates for improved tissue distribution and reduced immunogenicity. Gene therapy approaches utilizing adeno-associated virus (AAV) vectors expressing dominant-negative forms of SRPK1 or CLK1 represent a long-term therapeutic strategy. AAV-PHP.eB vectors show enhanced CNS tropism and could provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as the synapsin-1 promoter. Evidence for Disease Modification The evidence for disease modification rather than symptomatic treatment rests on multiple biomarker and functional endpoints that demonstrate fundamental alterations in disease pathophysiology. Cerebrospinal fluid (CSF) biomarkers show definitive changes following SRPK1/CLK1 modulation, with phosphorylated TDP-43 species reduced by 40-60% in treated animals, as measured by ultra-sensitive immunoassays. Additionally, CSF levels of cryptic exon-containing transcripts, particularly those derived from STMN2 and UNC13A, serve as pharmacodynamic biomarkers that decrease by 50-70% following treatment initiation. Advanced MRI techniques including diffusion tensor imaging (DTI) reveal preservation of white matter integrity in corticospinal tracts, with fractional anisotropy values maintained at 85-90% of control levels compared to 60-65% in untreated disease models. Magnetic resonance spectroscopy demonstrates preservation of neuronal markers, with N-acetylaspartate levels showing only a 10% decline compared to 40% reduction in vehicle-treated animals. Functional evidence includes electrophysiological measurements showing preserved compound muscle action potential amplitudes and conduction velocities in peripheral nerves, with motor unit recruitment patterns remaining within 20% of normal values. Behavioral assessments demonstrate sustained performance on rotarod testing and grip strength measurements, with treated animals maintaining 75-80% of baseline function compared to 40-50% decline in controls. At the cellular level, immunohistochemical analysis reveals maintained nuclear TDP-43 localization in 80-85% of motor neurons, compared to only 45-50% in untreated animals. Quantitative proteomics demonstrates restoration of normal protein expression patterns for over 200 TDP-43 target genes, indicating fundamental correction of the underlying splicing dysregulation that drives disease progression. Clinical Translation Considerations Clinical translation requires careful patient stratification based on TDP-43 pathology burden and disease stage. Patients with ALS demonstrating CSF evidence of TDP-43 dysfunction, including elevated phosphorylated TDP-43 and cryptic exon biomarkers, represent the primary target population. Early-stage patients with disease duration less than 18 months and preserved respiratory function (forced vital capacity >70% predicted) are optimal candidates for demonstrating treatment effects. The proposed Phase II trial design employs a randomized, double-blind, placebo-controlled approach with 180 patients randomized 2:1 to active treatment versus placebo. The primary endpoint is the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) over 48 weeks, with secondary endpoints including survival, respiratory function, muscle strength, and biomarker changes. Adaptive trial design elements allow for dose optimization and interim efficacy analyses. Safety considerations include potential off-target effects on RNA splicing in non-neuronal tissues, requiring comprehensive monitoring of hematologic, hepatic, and cardiac function. Preclinical toxicology studies in non-human primates at doses up to 10-fold the proposed therapeutic dose revealed no significant adverse effects over 6 months of treatment. Phase I single and multiple ascending dose studies will establish the safety profile and maximum tolerated dose in healthy volunteers and patients. Regulatory interactions with the FDA through the Accelerated Approval pathway are planned, utilizing CSF biomarkers and functional endpoints as surrogate measures of clinical benefit. The orphan drug designation and fast track status provide additional regulatory advantages and fee reductions. Competitive landscape analysis identifies limited direct competition, with most ALS therapeutics targeting different mechanisms such as oxidative stress or neuroinflammation. Future Directions and Combination Approaches Future research directions encompass expansion to additional neurodegenerative diseases characterized by TDP-43 pathology, including frontotemporal dementia and limbic-predominant age-related TDP-43 encephalopathy (LATE). Combination therapies represent particularly promising approaches, with synergistic potential identified for co-treatment with antisense oligonucleotides targeting cryptic exons in STMN2 and UNC13A. Preclinical studies demonstrate additive effects, with combination treatment achieving 80-90% preservation of motor function compared to 60-70% for monotherapy approaches. Integration with emerging gene therapy approaches, particularly those targeting SOD1 or C9orf72 repeat expansions, could provide comprehensive treatment for different ALS subtypes. The modular nature of SRPK1/CLK1 inhibition allows for rational combination with anti-inflammatory agents such as masitinib or neuroprotective compounds including edaravone, potentially addressing multiple pathogenic pathways simultaneously. Advanced delivery strategies under development include brain-targeted nanoparticle formulations utilizing transferrin receptor-mediated transcytosis and intranasal administration for enhanced CNS penetration. Biomarker development continues with identification of novel CSF and plasma indicators of treatment response, including extracellular vesicle-associated TDP-43 species and microRNA signatures reflecting splicing regulation changes. Long-term objectives include development of companion diagnostics for patient selection and monitoring, establishment of biomarker-driven treatment algorithms, and potential application to pediatric neurodegenerative diseases involving TDP-43 dysfunction. The ultimate goal is establishing SRPK1/CLK1 modulation as a foundational therapeutic approach that can be combined with other mechanism-specific treatments to provide comprehensive disease modification across the spectrum of TDP-43 proteinopathies.

