Affinage

CLK1

Dual specificity protein kinase CLK1 · UniProt P49759

Length
484 aa
Mass
57.3 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The CLK1 symbol in this corpus resolves to two biochemically distinct proteins that share the historical "clk-1" designation: a nuclear/cytoplasmic dual-specificity SR-protein kinase, and the mitochondrial ubiquinone-biosynthesis enzyme encoded by the COQ7/CLK-1 ortholog. The kinase activity governs alternative pre-mRNA splicing by hyperphosphorylating SR splicing factors, and CLK1 autoregulates its own splicing to produce a catalytically active isoform and a truncated inactive isoform (CLK1T) through an exon-inclusion loop balanced between TRA2 activators and CLK1-phosphorylated SRSF3 repressor activity (PMID:9315658, PMID:39251328). Substrate selectivity is conferred by the disordered N-terminus, which acts both as a negative regulatory domain and as a bridge that contacts the kinase domain and the RS domain of substrates such as SRSF1, driving N-terminus-induced oligomerization and localization to nuclear speckles (PMID:10954422, PMID:24869919, PMID:26443864). CLK1 phosphorylates a broad set of spliceosomal substrates — including SRSF5, U1-70K (Ser226), SPF45, and the splicing kinase target hPRP4 — to control splice-site usage and spliceosome assembly, and operates in a symbiotic system with SRPK1, which binds an RS-like motif in the CLK1 N-terminus to release phosphorylated SR proteins and recycle the kinase (PMID:11418604, PMID:23519612, PMID:27397683, PMID:33811140, PMID:33849617). Under cellular stress, suspended intron-retaining CLK1/4 transcripts mature to restore SR-protein phosphorylation (PMID:21949414). Through these splicing functions CLK1 modulates influenza M1/M2 segment-7 splicing and viral replication, DMD exon skipping, and multiple cancer-associated splicing programs (ERCC1, METTL14/Cyclin L2, ATM), the latter conferring PARP-inhibitor synthetic lethality and chemoresistance phenotypes (PMID:28555643, PMID:31176694, PMID:33849617, PMID:41191919, PMID:40840404). The independently characterized mitochondrial COQ7/CLK-1 protein is a carboxylate-bridged diiron hydroxylase that converts demethoxyubiquinone to hydroxyubiquinone in ubiquinone biosynthesis, a function conserved from bacteria and yeast to nematode and human, imported into the matrix by an unusual membrane-potential-independent mechanism; loss of this activity, not any nuclear role, accounts for the C. elegans clk-1 lifespan and mitochondrial phenotypes (PMID:9020081, PMID:10501970, PMID:11244089, PMID:11387338, PMID:12753928, PMID:20923139, PMID:28404998). In the divergent trypanosome ortholog (KKT10), CLK1 instead functions as a kinetochore kinase that phosphorylates KKT2 to drive kinetochore assembly and cell-cycle progression (PMID:32661312, PMID:34128702).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Established that CLK1 is a functional regulator of alternative splicing and uncovered its self-governing isoform switch, defining the kinase as both an effector and target of splicing control.

    Evidence In vivo transfection and alternative splicing analysis with domain-deletion mutants on CLK1 and adenovirus pre-mRNAs

    PMID:9315658

    Open questions at the time
    • Did not identify the full SR substrate spectrum
    • Mechanism of substrate selection not yet defined
  2. 1999 High

    Resolved that the clk-1 gene shared with the splicing kinase symbol actually encodes a conserved mitochondrial metabolic enzyme, separating the metabolic ortholog from the kinase function.

    Evidence Cross-species genetic complementation of yeast coq7/cat5 nulls with C. elegans and human clk-1, plus GFP localization in worms

    PMID:10202142 PMID:10501970 PMID:9020081 PMID:9452453

    Open questions at the time
    • Did not yet define the enzymatic reaction catalyzed
    • Did not address whether the kinase and metabolic activities reside in the same human protein
  3. 1999 High

    Showed CLK1 kinase has substrates beyond SR proteins, demonstrating phosphorylation-dependent activation of PTP-1B at Ser50.

    Evidence In vitro kinase assay, HEK293 co-expression, and Ser50 site-directed mutagenesis

    PMID:10480872

    Open questions at the time
    • Physiological context of PTP-1B activation not established
    • Not linked to splicing pathway
  4. 2000 High

    Defined the N-terminus as an autoinhibitory domain and revealed multi-site phosphorylation as a bidirectional regulator of kinase output, framing CLK1 activity as tightly tuned.

    Evidence N-terminal truncation mutants, in vitro kinase assays, PP2A/tyrosine phosphatase treatment, and subcellular fractionation

    PMID:10954422

    Open questions at the time
    • Identities of the regulatory phospho-sites not mapped
    • Upstream kinases/phosphatases not identified
  5. 2001 High

    Pinned the metabolic ortholog's role to ubiquinone biosynthesis and clarified why respiration persists in mutants, by identifying DMQ9 accumulation as a partially functional electron carrier.

    Evidence HPLC/MS lipid analysis and in vitro respiratory chain assays in C. elegans mitochondria, plus mitochondrial import assays with membrane-potential disruption

    PMID:11244089 PMID:11387338

    Open questions at the time
    • Mechanism of potential-independent import not structurally defined
    • Catalytic chemistry not yet characterized
  6. 2001 High

    Identified hPRP4 as a direct CLK1 interactor and substrate, extending kinase targets to core spliceosomal regulators and linking CLK1 activity to speckle dynamics.

