Affinage

TTK

Dual specificity protein kinase TTK · UniProt P33981

Length
857 aa
Mass
97.1 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TTK (MPS1) is a cell-cycle-regulated dual-specificity kinase that serves as the apical activator of the spindle assembly checkpoint (SAC) and additionally couples mitotic surveillance to the DNA damage response (PMID:1639825, PMID:22660415, PMID:22521786). Its mRNA, protein, and kinase activity peak at G2/M, and during mitosis it localizes dynamically from nuclear pore-adjacent sites to the corona of unattached kinetochores and then to centrosomes (PMID:8302607, PMID:14728800). At kinetochores, MPS1/Mph1 phosphorylates the MELT repeats of KNL1/Spc7 to recruit the Bub1-Bub3 complex, which in turn licenses downstream Mad1-Mad2-Mad3 loading—placing MPS1 at the top of a three-tiered SAC recruitment hierarchy whose own kinetochore targeting depends on the Ndc80 hairpin platform (PMID:22660415, PMID:22521786, PMID:22825872, PMID:22184248, PMID:26900649). Mph1 kinase activity is further required for stable association of Mad2 and Mad3 with the APC/C, and genetic disruption of APC/C components confers resistance to TTK inhibition, identifying the APC/C as the epistatic effector downstream of SAC inactivation (PMID:22281223, PMID:29378962). Beyond mitosis, TTK phosphorylates CHK2 (Thr68), p53 (Thr18), and MDM2 to enforce DNA damage and tetraploidy checkpoints: p53 Thr18 phosphorylation disrupts the p53-MDM2 interaction and stabilizes p53, MDM2 phosphorylation under oxidative stress drives H2B ubiquitination, chromatin decompaction, and ATR-CHK1 signaling, and TTK kinase activity is required for Rad51-dependent homologous recombination repair (PMID:15618221, PMID:19332559, PMID:26531827, PMID:31961339). TTK also phosphorylates c-Abl at Thr735 to promote 14-3-3 binding and cytoplasmic sequestration of c-Abl (PMID:18794806). TTK abundance is set post-translationally by a CHK2-mediated feedback phosphorylation at Thr288 that stabilizes the kinase after DNA damage and by USP9X-mediated K48 deubiquitination (PMID:19151762, PMID:29721084). Structural and chemical-biology work has defined distinct inhibitor mechanisms, including a glycine-loop 'lysine trap' engaging the catalytic Lys553 and an irreversible covalent inhibitor targeting a hinge cysteine (PMID:28539250, PMID:35167750).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 Medium

    Established the fundamental enzymatic identity of TTK by showing it is catalytically active as a dual-specificity kinase, the prerequisite for assigning it any signaling role.

    Evidence Kinase domain expressed in E. coli with phosphoamino acid analysis

    PMID:1639825

    Open questions at the time
    • Single method without mutagenesis validation of the active site
    • Physiological substrates not identified
    • Tyrosine activity only marginally elevated
  2. 1994 Medium

    Linked TTK to mitosis by demonstrating its expression and activity peak at G2/M, framing it as a cell-cycle-regulated kinase rather than a constitutive one.

    Evidence Cell synchronization with mRNA, protein, and kinase activity assays

    PMID:8302607

    Open questions at the time
    • Does not identify the mitotic process TTK controls
    • Mechanism of cell-cycle-dependent regulation unresolved
  3. 1998 High

    Placed the MPS1 homolog functionally within the spindle assembly checkpoint, showing it acts upstream of Mad2 and is sufficient to impose checkpoint arrest.

    Evidence Genetic epistasis, overexpression, and complementation in S. pombe (Mph1)

    PMID:9601094

    Open questions at the time
    • Molecular substrate at the kinetochore not identified
    • Human ortholog SAC role not yet established in this study
  4. 2003 Medium

    Resolved where TTK acts during mitosis at ultrastructural resolution, localizing it to the kinetochore corona of unattached kinetochores and to centrosomes.

    Evidence Immunoelectron microscopy of HeLa cells

    PMID:14728800

    Open questions at the time
    • Single method and single lab
    • Functional consequence of each localization not dissected
  5. 2004 High

    Extended TTK function beyond mitosis to the DNA damage checkpoint by establishing it as a direct upstream kinase of CHK2 at Thr68 required for G2/M arrest.