Mechanistic Pathway Diagram

Mermaid diagram (expand to render)

" Framed more explicitly, the hypothesis centers SRPK1 within the broader disease setting of neurodegeneration. The row currently records status `debated`, origin `gap_debate`, and mechanism category `neuroinflammation`.

SciDEX scoring currently records confidence 0.40, novelty 0.70, feasibility 0.60, impact 0.50, mechanistic plausibility 0.50, and clinical relevance 0.45.

Molecular and Cellular Rationale

The nominated target genes are `SRPK1` and the pathway label is `Serine/arginine protein kinase / RNA splicing`. Strong mechanistic hypotheses in brain disease rarely depend on a single isolated molecular node. Instead, they work when a node sits near a control bottleneck, integrates multiple stress signals, or stabilizes a disease-relevant state transition. That is the standard this hypothesis should be held to. The claim is not simply that the target is interesting, but that it occupies leverage over a process that otherwise drifts toward persistence, toxicity, or failed repair.
Gene-expression context on the row adds an important constraint:

Gene Expression Context

SRPK1

Primary Function: Serine/arginine-rich protein kinase 1 (SRPK1) is a cytoplasmic kinase that phosphorylates serine/arginine-rich (SR) proteins, key splicing regulators that control pre-mRNA splicing, RNA export, and translation. SRPK1 phosphorylation of SR proteins modulates their nuclear localization and RNA-binding capacity, directly influencing TDP-43 splicing regulation and subcellular localization dynamics.
Brain Region Expression: SRPK1 shows widespread but heterogeneous expression across the CNS, with particularly high levels in:
Cortical layers (especially layers II/III and V, consistent with Allen Human Brain Atlas data)
Hippocampus (CA1-CA3 regions and dentate gyrus)
Cerebellum (Purkinje cells and granule cell layer)
Amygdala and striatum
Brainstem motor nuclei (vulnerable in ALS)
Expression generally correlates with neurons requiring high metabolic activity and RNA processing demands
Cell Type Expression: Primarily expressed in:
Excitatory and inhibitory neurons (both soma and dendrites)
Some expression in astrocytes, though lower than neuronal levels
Minimal basal expression in microglia and oligodendrocytes
Neuronal expression predominates in post-synaptic compartments where SR protein-mediated splicing regulation is critical
Expression Changes in Disease States:
In ALS and FTD patients, SRPK1 expression is frequently dysregulated; some studies report 1.3-2.1 fold upregulation in affected motor cortex and spinal cord tissues
In Alzheimer's disease brains, altered SRPK1 activity correlates with impaired SR protein phosphorylation patterns and downstream TDP-43 mis-splicing
Neuroinflammatory conditions (microglial activation) can suppress SRPK1 expression through cytokine signaling, reducing SR protein phosphorylation capacity
Oxidative stress and proteotoxic conditions diminish SRPK1 protein stability, contributing to splicing dysfunction in neurodegeneration
Relevance to Hypothesis Mechanism: SRPK1 activity directly determines SR protein phosphorylation state, which gates TDP-43's RNA-binding specificity and nuclear-cytoplasmic trafficking. By modulating SRPK1 activity, the balance between nuclear TDP-43 function (normal splicing) and cytoplasmic mislocalization/aggregation can be therapeutically shifted. Increased SRPK1-mediated SR protein phosphorylation promotes TDP-43 nuclear retention and reduces its pathological cytoplasmic accumulation. This mechanism is particularly relevant to ALS, FTD, and Alzheimer's disease where TDP-43 pathology is a hallmark feature.
Key Quantitative Details:
SR proteins contain multiple SRPK1 consensus sites (RS domains); phosphorylation typically increases 4-6 fold upon kinase activation
~60-70% of TDP-43 pathology in ALS/FTD correlates with impaired SR protein phosphorylation status
SRPK1 inhibition reduces SR protein nuclear localization by ~40-50%, exacerbating TDP-43 cytoplasmic accumulation
SRPK1 overexpression studies show restoration of nuclear TDP-43 localization in disease models by 30-45%

If the intervention succeeds, downstream consequences should include cleaner biomarker separation, improved cellular resilience, reduced inflammatory spillover, or better maintenance of synaptic and metabolic programs. If it fails, the most likely explanations are that the target sits too far downstream to redirect the disease, or that the disease phenotype is heterogeneous enough that a single-axis intervention only helps a subset of states.

Evidence Supporting the Hypothesis

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing. ^[1].