    Evidence Co-immunoprecipitation, in vitro kinase assay, and immunofluorescence with wild-type vs kinase-dead CLK1

    PMID:11418604

    Open questions at the time
    • Functional splicing consequence of hPRP4 phosphorylation not quantified
  7. 2003 High

    Defined the metabolic ortholog as a diiron-carboxylate demethoxyubiquinone hydroxylase, assigning its precise enzymatic reaction.

    Evidence E. coli ubiF complementation, di-iron motif analysis, and Mössbauer/EPR spectroscopy with NADH-driven in vitro turnover

    PMID:11435415 PMID:12753928 PMID:20923139

    Open questions at the time
    • Human enzyme structure not solved
    • Physiological reductant in mammalian mitochondria not confirmed
  8. 2011 High

    Connected CLK1 isoform maturation to stress signaling, showing intron-retained transcripts are released to rephosphorylate SR proteins and restore splicing homeostasis.

    Evidence RT-PCR of intron-retaining forms, stress induction, and CLK inhibitor TG003 with SR phosphorylation readouts

    PMID:21949414

    Open questions at the time
    • Signal coupling stress to intron removal not defined
    • SR substrate breadth under stress not fully mapped
  9. 2014 High

    Explained how CLK1 achieves SR-protein hyperphosphorylation, showing the N-terminus bridges the kinase and RS domains to enhance phosphoryl content and cooperative RNA binding.

    Evidence In vitro kinase assays with truncation mutants, EMSA, and phosphorylation stoichiometry on SRSF1/2/5 and Tra2β1

    PMID:24869919

    Open questions at the time
    • Structural basis of the N-terminal bridge not solved
  10. 2015 Medium

    Proposed N-terminus-induced oligomerization as the substrate-discrimination mechanism, distinguishing physiological from non-physiological targets without a docking groove.

    Evidence Concentration-dependent in vitro specificity assays, size-exclusion chromatography, and speckle localization

    PMID:26443864

    Open questions at the time
    • Oligomer stoichiometry in cells not defined
    • Single-lab biochemical model
  11. 2015 Medium

    Advanced a contested model that a nuclear CLK-1 form drives lifespan via mitochondrial ROS retrograde signaling, independent of the metabolic enzyme role.

    Evidence Subcellular fractionation, nuclear-specific constructs, ROS measurement, and lifespan assays in C. elegans

    PMID:25961505

    Open questions at the time
    • Nuclear localization later not reproduced (#20)
    • Mechanism of retrograde gene-expression control undefined
  12. 2016 High

    Resolved how phosphorylated SR proteins are released from the kinase, establishing a symbiotic CLK1–SRPK1 system required for spliceosome assembly.

    Evidence Reciprocal co-IP, domain mapping of the CLK1 N-terminal RS-like motif, and in vitro splicing/SR-release assays

    PMID:27397683

    Open questions at the time
    • In vivo stoichiometry of CLK1:SRPK1 not measured
    • Regulation of the handoff not defined
  13. 2017 High

    Definitively attributed all C. elegans clk-1 phenotypes to lost ubiquinone biosynthesis and failed to detect nuclear CLK-1, directly disputing the retrograde nuclear-signaling model.

    Evidence Pharmacological UQ restoration, immunohistochemistry, and fractionation in worms and mammalian cells

    PMID:28404998

    Open questions at the time
    • Does not exclude condition-specific nuclear pools
    • Addresses the metabolic ortholog, not the human splicing kinase
  14. 2017 Medium

    Demonstrated translatable splicing control by CLK1, showing inhibition promotes therapeutic DMD exon skipping in patient cells and modulates SR phosphorylation in vivo.

    Evidence Patient-derived cell splicing assays, dystrophin Western blots, and oral TG693 dosing in mice

    PMID:28555643

    Open questions at the time
    • Direct SR substrate driving exon 31 skipping not specified
    • Single-lab in vivo evidence
  15. 2021 High

    Mapped specific CLK1 phospho-sites and their splicing/assembly consequences across multiple substrates, building a residue-level picture of how CLK1 controls spliceosome dynamics and cancer-relevant splicing.

    Evidence Phosphoproteomics, in vitro kinase assays, mutagenesis, co-IP, and RNA-based splicing readouts on SPF45, U1-70K(Ser226), and SRSF5(Ser250)

    PMID:23519612 PMID:33811140 PMID:33849617

    Open questions at the time
    • Comprehensive substrate-site map still incomplete
    • Cross-talk between sites not resolved
  16. 2020 High

    Revealed a divergent role of the trypanosome CLK1 ortholog (KKT10) as a kinetochore kinase phosphorylating KKT2 to drive kinetochore assembly and cell-cycle progression.

    Evidence Co-crystal structure with AB1 inhibitor, target deconvolution with kinase mutants, in vitro kinase assay/mutagenesis of KKT2-Ser508, and cell-cycle assays

    PMID:32661312 PMID:34128702

    Open questions at the time
    • Relationship to the mammalian splicing-kinase function not established
    • Whether human CLK1 has any kinetochore role unknown
  17. 2021 Medium

    Linked CLK1 splicing control to therapeutic vulnerabilities and metabolic disease, including PARP-inhibitor synthetic lethality via ERCC1 isoform switching and THRAP3-PPARγ-mediated insulin resistance.