    Evidence In vitro kinase assay, kinase-dead D647A mutant, and siRNA with cell cycle readout

    PMID:15618221

    Open questions at the time
    • In vivo Thr68 phosphorylation relative to ATM not fully separated
    • How DNA damage activates TTK toward CHK2 unresolved
  6. 2004 Medium

    Connected TTK kinase activity to centrosome and chromosome organization through a requirement for centrosomal TACC2 localization.

    Evidence Co-IP with kinase-dead mutant, immunofluorescence, TTK knockdown

    PMID:15304323

    Open questions at the time
    • Direct TACC2 phosphorylation site not mapped
    • Single lab without structural detail
  7. 2008 High

    Identified c-Abl as a TTK substrate (Thr735), revealing a mechanism by which TTK controls c-Abl localization and apoptotic output under oxidative stress.

    Evidence Expression cloning, in vitro kinase assay, phosphospecific antibody, siRNA, fractionation

    PMID:18794806

    Open questions at the time
    • Quantitative contribution to stress-induced apoptosis not bounded
    • Interplay with mitotic role of TTK unexplored
  8. 2009 High

    Defined a feedback architecture in which TTK phosphorylates p53 at Thr18 to stabilize p53 while CHK2 reciprocally phosphorylates TTK at Thr288 to stabilize TTK after DNA damage.

    Evidence In vitro kinase assays, ubiquitination assay, phospho-mimetic/deficient and T288A mutants, rescue and cell cycle analysis

    PMID:19151762 PMID:19332559

    Open questions at the time
    • Stoichiometry and temporal order of the CHK2-TTK-p53 loop not fully resolved
    • MDM2 phosphorylation step not yet defined here
  9. 2012 High

    Established the molecular basis of SAC initiation by showing MPS1/Mph1 phosphorylates KNL1/Spc7 MELT repeats to recruit Bub1-Bub3 and sits atop a defined kinetochore signaling hierarchy that ultimately stabilizes Mad2/Mad3 on the APC/C.

    Evidence In vitro kinase and binding assays, phospho-mimetic/non-phosphorylatable mutants, forced kinetochore tethering, and APC/C pulldowns in yeast and human cells

    PMID:22184248 PMID:22281223 PMID:22521786 PMID:22660415 PMID:22825872

    Open questions at the time
    • Precise contribution of human MPS1 to each hierarchical layer not fully separated from yeast data
    • Phosphatase counteraction of MELT phosphorylation not addressed here
  10. 2015 High

    Broadened TTK's genome-maintenance role by showing it phosphorylates MDM2 to drive H2B ubiquitination/chromatin decompaction supporting ATR-CHK1 signaling, and that its kinase activity is required for Rad51-dependent homologous recombination.

    Evidence In vitro kinase assays, H2B ubiquitination assay, Rad51 foci, kinase-dead and phospho-deficient rescue, clonogenic survival, xenograft

    PMID:26531827 PMID:31961339

    Open questions at the time
    • Direct HR substrate of TTK not identified
    • Selectivity of MDM2 phosphorylation for ATR over ATM pathway mechanistically incomplete
  11. 2016 Medium

    Defined the kinetochore docking platform for MPS1, showing the Ndc80 hairpin is required for its recruitment and that forced tethering bypasses loss of the platform.

    Evidence Ndc80 point mutagenesis, forced kinetochore tethering, checkpoint assays in S. pombe

    PMID:26900649

    Open questions at the time
    • Direct MPS1-Ndc80 contact interface not structurally resolved
    • Conservation to human kinetochores not tested here
  12. 2018 High

    Identified post-translational and genetic determinants of TTK function in cancer: USP9X stabilizes TTK by K48 deubiquitination, and APC/C disruption mediates resistance to TTK inhibitors, confirming the APC/C as the downstream effector of SAC release.

    Evidence Co-IP, deubiquitination assay, genome-wide CRISPR screen with siRNA validation, xenografts

    PMID:29378962 PMID:29721084

    Open questions at the time
    • USP9X target lysines on TTK not mapped
    • How APC/C loss bypasses mitotic catastrophe mechanistically incomplete
  13. 2022 High

    Advanced TTK as a druggable target by defining inhibitor binding mechanisms, including a catalytic-lysine glycine-loop trap and an irreversible covalent hinge-cysteine inhibitor.