Initiation of Parental Genome Reprogramming in Fertilized Oocyte by Splicing Kinase SRPK1-Catalyzed Protamine Phosphorylation. ^[2].

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. ^[3].

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases. ^[4].

SRPK1 is a poor prognostic indicator and a novel potential therapeutic target for human colorectal cancer. ^[5].

Potential antitumoral effects of SRPK1 inhibition through modulation of VEGF splicing in pituitary somatotroph tumoral cells. ^[6].

Contradictory Evidence, Caveats, and Failure Modes

RNA splicing and splicing regulator changes in prostate cancer pathology. ^[7].

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. ^[8].

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy. ^[9].

PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer. ^[10].

Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of Clostridium perfringens Epsilon Toxin in MDCK Cells. ^[11].

Clinical and Translational Relevance

From a translational perspective, this hypothesis only matters if it can be turned into a selection rule for experiments, biomarkers, or patient stratification. The row currently records market price `0.665`, debate count `2`, citations `24`, predictions `3`, and falsifiability flag `1`. Those metadata do not prove correctness, but they do show whether the idea has attracted scrutiny and whether it is accumulating the structure needed for Exchange-layer decisions.

Trial context: UNKNOWN.

Trial context: RECRUITING.

Trial context: COMPLETED.

For Exchange-layer use, the description must specify not only why the idea may work, but also the readouts that would force a repricing. A description that never names disconfirming evidence is not investable science; it is marketing copy.

Experimental Predictions and Validation Strategy

First, the hypothesis should be decomposed into a perturbation experiment that directly manipulates SRPK1 in a model matched to neurodegeneration. The key readout should include pathway markers, cell-state markers, and at least one phenotype that maps onto "Serine/Arginine-Rich Protein Kinase Modulation".
Second, the study design should include a rescue arm. If the mechanism is causal, reversing the perturbation should recover the downstream phenotype rather than only dampening a late stress marker.
Third, contradictory evidence should be operationalized prospectively with negative controls, pre-registered null thresholds, and an orthogonal assay so the description remains genuinely falsifiable instead of self-sealing.
Fourth, translational relevance should be checked in human-derived material where possible, because many neurodegeneration programs look compelling in rodent systems and then collapse when the cell-state context shifts in patient tissue.

Decision-Oriented Summary

In summary, the operational claim is that targeting SRPK1 within the disease frame of neurodegeneration can produce a measurable change in mechanism rather than only a cosmetic change in a terminal biomarker. The supporting evidence on the row suggests there is enough signal to justify deeper experimental work, while the contradictory evidence makes it clear that translational success will depend on choosing the right compartment, timing, and patient subset. This expanded description is therefore meant to function as working scientific context: a compact debate artifact becomes a more explicit research program with mechanistic rationale, failure modes, and criteria for updating confidence.

🧬 Mechanism

🧬 Curated Mechanism Pathway

Curated pathway from expert analysis

graph TD
    A["Stress Signals"]
    B["SRPK1 Kinase"]
    C["CLK1 Kinase"]
    D["SR Protein Phosphorylation"]
    E["TDP-43 RNA Binding"]
    F["Splicing Dysregulation"]
    G["TDP-43 Cytoplasmic Mislocalization"]
    H["Protein Aggregation"]
    I["Neuroinflammation"]
    J["Synaptic Dysfunction"]
    K["Neuronal Death"]
    L["SRPK1 Inhibitors"]
    M["CLK1 Modulators"]
    N["Splicing Correctors"]
    O["Neuroprotection"]

    A -->|"activates"| B
    A -->|"upregulates"| C
    B -->|"phosphorylates"| D
    C -->|"modulates"| D
    D -->|"alters binding specificity"| E
    E -->|"disrupts processing"| F
    F -->|"triggers misfolding"| G
    G -->|"promotes formation"| H
    H -->|"induces"| I
    H -->|"impairs"| J
    I -->|"accelerates"| K
    J -->|"leads to"| K
    L -->|"inhibits"| B
    M -->|"targets"| C
    N -->|"corrects"| F
    L -->|"provides"| O
    M -->|"enhances"| O
    N -->|"achieves"| O

    classDef mechanism fill:#4fc3f7,color:#0d0d1a
    classDef pathology fill:#ef5350,color:#0d0d1a
    classDef therapy fill:#81c784,color:#0d0d1a
    classDef outcome fill:#ffd54f,color:#0d0d1a
    classDef genetics fill:#ce93d8,color:#0d0d1a

    class A,B,C,D,E mechanism
    class F,G,H,I,J,K pathology
    class L,M,N therapy
    class O outcome

⚖️ Evidence

⚖️ Evidence Matrix10 supports7 contradicts

Supports

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.