    Evidence Genome-wide CRISPR screen, ERCC1 isoform RT-PCR, xenografts, and phosphoproteomics/co-IP plus CLK1 knockout metabolic phenotyping in mice

    PMID:34526909 PMID:41191919

    Open questions at the time
    • Direct substrate driving ERCC1-202 switching not pinpointed
    • Single-lab in vivo metabolic models
  18. 2024 Medium

    Dissected the molecular logic of CLK1 autoregulation, defining a TRA2-activator versus CLK1-phosphorylated SRSF3-repressor balance at exon 4.

    Evidence CRISPR/Cas9 knockouts, dCas13Rx, RNA immunoprecipitation, and CLK1 inhibitor treatment

    PMID:39251328

    Open questions at the time
    • Quantitative contribution of each factor not resolved
    • Single-lab system
  19. 2025 Medium

    Extended CLK1's oncogenic splicing reach to chemoresistance and signaling, showing circRNA-scaffolded SRSF7 phosphorylation drives ATM splicing and a CLK1-YAP cascade in liver/pancreatic cancers.

    Evidence LC-MS for RNA-binding proteins, co-IP, phospho-specific and splice-variant analysis, and PDO/PDX and hydrodynamic mouse models

    PMID:39693605 PMID:40840404

    Open questions at the time
    • Direct CLK1-YAP mechanism (WWC2 role) not fully validated
    • Single-lab models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the human CLK1 splicing kinase and the mitochondrial COQ7/CLK-1 hydroxylase are truly the same gene product or distinct proteins conflated by symbol history, and how their respective regulatory inputs integrate, remains unresolved in this corpus.
  • No single study demonstrates both activities in one human protein
  • Structural model of human kinase N-terminal regulation lacking
  • In vivo SRPK1 handoff dynamics not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016491 oxidoreductase activity 4 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005739 mitochondrion 4 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-8953854 Metabolism of RNA 5 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2
Partners
KKT2PRP4PTP-1BSPF45SRPK1SRSF1SRSF5U1-70K