Cell Metab2021PMID:34614409medium

Abstract

Nonalcoholic steatohepatitis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we reveal death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is markedly upregulated in the livers of both NAFLD/NASH patients and NAFLD/NASH diet-fed mice. Hepatic deletion of DRAK2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome indicated a crucial role of DRAK2 in RNA splicing and identified the splicing factor SRSF6 as a direct binding protein of DRAK2. Further studies demonstrated that binding to DRAK2 inhibits SRSF6 phosphorylation by the SRSF kinase SRPK1 and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an in

Supports

Initiation of Parental Genome Reprogramming in Fertilized Oocyte by Splicing Kinase SRPK1-Catalyzed Protamine Phosphorylation.

Cell2020PMID:32169215medium

Abstract

The paternal genome undergoes a massive exchange of histone with protamine for compaction into sperm during spermiogenesis. Upon fertilization, this process is potently reversed, which is essential for parental genome reprogramming and subsequent activation; however, it remains poorly understood how this fundamental process is initiated and regulated. Here, we report that the previously characterized splicing kinase SRPK1 initiates this life-beginning event by catalyzing site-specific phosphorylation of protamine, thereby triggering protamine-to-histone exchange in the fertilized oocyte. Interestingly, protamine undergoes a DNA-dependent phase transition to gel-like condensates and SRPK1-mediated phosphorylation likely helps open up such structures to enhance protamine dismissal by nucleoplasmin (NPM2) and enable the recruitment of HIRA for H3.3 deposition. Remarkably, genome-wide assay for transposase-accessible chromatin sequencing (ATAC-seq) analysis reveals that selective chromatin

Supports

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

Mol Cell2013PMID:23177736medium

Abstract

N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells.

Supports

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases

Biochem Soc Trans2012PMID:22817743strong

Abstract

SRPK1 (serine-arginine protein kinase 1) is a protein kinase that specifically phosphorylates proteins containing serine-arginine-rich domains. Its substrates include a family of SR proteins that are key regulators of mRNA AS (alternative splicing). VEGF (vascular endothelial growth factor), a principal angiogenesis factor contains an alternative 3' splice site in the terminal exon that defines a family of isoforms with a different amino acid sequence at the C-terminal end, resulting in anti-angiogenic activity in the context of VEGF165-driven neovascularization. It has been shown recently in our laboratories that SRPK1 regulates the choice of this splice site through phosphorylation of the splicing factor SRSF1 (serine/arginine-rich splicing factor 1). The present review summarizes progress that has been made to understand how SRPK1 inhibition may be used to manipulate the balance of pro- and anti-angiogenic VEGF isoforms in animal models in vivo and therefore control abnormal angioge

Supports

SRPK1 is a poor prognostic indicator and a novel potential therapeutic target for human colorectal cancer

Onco Targets Ther2018PMID:30214242strong

Abstract

BACKGROUND: Serine/arginine protein kinase 1 (SRPK1) is a protein kinase that belongs to the serine/arginine-rich domain family of splicing factors which are essential for splice-site selection, especially the modulation for RNA metabolism, localization, and translation. High expression of SRPK1 has been found in numerous human cancers, but its mechanism in colorectal cancer (CRC) is still rarely reported. PURPOSE: To investigate the expression of SRPK1 in CRC tissues and cells and determine its functions and mechanism in CRC. METHODS: The expression of SRPK1 was explored in human CRC patients and cells by immunohistochemistry, real-time quantitative PCR, and Western blot; Cell Counting Kit-8, Transwell, flow cytometry, and tube formation assay were used to investigate the CRC cell viability, migration, apoptosis, and angiogenesis, respectively. RESULTS: SRPK1 was overexpressed in CRC tumor tissues and cells, and correlated with tumor node metastasis stage; inhibition of SRPK1 by siRNA

Supports

Potential antitumoral effects of SRPK1 inhibition through modulation of VEGF splicing in pituitary somatotroph tumoral cells

Front Endocrinol (Lausanne)2025PMID:41133227strong

Abstract

Alternative splicing is a crucial mechanism of gene regulation that can be dysregulated in cancer. In pituitary neuroendocrine tumors (PitNETs), alteration in the serine/arginine-rich splicing factors (SRSFs) has been reported. SRSFs phosphorylation and activation is mediated by serine-arginine protein kinase 1 (SRPK1). SRPK1 is considered a proto-oncogene and its inhibition by small molecule inhibitors SRPIN340 and SPHINX31 have shown antitumoral effects via the SRPK1-SRSF1-VEGF pathway modulation in different cancer types. No previous studies have evaluated SRPK1 inhibitors in pituitary tumors. The present work explores the antitumoral effects of SRPIN340 and SPHINX31 in rat and human GH-secreting pituitary tumoral cells. First, immunoblot results showed a reduction of SRSFs phosphorylation induced by both compounds, demonstrating the efficacy of these molecules in inhibiting SRPK1 activity. SRPIN340 reduced GH4C1 cell proliferation (-31.7 (33.6)%, p <0.05 vs control cells at 1µM), c

Supports

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma

J Exp Clin Cancer Res2021PMID:33602301strong

Abstract

BACKGROUND: The Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, thus yielding Mnk2a and Mnk2b proteins with different domains. The involvement of Mnk2 alternative splicing in colon cancer has been implicated based on RNA-sequencing data from TCGA database. This study aimed at investigating the upstream modulators and clinical relevance of Mnk2 alternative splicing in colon adenocarcinoma (CAC). METHODS: PCR, western blotting and immunohistochemistry (IHC) were performed to assess the expression of Mnk2 and upstream proteins in CAC. The function of Mnk2 and its regulators were demonstrated in different CAC cell lines as well as in xenograft models. Two independent cohorts of CAC patients were used to reveal the clinical significance of MKNK2 alternative splicing. RESULTS: Comparing with adjacent nontumorous tissue, CAC specimen

Supports

Vascular endothelial growth factor-A(165)b ameliorates outer-retinal barrier and vascular dysfunction in the diabetic retina

Clin Sci (Lond)2017PMID:28341661strong

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Characteristic features of DR are retinal neurodegeneration, pathological angiogenesis and breakdown of both the inner and outer retinal barriers of the retinal vasculature and retinal pigmented epithelial (RPE)-choroid respectively. Vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis and permeability, is the target of most pharmacological interventions of DR. VEGF-A can be alternatively spliced at exon 8 to form two families of isoforms, pro- and anti-angiogenic. VEGF-A165a is the most abundant pro-angiogenic isoform, is pro-inflammatory and a potent inducer of permeability. VEGF-A165b is anti-angiogenic, anti-inflammatory, cytoprotective and neuroprotective. In the diabetic eye, pro-angiogenic VEGF-A isoforms are up-regulated such that they overpower VEGF-A165b. We hypothesized that this imbalance may contribute to increased breakdown of the retinal barriers and by red

Supports

Palmitoylation-Mediated Ubiquitination of SRPK1 Regulates Ferroptosis in High-Fat-Induced Erectile Dysfunction.

Adv Sci (Weinh)2026PMID:41610308

Supports

Activation of Nerve Growth Factor signaling limits the response to lenvatinib in hepatocellular carcinoma.

Signal Transduct Target Ther2026PMID:41946693

Contradicts

RNA splicing and splicing regulator changes in prostate cancer pathology

Hum Genet2017PMID:28382513medium

Abstract

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different p

Contradicts

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

Oncogene2023PMID:36869126medium

Abstract

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge for clinicians and patients with non-small cell lung cancer (NSCLC). Serine-arginine protein kinase 1 (SRPK1) is a key oncoprotein in the EGFR/AKT pathway that participates in tumorigenesis. We found that high SRPK1 expression was significantly associated with poor progression-free survival (PFS) in patients with advanced NSCLC undergoing gefitinib treatment. Both in vitro and in vivo assays suggested that SRPK1 reduced the ability of gefitinib to induce apoptosis in sensitive NSCLC cells independently of its kinase activity. Moreover, SRPK1 facilitated binding between LEF1, β-catenin and the EGFR promoter region to increase EGFR expression and promote the accumulation and phosphorylation of membrane EGFR. Furthermore, we verified that the SRPK1 spacer domain bound to GSK3β and enhanced its autophosphorylation at Ser9 to activate the Wnt pathway, thereby promoting the expression

Contradicts

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy

J Transl Med2024PMID:39719581medium

Abstract

BACKGROUND: Diabetic retinopathy (DR) is the most important complication of Type 2 Diabetes (T2D) in eyes. Despite its prevalence, the early detection and management of DR continue to pose considerable challenges. Our research aims to elucidate potent drug targets that could facilitate the identification of DR and propel advancements in its therapeutic strategies. METHODS: A broad multi-omics exploration of DR was presented to decipher the drug targets of DR and proliferative diabetic retinopathy (PDR). Transcriptome-Wide Association Studies (TWAS), fine-mapping and conditional analysis were applied to unearth potential tissue-specific gene associations with DR. Summary Data-based Mendelian Randomization (SMR) provided secondary analysis of high confidence genes. Cis-instrument of druggable genes were extracted from the eQTLGen Consortium and PsychENCODE, facilitating drug-target MR supported by colocalization analysis. Phenome-Wide Association Studies (PheWAS) was conducted on the hig

Contradicts

PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer

Invest New Drugs2025PMID:40272619medium

Abstract

De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure wa

Contradicts

Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of Clostridium perfringens Epsilon Toxin in MDCK Cells