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CLK1 kinase phosphorylates SR proteins and regulates alternative pre-mRNA splicing in vivo; the peptide domain encoded by the alternatively spliced exon of CLK1 is essential for this regulatory activity. CLK1 also autoregulates its own pre-mRNA splicing, producing catalytically active (CLK1) and truncated inactive (CLK1T) isoforms. In vivo expression/transfection assays, alternative splicing analysis of CLK1 and adenovirus pre-mRNAs Molecular and cellular biology High 9315658
1997 C. elegans CLK-1 protein is structurally and functionally conserved with yeast Cat5p/Coq7p, a metabolic regulator; clk-1 complements cat5/coq7 null mutants, demonstrating shared biochemical function at the level of cellular physiology. Genetic complementation of yeast coq7/cat5 null mutants with C. elegans clk-1 Science High 9020081
1998 Yeast Coq7p/Cat5p (CLK-1 homologue) is a mitochondrial inner membrane protein directly involved in ubiquinone biosynthesis; the defect in gluconeogenic gene activation in coq7/cat5 null mutants is a general consequence of defective respiration, not a direct regulatory role. Subcellular fractionation, mitochondrial localization assays, respiratory growth assays The Journal of biological chemistry High 9452453
1999 C. elegans CLK-1 fused to GFP is fully active and localizes to the mitochondria of all somatic cells. Overexpression of CLK-1 in wild-type worms increases mitochondrial activity, accelerates behavioral rates during aging, and shortens lifespan, demonstrating that clk-1 regulates and controls these processes. GFP fusion live imaging, in vivo dye-uptake assay for mitochondrial membrane potential, succinate cytochrome c reductase activity assay, overexpression studies The EMBO journal High 10202142
1999 Human CLK-1 functionally complements yeast coq7 deletion mutants for growth on non-fermentable carbon sources, demonstrating conservation of the ubiquinone biosynthesis function from nematode to human. Yeast complementation assay with human CLK-1 cDNA introduced into coq7 deletion strains Mammalian genome High 10501970
1999 CLK1 and CLK2 phosphorylate PTP-1B in vitro and in vivo, activating its phosphatase activity approximately 2-5-fold. Phosphorylation of PTP-1B at Ser50 by CLK1 is responsible for enzymatic activation. In vitro kinase assay, co-expression in HEK293 cells, site-directed mutagenesis (Ser50) The Journal of biological chemistry High 10480872
2000 The N-terminus of CLK1 acts as a negative regulatory domain; N-terminal truncation causes a 45-fold increase in Vmax. CLK1 activity is positively regulated by phosphorylation on tyrosine residues or serine/threonine residues, and negatively regulated by phosphorylation of a subset of serine/threonine residues within the catalytic domain (PP2A treatment increases activity 2-6-fold; combined tyrosine + serine/threonine dephosphorylation abolishes activity). CLK1 protein is primarily found in the cytoplasm of neuronal cells, with only a small fraction in the nucleus. N-terminal truncation mutants, in vitro kinase assays, phosphatase (PP2A, tyrosine phosphatase) treatment, subcellular fractionation, immunofluorescence Journal of cell science High 10954422
2001 CLK-1 is absolutely required for ubiquinone (UQ9) biosynthesis in C. elegans; clk-1 mutant mitochondria lack UQ9 and instead accumulate demethoxyubiquinone (DMQ9). DMQ9 can function as an electron carrier for both complex I and complex II, explaining near-normal respiration in mutants. Lipid analysis by HPLC/MS, synthesis of DMQ2, in vitro respiratory chain activity assays with isolated mitochondria The Journal of biological chemistry High 11244089
2001 Coq7/CLK-1 is a member of the di-iron carboxylate protein family based on a conserved sequence motif for iron ligands; the Pseudomonas aeruginosa Coq7 ortholog complements an E. coli ubiF mutant lacking 5-demethoxyubiquinone hydroxylase activity, providing evidence that Coq7 directly functions as a hydroxylase. Sequence analysis, identification of di-iron motif, bacterial complementation assay The Journal of biological chemistry Medium 11435415
2001 Mouse CLK-1 (mCLK1) is imported into the mitochondrial matrix where a leader sequence is cleaved and the protein becomes loosely associated with the inner membrane. Unusually, this import does not require a mitochondrial membrane potential, unlike all other known mitochondrial proteins with cleavable pre-sequences. Subcellular fractionation, mitochondrial import assays with membrane potential disruption, pulse-chase/processing assays The Journal of biological chemistry High 11387338
2001 Human PRP4 (hPRP4) interacts directly with CLK1 at its C-terminus; the RS-rich domain of hPRP4 is phosphorylated by CLK1 in vitro. Overexpression of active CLK1 causes redistribution of hPRP4 from nuclear speckles to a diffuse nucleoplasmic pattern, while catalytically inactive CLK1 does not. Co-immunoprecipitation, in vitro kinase assay, indirect immunofluorescence, overexpression of wild-type and kinase-dead CLK1 The Journal of biological chemistry High 11418604
2002 C. elegans CLK-1 and mouse CLK-1 have DNA-binding activity specific to the OL region of mitochondrial DNA; this DNA-binding activity is inhibited by ADP and is altered by clk-1 mutations that extend lifespan, suggesting a possible role in mtDNA replication or transcription regulation. In vitro DNA-binding assay (electrophoretic mobility shift), ADP inhibition experiment FEBS letters Medium 11959146
2003 CLK-1 is a hydroxylase catalyzing the conversion of demethoxyubiquinone to hydroxyubiquinone (a ubiquinone precursor); C. elegans CLK-1 expressed from a plasmid rescues aerobic respiration on a non-fermentable carbon source and restores ubiquinone biosynthesis in an E. coli ubiF mutant, providing direct evidence of demethoxyubiquinone hydroxylase activity. Bacterial complementation of E. coli ubiF mutant, respiratory growth assay, ubiquinone biosynthesis assay FEBS letters High 12753928
2010 Mouse CLK-1 (MCLK1) belongs to the carboxylate-bridged diiron protein family, confirmed by Mössbauer and EPR spectroscopy. NADH can serve directly as a reductant for catalytic activation of dioxygen and substrate oxidation by MCLK1 in vitro, with no requirement for an additional reductase protein component. Mössbauer spectroscopy, EPR spectroscopy, in vitro enzymatic activity assay with NADH and quinone substrates Biochemistry High 20923139
2011 Splicing of CLK1/4 mRNAs is normally suspended with intron-retaining intermediate forms pooled in the nucleus. Under stress conditions (heat shock, osmotic stress), maturation of CLK1/4 mRNAs is promoted, leading to translation of CLK1/4 proteins that catalyze rephosphorylation of SR proteins (especially SRSF4 and SRSF10), thereby restoring the phosphorylation state of SR proteins after stress-induced dephosphorylation. RT-PCR for intron-retaining forms, CLK-specific inhibitor TG003, stress induction, SR protein phosphorylation assays The Journal of cell biology High 21949414
2013 CLK1 phosphorylates SPF45 (alternative splicing factor 45) on eight serine residues. CLK1 phosphorylation of SPF45 regulates its splice-site utilization (Fas mRNA exon 6 exclusion), enhances SPF45 protein stability (CLK1 inhibition increases SPF45 proteasomal degradation), and promotes ovarian cancer cell migration and invasion. In vitro kinase assay, mutagenesis of phosphorylation sites, CLK1 inhibition/overexpression, proteasome inhibitor experiments, RT-PCR for Fas splicing, migration/invasion assays Nucleic acids research High 23519612
2014 The N-terminus of CLK1 contacts both the CLK1 kinase domain and the RS domain of SR protein SRSF1, facilitating hyperphosphorylation and cooperative RNA binding by SRSF1. The N-terminus enhances total phosphoryl content of SRSF1, SRSF2, SRSF5 and Tra2β1 by 2-3-fold, acting as a bridge connecting the kinase domain to the RS domain substrate. In vitro kinase assays with truncation mutants, RNA binding assays (EMSA), phosphorylation stoichiometry measurements The Biochemical journal High 24869919
2015 C. elegans CLK-1 has a distinct nuclear form that independently regulates lifespan through a retrograde signaling pathway conserved from C. elegans to humans. Nuclear CLK-1 responds to mitochondrial reactive oxygen species, modulates gene expression to regulate mitochondrial ROS metabolism and the mitochondrial unfolded protein response. Subcellular fractionation, nuclear/mitochondrial CLK-1 separation, ROS measurement, lifespan assays with nuclear-specific CLK-1 constructs, gene expression analysis Nature cell biology Medium 25961505
2015 CLK1 uses N-terminus-induced oligomerization (rather than a classical docking groove or adaptor) as a substrate selection mechanism for SR proteins. The disordered N-terminus induces oligomerization necessary for preferential phosphorylation of SRSF1 over non-physiological substrates; CLK1 self-association occurs in the nucleus and drives localization to nuclear speckles. In vitro kinase specificity assays at varying concentrations, size-exclusion chromatography, N-terminal truncation mutants, nuclear localization by immunofluorescence The Biochemical journal Medium 26443864
2016 SRPK1 interacts with an RS-like domain in the N-terminus of CLK1 to facilitate release of phosphorylated SR proteins from CLK1, enabling efficient splice-site recognition and spliceosome assembly. CLK1 alone cannot release phosphorylated SR proteins (thus inactivating them); SRPK1 provides the release function in a symbiotic kinase system. Co-immunoprecipitation, in vitro splicing assays, CLK1/SRPK1 interaction mapping, SR protein release assays Molecular cell High 27397683
2017 All phenotypes of C. elegans clk-1 mutants (behavioral, developmental, lifespan, mitochondrial quality control gene expression) result exclusively from loss of ubiquinone biosynthesis; pharmacological restoration of UQ biosynthesis rescues all phenotypes. Nuclear localization of MCLK1/CLK-1 could not be detected by immunohistochemistry or protein purification. Pharmacological UQ restoration in clk-1 null mutants, immunohistochemical localization in worms, subcellular fractionation of mammalian cells, lifespan and behavioral assays Scientific reports High 28404998
2017 CLK1 inhibition (TG693, an orally available inhibitor) promotes skipping of the mutated exon 31 in DMD patient-derived cells and increases production of functional exon-31-skipped dystrophin. Oral administration to mice inhibits phosphorylation of SR protein substrates of CLK1 and modulates pre-mRNA splicing in skeletal muscle in vivo. Patient-derived cell splicing assays, Western blotting for dystrophin, oral dosing in mice, SR protein phosphorylation assays in skeletal muscle Scientific reports Medium 28555643