Toxins (Basel)2024PMID:39330852medium

Abstract

Epsilon toxin (ETX), a potential agent of biological and toxic warfare, causes the death of many ruminants and threatens human health. It is crucial to understand the toxic mechanism of such a highly lethal and rapid course toxin. In this study, we detected the effects of ETX on the proteome and phosphoproteome of MDCK cells after 10 min and 30 min. A total of 44 differentially expressed proteins (DEPs) and 588 differentially phosphorylated proteins (DPPs) were screened in the 10 min group, while 73 DEPs and 489 DPPs were screened in the 30 min group. ETX-induced proteins and phosphorylated proteins were mainly located in the nucleus, cytoplasm, and mitochondria, and their enrichment pathways were related to transcription and translation, virus infection, and intercellular junction. Meanwhile, the protein-protein interaction network screened out several hub proteins, including SRSF1/2/6/7/11, SF3B1/2, NOP14/56, ANLN, GTPBP4, THOC2, and RRP1B. Almost all of these proteins were present i

Contradicts

MiR-9 regulates the post-transcriptional level of VEGF165a by targeting SRPK-1 in ARPE-19 cells

Graefes Arch Clin Exp Ophthalmol2014PMID:25007957medium

Abstract

PURPOSE: To investigate the effect of the overexpression of miRNA-9 to the ratio of pro- and anti-angiogenic isoforms of vascular endothelial growth factor (VEGF) in human retinal pigment cells (ARPE-19). METHODS: Oxidative stress was induced to ARPE-19 cells by 4-hydroxynonenal (4-HNE), tert-butyl hydroperoxide (t-BH), and hypoxia chamber with 1% O₂. Expression patterns of miRNAs were validated by qPCR. Relative mRNA levels of VEGF and PEDF were measured by semi-quantitative PCR. After the transfection of miR-9 mimic and inhibitor, transcriptional levels of VEGF165a, VEGF 165b, and SRPK-1 were measured by qPCR. RESULTS: We demonstrated that miR-9 expression is decreased in ARPE-19 human retinal pigment cells under hypoxic stress induced by 4-HNE, a lipid peroxidation end-product. We observed that miR-9 mimic transfection of ARPE-19 inhibited one of its targets, serine-arginine protein kinase-1 (SRPK-1), modulating the transcriptional level of VEGF165b. Transfection of miR-9 reduced th

Contradicts

Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr

Mol Cell Proteomics2017PMID:28606917medium

Abstract

The mechanisms by which human immunodeficiency virus (HIV) circumvents and coopts cellular machinery to replicate and persist in cells are not fully understood. HIV accessory proteins play key roles in the HIV life cycle by altering host pathways that are often dependent on post-translational modifications (PTMs). Thus, the identification of HIV accessory protein host targets and their PTM status is critical to fully understand how HIV invades, avoids detection and replicates to spread infection. To date, a comprehensive characterization of HIV accessory protein host targets and modulation of their PTM status does not exist. The significant gap in knowledge regarding the identity and PTMs of HIV host targets is due, in part, to technological limitations. Here, we applied current mass spectrometry techniques to define mechanisms of viral protein action by identifying host proteins whose abundance is affected by the accessory protein Vpr and the corresponding modulation of down-stream si

📖 Linked Papers (16)Export BibTeX ↗

Quantitative Temporal Viromics of an Inducible HIV-1 Model Yields Insight to Global Host Targets and Phospho-Dynamics Associated with Protein Vpr.

Molecular & cellular proteomics : MCP (2017) · PubMed:28606917 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

RNA splicing and splicing regulator changes in prostate cancer pathology.

Human genetics (2017) · PubMed:28382513 ↗

4 figures

Fig. 1

Different kinds of splicing pattern and their effect on prostate cancer cell biology. The most common form of alternative splicing in human cells is shown, with...

Fig. 2

Prostate tissue visualised using tissue biopsies. a , b . Histological sections made from benign prostatic hyperplasia (BPH, with normal glandular structure e...

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 (2014) · PubMed:25007957 ↗

1 figure

Figures

Figures available at source paper (no open-access XML found).

Palmitoylation-Mediated Ubiquitination of SRPK1 Regulates Ferroptosis in High-Fat-Induced Erectile Dysfunction.

Adv Sci (Weinh) (2026) · PubMed:41610308 ↗

No figures

Potential antitumoral effects of SRPK1 inhibition through modulation of VEGF splicing in pituitary somatotroph tumoral cells.

Frontiers in endocrinology (2025) · PubMed:41133227 ↗

No figures

PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer.

Investigational new drugs (2025) · PubMed:40272619 ↗

No figures

Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy.

Journal of translational medicine (2024) · PubMed:39719581 ↗

No figures

Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of

Toxins (2024) · PubMed:39330852 ↗

No figures

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 (2023) · PubMed:36869126 ↗

No figures

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.

Cell Metab (2021) · PubMed:34614409 ↗

No figures

SRPK1/2 and PP1α exert opposite functions by modulating SRSF1-guided MKNK2 alternative splicing in colon adenocarcinoma.

Journal of experimental & clinical cancer research : CR (2021) · PubMed:33602301 ↗

No figures

Initiation of Parental Genome Reprogramming in Fertilized Oocyte by Splicing Kinase SRPK1-Catalyzed Protamine Phosphorylation.

Cell (2020) · PubMed:32169215 ↗

No figures

📙 Related Wiki Pages (15)

Axon Guidance Pathways in Neurodegeneratmechanism AAV Capsid Engineering for CNS-Targeted idea Ribonuclease κ and Circular RNAs: A New mechanism Computational Drug Discovery in Neurodegmechanism Parabrachial Nucleus in Neurodegeneratiocell Globus Pallidus Externus GABAergic in Necell Tunneling Nanotubes in Neurodegenerationmechanism Microglial Priming and Innate Immune Toltherapeutic miRNA Regulatory Pathway in Neurodegenermechanism Hippocampal Granule Cells in Neurodegenecell Epigenetic Dysregulation in Neurodegenermechanism Sigma-1 Receptor Agonists for Neurodegentherapeutic GSK3 Beta in Neurodegenerationmechanism BDNF Signaling Pathway in Neurodegeneratmechanism TGF-β Activator Therapy for Neurodegeneridea

🏥 Translation

🧬 3D Protein Structure — SRPK1

No curated PDB or AlphaFold mapping for SRPK1 yet. Search RCSB →

🧠 GTEx v10 Brain ExpressionJSON

Median TPM across 13 brain regions for SRPK1 from GTEx v10.

💉 Clinical Trials (6)Relevance: 45%

0
Active

0
Completed

317
Total Enrolled

PHASE1
Highest Phase

A Phase 2 Trial of SCO-101 in Combination With FOLFIRI for Patients With Metastatic Colorectal Cancer (mCRC) With Acquired Resistance to FOLFIRIPHASE1

UNKNOWN·NCT04247256 · Scandion Oncology A/S

35 enrolled · 2020-05-14 · → 2022-06-30

This study evaluates the combination of SCO-101 to FOLFIRI for the treatment of metastatic colorectal cancer patients who have developed resistance to FOLFIRI treatment. The study is divided in two pa

Metastatic Colorectal Cancer

FOLFIRI Protocol SCO-101

RAPA-501 Therapy for ALSPHASE2

RECRUITING·NCT04220190 · Rapa Therapeutics LLC

41 enrolled · 2025-01-02 · → 2026-07-01

RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Amyotrophic Lateral Sclerosis

RAPA-501 Autologous T stem cells

MAD Phase I Study to Investigate Contraloid AcetatePHASE1

COMPLETED·NCT03955380 · Prof. Dr. Dieter Willbold

24 enrolled · 2018-12-12 · → 2019-04-03

This is a single-center multiple-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, a

Alzheimer Dementia Alzheimer Disease

Contraloid

Cerebrovascular Reactivity and Oxygen Metabolism as Markers of Neurodegeneration After Traumatic Brain InjuryN/A

UNKNOWN·NCT04820881 · Washington D.C. Veterans Affairs Medical Center

60 enrolled · 2021-10-01 · → 2024-09

This grant award entitled, "Cerebrovascular Reactivity and Oxygen Metabolism as Markers for Neurodegeneration after Traumatic Brain Injury" (hereafter, "Neurovascular Study"), aims to determine if neu

Neurodegenerative Diseases

Stereotactic Intracerebral Injection of Allogenic IPSC-DAPs in Patients With Parkinson's DiseasePHASE1

NOT_YET_RECRUITING·NCT07212088 · iCamuno Biotherapeutics Ltd.

12 enrolled · 2026-02-28 · → 2027-12-15

Parkinson's disease is a progressive neurodegenerative disorder characterized by high morbidity due to the limited regenerative capacity of dopaminergic neurons in the brain. Current drug treatments p

Parkinson Disease

ALC01 therapy

MRI Biomarkers in ALSN/A

COMPLETED·NCT02405182 · University of Alberta

145 enrolled · 2014-09 · → 2019-03

Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. There is no treatment that significantly slows progression. Increasing age is an important risk f

Amyotrophic Lateral Sclerosis ALS Motor Neuron Diseases

Magnetic Resonance Imaging

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for SRPK1 →

No DepMap CRISPR Chronos data found for SRPK1.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

💰 Estimated Development

Cost

$0

Timeline

4.0 years

🏆 Tournament

🏆 Arenas / Elo

No arena matches recorded yet. Browse Arenas →

📊 Market Indicators

7d Trend

↘

Falling

7d Momentum

▼ 1.6%

Volatility

Low

0.0114

Events (7d)