2019 CLK1 regulates splicing of influenza A virus mRNA segment 7 (encoding M1/M2 proteins); CLK1 knockdown reduces influenza replication and increases splicing of segment 7. CLK1-/- mice support lower levels of influenza virus replication than wild-type mice. siRNA knockdown in A549 cells, CLK1 knockout mice challenged with influenza, RT-PCR for M1/M2 splicing, viral titer assays Antiviral research High 31176694
2020 Trypanosoma brucei CLK1 (KKT10) is a kinetochore kinase; amidobenzimidazole (AB1) inhibitors irreversibly inhibit TbCLK1 via a Michael acceptor bond with Cys215 in the ATP-binding pocket. Chemical inhibition of CLK1 impairs inner kinetochore recruitment and compromises cell-cycle progression leading to cell death. Co-crystal structure of TbCLK1 with AB1 inhibitor, biochemical target deconvolution with 29 kinase overexpression mutants, cell biology/cell-cycle assays Nature microbiology High 32661312
2021 CLK1 phosphorylates Ser-226 in the C-terminus of U1-70K, releasing it from subnuclear granules and facilitating interaction with U1 snRNP and SR protein SRSF1. CLK1 breaks contacts between the C-terminus and the RNA recognition motif (RRM) of U1-70K, permitting stable interactions with U1 snRNP-associated proteins. Nuclear induction of SRPK1 facilitates CLK1 dissociation from U1-70K to recycle the kinase. Quantitative phosphoproteomics, in vitro kinase assays, co-immunoprecipitation, subnuclear localization by immunofluorescence, SRPK1 nuclear induction experiments Proceedings of the National Academy of Sciences of the United States of America High 33811140
2021 CLK1 phosphorylates SRSF5 at Ser250, which inhibits METTL14 exon 10 skipping while promoting Cyclin L2 exon 6.3 skipping in pancreatic cancer cells. The CLK1/SRSF5 axis thereby promotes pancreatic cancer cell growth and metastasis through these two alternative splicing events. Phosphorylation mass spectrometry identifying SRSF5-Ser250, RNA-seq for splicing events, RIP assays, RNA pulldown, CLIP-qPCR, in vitro and in vivo tumor models Journal of hematology & oncology Medium 33849617
2021 Trypanosoma brucei KKT2 is a direct substrate of CLK1; phosphorylation of KKT2 at Ser508 by CLK1 is essential for KKT2 function and for kinetochore assembly. Chemical inhibition of CLK1 with AB1 impairs inner kinetochore recruitment. CLK1 and aurora kinase AUK1 are in separate regulatory pathways for KKT2 phosphorylation. In vitro kinase assay, site-directed mutagenesis of KKT2-S508, chemical inhibition with AB1, immunofluorescence for kinetochore assembly, AUK1 inhibitor epistasis experiment mBio High 34128702
2021 CLK1 inhibition of CLK1 downregulates the functional ERCC1-202 isoform through altered alternative splicing, resulting in enhanced DNA damage and apoptosis. CLK1 knockdown is synthetically lethal with PARP inhibitors in ovarian cancer, and the combination of olaparib with CLK1 inhibitor TG003 shows potent anti-proliferative effects in vitro and in vivo. Genome-wide CRISPR-Cas9 screen, siRNA knockdown, CLK1 inhibitor TG003, ERCC1 isoform RT-PCR, DNA damage markers, in vivo xenograft experiments Protein & cell Medium 41191919
2021 CLK1 phosphorylates THRAP3 at Ser243; phosphorylated THRAP3 interacts with phosphorylated PPARγ to impair adipose tissue browning and insulin sensitivity. CLK1 genetic knockout or chemical inhibition in mice ameliorates diet-induced obesity and insulin resistance. Phosphoproteomics, co-immunoprecipitation, site-directed mutagenesis (Ser243), CLK1 knockout mice, metabolic phenotyping Frontiers in physiology Medium 34526909
2024 CLK1 exon 4 inclusion is controlled by a balance between TRA2 protein activators and CLK1-phosphorylated SRSF3 as a repressor; SRSF10 and SRSF12 interact with TRA2 proteins to prevent their enhancer activity, allowing SRSF3 to enforce exon 4 skipping. An exonic enhancer in exon 4 interacts with TRA2β. CLK1 kinase inhibitors antagonize the repressor activity of SRSF10, SRSF12, and SRSF3 in this autoregulatory loop. CRISPR/Cas9 knockouts, tagged protein expression, CRISPR/dCas13Rx, RNA immunoprecipitation, CLK1 inhibitor treatment RNA Medium 39251328
2025 CLK1 activates YAP to promote intrahepatic cholangiocarcinoma (ICC); WWC2 was identified as a potential mediator of the CLK1-YAP cascade by 4D label-free mass spectrometry and co-immunoprecipitation. Loss of YAP completely retards AKT/CLK1-induced ICC tumor formation in mice. RNA sequencing, 4D label-free mass spectrometry, co-immunoprecipitation, hydrodynamic transfection mouse model, YAP inhibition/deletion experiments Cancer research Medium 39693605
2025 cALG8 (a circRNA) functions as a protein scaffold enabling CLK1 to phosphorylate SRSF7 at Ser231, facilitating SRSF7-dependent alternative splicing of ATM kinase to produce the ATM203 variant, which enhances ATM translation, DNA damage repair, and immune microenvironment remodeling to promote gemcitabine resistance in pancreatic cancer. LC-MS for RNA-binding proteins, molecular biology validation of cALG8-CLK1-SRSF7 interaction, phospho-specific detection, splice variant analysis, PDO/PDX models Drug resistance updates Medium 40840404

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 348 7768437
1997 Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science (New York, N.Y.) 255 9020081
1999 CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. The EMBO journal 235 10202142
1999 A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 191 10335847
2010 Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding activity. Journal of immunology (Baltimore, Md. : 1950) 170 20956340
2001 Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. The Journal of biological chemistry 168 11244089
2001 A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Proceedings of the National Academy of Sciences of the United States of America 155 11136229
1997 In vivo regulation of alternative pre-mRNA splicing by the Clk1 protein kinase. Molecular and cellular biology 153 9315658
2011 Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor. The Journal of cell biology 132 21949414
2006 Identification and characterization of a novel human collectin CL-K1. Microbiology and immunology 122 17179669
1998 Yeast Clk-1 homologue (Coq7/Cat5) is a mitochondrial protein in coenzyme Q synthesis. The Journal of biological chemistry 110 9452453
2001 A new member of the family of di-iron carboxylate proteins. Coq7 (clk-1), a membrane-bound hydroxylase involved in ubiquinone biosynthesis. The Journal of biological chemistry 108 11435415
2021 CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer. Journal of hematology & oncology 102 33849617
2016 Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing. Molecular cell 81 27397683
2012 Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1). Immunobiology 79 22475410
2015 A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity. Nature cell biology 76 25961505
2014 Human CDC2-like kinase 1 (CLK1): a novel target for Alzheimer's disease. Current drug targets 76 24568585
2016 The collectins CL-L1, CL-K1 and CL-P1, and their roles in complement and innate immunity. Immunobiology 71 27377710
2000 clk-1, mitochondria, and physiological rates. BioEssays : news and reviews in molecular, cellular and developmental biology 66 10649290
1999 The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. The Journal of biological chemistry 64 10480872
1998 clk1, a serine/threonine protein kinase-encoding gene, is involved in pathogenicity of Colletotrichum lindemuthianum on common bean. Molecular plant-microbe interactions : MPMI 63 9450334
2017 Activation of AMPK/mTORC1-Mediated Autophagy by Metformin Reverses Clk1 Deficiency-Sensitized Dopaminergic Neuronal Death. Molecular pharmacology 60 29025968
2013 Phosphorylation of the alternative mRNA splicing factor 45 (SPF45) by Clk1 regulates its splice site utilization, cell migration and invasion. Nucleic acids research 60 23519612
2001 Cloning of human PRP4 reveals interaction with Clk1. The Journal of biological chemistry 57 11418604
1999 Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging. Mammalian genome : official journal of the International Mammalian Genome Society 56 10501970
2013 Characterization of the interaction between collectin 11 (CL-11, CL-K1) and nucleic acids. Molecular immunology 53 23954398
2020 Targeting the trypanosome kinetochore with CLK1 protein kinase inhibitors. Nature microbiology 52 32661312
2016 Clk1 deficiency promotes neuroinflammation and subsequent dopaminergic cell death through regulation of microglial metabolic reprogramming. Brain, behavior, and immunity 50 27769915
2011 An enzyme-linked immunosorbent assay (ELISA) for quantification of human collectin 11 (CL-11, CL-K1). Journal of immunological methods 50 22301270
2020 Phosphoproteomic analysis identifies CLK1 as a novel therapeutic target in gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 49 32333232
2017 Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy. Scientific reports 49 28555643
2008 The anti-neurodegeneration drug clioquinol inhibits the aging-associated protein CLK-1. The Journal of biological chemistry 48 18927074
2000 Biochemical characterization and localization of the dual specificity kinase CLK1. Journal of cell science 48 10954422
2017 Development of Selective Clk1 and -4 Inhibitors for Cellular Depletion of Cancer-Relevant Proteins. Journal of medicinal chemistry 44 28561591
2014 Hydroxybenzothiophene Ketones Are Efficient Pre-mRNA Splicing Modulators Due to Dual Inhibition of Dyrk1A and Clk1/4. ACS medicinal chemistry letters 44 25221649
2013 TAF-4 is required for the life extension of isp-1, clk-1 and tpk-1 Mit mutants. Aging 42 24107417
2017 Clk1-regulated aerobic glycolysis is involved in glioma chemoresistance. Journal of neurochemistry 40 28581641
1996 Identification and characterization of the CLK1 gene product, a novel CaM kinase-like protein kinase from the yeast Saccharomyces cerevisiae. The Journal of biological chemistry 40 8939941
2001 Phenotypic and suppressor analysis of defecation in clk-1 mutants reveals that reaction to changes in temperature is an active process in Caenorhabditis elegans. Genetics 39 11729148
2018 Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK1/2 Inhibitor for Treatment of Triple-Negative Breast Cancer with a Compromised G1-S Checkpoint. Molecular cancer therapeutics 37 29866747
2014 N-terminus of the protein kinase CLK1 induces SR protein hyperphosphorylation. The Biochemical journal 36 24869919
2012 Synthesis and biological evaluation of N-aryl-7-methoxybenzo[b]furo[3,2-d]pyrimidin-4-amines and their N-arylbenzo[b]thieno[3,2-d]pyrimidin-4-amine analogues as dual inhibitors of CLK1 and DYRK1A kinases. European journal of medicinal chemistry 36 23237976
2018 Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention. Gene 35 29802995
2001 Mouse CLK-1 is imported into mitochondria by an unusual process that requires a leader sequence but no membrane potential. The Journal of biological chemistry 33 11387338
2017 Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers. Journal of medicinal chemistry 32 28692292
2012 Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts. Planta medica 31 22673832
2010 The aging-associated enzyme CLK-1 is a member of the carboxylate-bridged diiron family of proteins. Biochemistry 31 20923139
2019 New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis. European journal of medicinal chemistry 30 30731399
2019 Regulation of influenza A virus mRNA splicing by CLK1. Antiviral research 30 31176694
2018 CL-L1 and CL-K1 Exhibit Widespread Tissue Distribution With High and Co-Localized Expression in Secretory Epithelia and Mucosa. Frontiers in immunology 29 30108587
2007 Immunolocalization of a novel collectin CL-K1 in murine tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 29 18040075
2022 An overview of cdc2-like kinase 1 (Clk1) inhibitors and their therapeutic indications. Medicinal research reviews 28 36262046
2015 Genetic variation of COLEC10 and COLEC11 and association with serum levels of collectin liver 1 (CL-L1) and collectin kidney 1 (CL-K1). PloS one 28 25710878
2003 Sensitivity of Caenorhabditis elegans clk-1 mutants to ubiquinone side-chain length reveals multiple ubiquinone-dependent processes. The Journal of biological chemistry 28 12893826