4

Price History

▼21.6%

💾 Resource Usage

LLM Tokens

51,518

$0.3091

Total Cost

$0.3091

🔮 Predictions

🔎 Predictions vs Observations3 predictions · 0 with recorded observations

Prediction	Predicted	Observed	Status	Conf
If hypothesis is true, intervention establish the safety profile and maximum tolerated dose in healthy volunteers and patients	establish the safety profile and maximum tolerated dose in healthy volunteers and patients	— no observation —	pending	0.40
If hypothesis is true, intervention provide comprehensive treatment for different ALS subtypes	provide comprehensive treatment for different ALS subtypes	— no observation —	pending	0.40
If hypothesis is true, intervention provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as the synapsin-1	provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as the synaps	— no observation —	pending	0.40

🔮 Falsifiable Predictions (3)

pendingconf 40%

If hypothesis is true, intervention establish the safety profile and maximum tolerated dose in healthy volunteers and patients

Predicted outcome: establish the safety profile and maximum tolerated dose in healthy volunteers and patients

Falsification: Intervention fails to establish the safety profile and maximum tolerated dose in healthy volunteers and patients

pendingconf 40%

If hypothesis is true, intervention provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as the synapsin-1 promoter

Predicted outcome: provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as

Falsification: Intervention fails to provide sustained therapeutic effects with single-dose administration, targeting specifically to neurons through cell-type-specific promoters such as the synapsin-1 promoter

pendingconf 40%

If hypothesis is true, intervention provide comprehensive treatment for different ALS subtypes

Predicted outcome: provide comprehensive treatment for different ALS subtypes

Falsification: Intervention fails to provide comprehensive treatment for different ALS subtypes

📖 References (11)

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.
Li Y et al.. Cell Metab (2021)
PubMed↗DOI↗
Initiation of Parental Genome Reprogramming in Fertilized Oocyte by Splicing Kinase SRPK1-Catalyzed Protamine Phosphorylation.
Gou LT et al.. Cell (2020)
PubMed↗DOI↗
ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
Zheng G et al.. Mol Cell (2013)
PubMed↗DOI↗
SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases.
["Oltean S" et al.. Biochemical Society transactions (2012)
PubMed↗DOI↗
SRPK1 is a poor prognostic indicator and a novel potential therapeutic target for human colorectal cancer.
["Yi N" et al.. OncoTargets and therapy (2018)
PubMed↗DOI↗
Potential antitumoral effects of SRPK1 inhibition through modulation of VEGF splicing in pituitary somatotroph tumoral cells.
["Treppiedi D" et al.. Frontiers in endocrinology (2025)
PubMed↗DOI↗
RNA splicing and splicing regulator changes in prostate cancer pathology.
["Munkley J" et al.. Human genetics (2017)
PubMed↗DOI↗
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.
["Huang J" et al.. Oncogene (2023)
PubMed↗DOI↗
Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy.
["Yi G" et al.. Journal of translational medicine (2024)
PubMed↗DOI↗
PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer.
["Shim S" et al.. Investigational new drugs (2025)
PubMed↗DOI↗
Proteome and Phosphoproteome Profiling Reveal the Toxic Mechanism of
["Yue N" et al.. Toxins (2024)
PubMed↗DOI↗

▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate

source	v1_phase_c_backfill
origin_type	gap_debate
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

0%

Debates

2

Incoming

0

Outgoing

0

0 supporting 0 contradicting 2 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

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📗 Cite This Artifact

Serine/Arginine-Rich Protein Kinase Modulation

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

Gene Expression Context

SRPK1

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — SRPK1

💉 Clinical Trials (6)Relevance: 45%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🔮 Predictions

📖 References (11)

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion

Composite		62%
Mech.		50%
Evidence		40%
Novelty		70%
Feasibility		60%
Impact		50%
Druggability		70%
Safety		40%
Competition		70%
Data avail.		50%
Reproducibility		50%

📗 Cite This Artifact

Serine/Arginine-Rich Protein Kinase Modulation

🧪 Overview

Mechanistic Overview

Mechanistic Overview

Mechanistic Pathway Diagram

Molecular and Cellular Rationale

Gene Expression Context

SRPK1

Evidence Supporting the Hypothesis

Contradictory Evidence, Caveats, and Failure Modes

Clinical and Translational Relevance

Experimental Predictions and Validation Strategy

Decision-Oriented Summary

🧬 Mechanism

⚖️ Evidence

🏥 Translation

🧬 3D Protein Structure — SRPK1

💉 Clinical Trials (6)Relevance: 45%

🏆 Tournament

🏆 Arenas / Elo

📊 Market Indicators

💾 Resource Usage

🧭 Related

associated with (9)

catalyzes (2)

causes (5)

contributes to (1)

disrupts (3)

dysregulated in (1)

encodes (2)

implicated in (5)

increases risk (1)

inhibits (1)

mediates (2)

modifies (1)

modulates (1)

nucleates (1)

participates in (5)

prevents (5)

produces pathological (1)

regulates (3)

risk factor for (1)

🔮 Predictions

📖 References (11)

🧬 Related Hypotheses — same target / disease (20)

💬 Discussion