2015 Drug Discovery of Host CLK1 Inhibitors for Influenza Treatment. Molecules (Basel, Switzerland) 27 26540031
2017 A single biochemical activity underlies the pleiotropy of the aging-related protein CLK-1. Scientific reports 26 28404998
1999 Orthologues of the Caenorhabditis elegans longevity gene clk-1 in mouse and human. Genomics 25 10373327
2006 Uncoupling the pleiotropic phenotypes of clk-1 with tRNA missense suppressors in Caenorhabditis elegans. Molecular and cellular biology 24 16648490
2003 Molecular mechanism of maternal rescue in the clk-1 mutants of Caenorhabditis elegans. The Journal of biological chemistry 24 14517217
2021 CLK1 reorganizes the splicing factor U1-70K for early spliceosomal protein assembly. Proceedings of the National Academy of Sciences of the United States of America 22 33811140
2015 Nuclear protein kinase CLK1 uses a non-traditional docking mechanism to select physiological substrates. The Biochemical journal 18 26443864
2018 Development of a Quantitative Assay for the Characterization of Human Collectin-11 (CL-11, CL-K1). Frontiers in immunology 17 30323815
2008 Clk-1 deficiency induces apoptosis associated with mitochondrial dysfunction in mouse embryos. Mechanisms of ageing and development 17 18343482
2016 Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands. European journal of medicinal chemistry 16 27940419
2016 Systematic diversification of benzylidene heterocycles yields novel inhibitor scaffolds selective for Dyrk1A, Clk1 and CK2. European journal of medicinal chemistry 15 26896709
2015 Lectin complement protein Collectin 11 (CL-K1) and susceptibility to urinary schistosomiasis. PLoS neglected tropical diseases 14 25807310
2001 Mouse coq7/clk-1 orthologue rescued slowed rhythmic behavior and extended life span of clk-1 longevity mutant in Caenorhabditis elegans. Biochemical and biophysical research communications 13 11511092
2022 CLK1/CLK2-driven signalling at the Leishmania kinetochore is captured by spatially referenced proximity phosphoproteomics. Communications biology 12 36437406
2021 Dysregulation of iron homeostasis and methamphetamine reward behaviors in Clk1-deficient mice. Acta pharmacologica Sinica 12 34811513
2002 CLK-1 protein has DNA binding activity specific to O(L) region of mitochondrial DNA. FEBS letters 11 11959146
2020 Expression, purification and crystallization of CLK1 kinase - A potential target for antiviral therapy. Protein expression and purification 10 32866611
2012 Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous coenzyme Q(10). Experimental gerontology 10 22244837
2012 A MAP kinase gene, Clk1, is required for conidiation and pathogenicity in the phytopathogenic fungus Curvularia lunata. Journal of basic microbiology 10 22733544
2024 Regulatory interplay between SR proteins governs CLK1 kinase splice variants production. RNA (New York, N.Y.) 8 39251328
2022 Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker. European journal of medicinal chemistry 8 35635953
2021 Elevated mitochondrial DNA copy number found in ubiquinone-deficient clk-1 mutants is not rescued by ubiquinone precursor 2-4-dihydroxybenzoate. Mitochondrion 8 33581333
2021 5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency. Molecules (Basel, Switzerland) 8 33668683
2021 A CLK1-KKT2 Signaling Pathway Regulating Kinetochore Assembly in Trypanosoma brucei. mBio 8 34128702
2014 Extended lifespan, reduced body size and leg skeletal muscle mass, and decreased mitochondrial function in clk-1 transgenic mice. Experimental gerontology 8 25106098
2025 CLK1 Activates YAP to Promote Intrahepatic Cholangiocarcinogenesis. Cancer research 7 39693605
2025 Structure-guided screening identified bioactive phytoconstituents Hernandonine and Anolobine as potential inhibitors of dual specificity protein kinase CLK1. Scientific reports 7 40253440
2003 Complementation of Escherichia coli ubiF mutation by Caenorhabditis elegans CLK-1, a product of the longevity gene of the nematode worm. FEBS letters 7 12753928
2025 Targeting CLK1/SRSF7 axis-dependent alternative splicing sensitizes pancreatic ductal adenocarcinoma to chemotherapy and immunotherapy. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 6 40840404
2024 CL-K1 Promotes Complement Activation and Regulates Opsonophagocytosis of Macrophages with CD93 Interaction in a Primitive Vertebrate. Journal of immunology (Baltimore, Md. : 1950) 6 38180157
2022 Discovery of novel 5-methoxybenzothiophene hydrazides as metabolically stable Clk1 inhibitors with high potency and unprecedented Clk1 isoenzyme selectivity. European journal of medicinal chemistry 6 36580731
2021 Inhibition of a Novel CLK1-THRAP3-PPARγ Axis Improves Insulin Sensitivity. Frontiers in physiology 6 34526909
2025 Characterization of aberrant splicing in pediatric central nervous system tumors reveals CLK1 as a candidate oncogenic dependency. bioRxiv : the preprint server for biology 5 39149264
2021 Discovery of 3,6-disubstutited-imidazo[1,2-a]pyridine derivatives as a new class of CLK1 inhibitors. Bioorganic & medicinal chemistry letters 5 33662541
2009 Molecular cloning, expression, and chromosomal mapping of the porcine CDC-2-like kinase 1 (CLK1) gene. Biochemical genetics 5 19194796
2023 SGC-CLK-1: A chemical probe for the Cdc2-like kinases CLK1, CLK2, and CLK4. Current research in chemical biology 4 38009092
2025 YTHDC1 orchestrates oncogenic splicing via the CLK1-SRSF1 splicing machinery to regulate castration-resistant prostate cancer progression. Molecular and cellular biochemistry 2 40404917
2024 Design, synthesis, and structure-activity relationship studies of 6H-benzo[b]indeno[1,2-d]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors. RSC medicinal chemistry 2 39430953
2022 Induction of beige-like adipocyte markers and functions in 3T3-L1 cells by Clk1 and PKCβII inhibitory molecules. Journal of cellular and molecular medicine 2 35801494
2021 Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases. Molecules (Basel, Switzerland) 2 34770981
2025 Discovery and Characterization of Cell-Permeable Inhibitors of Leishmania mexicana CLK1 Using an In-Cell Target Engagement Assay. ACS infectious diseases 1 40994280
2023 Rational design and appraisal of selective Cdc2-Like kinase 1 (Clk1) inhibitors as novel autophagy inducers for the treatment of acute liver injury (ALI). European journal of medicinal chemistry 1 36780830
2022 Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core. Molecules (Basel, Switzerland) 1 36615235
2016 Identification of CLK1 Inhibitors by a Fragment-linking Based Virtual Screening. Molecular informatics 1 28000414
2026 Genome-wide CRISPR-Cas9 screening identifies CLK1 inhibition as a strategy to restore PARP inhibitor sensitivity via ERCC1 isoform switching. Protein & cell 0 41191919
2026 CLK1 Promotes Myeloid-Derived Suppressor Cell Trafficking and Reprograms the Tumor Microenvironment by Activating Hippo/YAP Signaling in Colorectal Cancer. Cancer immunology research 0 41686262

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