    Evidence X-ray crystallography, mass spectrometry, cellular KNL1 phosphorylation and target engagement assays

    PMID:28539250 PMID:35167750

    Open questions at the time
    • In vivo durability and selectivity of covalent inhibition not fully characterized
    • Resistance mechanisms to covalent inhibitors not defined
  14. 2023 Medium

    Integrated TTK into circadian and tissue-maintenance physiology via a BMAL1-TTK-MDM2-H2Bub1 positive feedback loop supporting osteogenic capacity.

    Evidence ChIP of BMAL1 on TTK promoter, phosphorylation assays, rAAV9 in vivo rescue in aging mice

    PMID:36910712

    Open questions at the time
    • Direct MDM2 phosphosites in this context not mapped
    • Single lab and tissue-specific generality unestablished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TTK's apical SAC kinase activity, DNA damage checkpoint substrates, and HR repair function are coordinately regulated within a single cell cycle remains unresolved.
  • No unified model linking kinetochore and nuclear TTK pools
  • Phosphatase and degradation control of TTK activity across mitosis incompletely mapped
  • Direct HR substrate of TTK still unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005694 chromosome 2 GO:0005815 microtubule organizing center 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-73894 DNA Repair 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-4839726 Chromatin organization 2
Partners
ABL1BUB1BUB3CHK2KNL1MDM2TP53USP9X

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 TTK is a dual-specificity kinase capable of phosphorylating serine, threonine, and tyrosine residues; when the kinase domain was expressed in E. coli, elevated phosphoserine and phosphothreonine (and slightly elevated phosphotyrosine) were detected, establishing its catalytic activity. Expression of kinase domain in E. coli with phosphoamino acid analysis The Journal of Biological Chemistry Medium 1639825
1994 TTK mRNA, protein, and kinase activity peak at G2/M phase of the cell cycle; levels are very low in starved/G1 cells and rise upon S-phase entry, establishing cell-cycle-dependent regulation of TTK. Cell synchronization, mRNA/protein quantification, kinase activity assays across cell cycle stages Oncogene Medium 8302607
1998 Fission yeast Mph1 (MPS1 homolog) functions upstream of Mad2 in the spindle assembly checkpoint; overexpression of mph1 mimics checkpoint activation and imposes metaphase arrest, while mph1 is required for checkpoint activation in response to spindle defects. Genetic epistasis places mph1 upstream of mad2. Genetic epistasis, overexpression, complementation analysis in S. pombe Journal of Cell Science High 9601094
2003 TTK localizes dynamically during mitosis in HeLa cells: at nuclear pore-adjacent complex in interphase, then to corona fibers of unattached kinetochores (extending ~90 nm from the outer plate), and migrates to centrosomes upon metaphase alignment, supporting a role in spindle checkpoint signaling at both kinetochore and centrosome. Immunoelectron microscopy of HeLa cells Cell Research Medium 14728800
2004 TTK/hMps1 directly phosphorylates CHK2 at Thr-68 in vitro; expression of a kinase-dead TTK(D647A) mutant impairs G2/M arrest and CHK2 Thr-68 phosphorylation after DNA damage; siRNA depletion of TTK reduces CHK2 Thr-68 phosphorylation and impairs growth arrest, placing TTK upstream of CHK2 in the DNA damage checkpoint. In vitro kinase assay, kinase-dead mutant expression, siRNA knockdown, cell cycle analysis The Journal of Biological Chemistry High 15618221
2004 TTK kinase activity is required for centrosomal localization of TACC2; TACC2 is pulled down by wild-type TTK but not kinase-dead TTK; expression of kinase-dead TTK or TTK depletion eliminates centrosomal TACC2, causing chromosome misalignment and reduced centrosome separation. Co-immunoprecipitation/pulldown with kinase-dead mutant, immunofluorescence, TTK knockdown FEBS Letters Medium 15304323
2008 TTK phosphorylates c-Abl at Thr735 (identified by expression cloning with a phosphospecific antibody); this phosphorylation promotes 14-3-3 binding to c-Abl, sequestering it in the cytoplasm; TTK knockdown abolishes oxidative stress-induced Thr735 phosphorylation and causes constitutive nuclear accumulation of c-Abl, enhancing apoptosis. Expression cloning, in vitro kinase assay, phosphospecific antibody, siRNA knockdown, subcellular fractionation/localization Oncogene High 18794806
2009 TTK/hMps1 phosphorylates p53 at Thr18 in vitro, disrupting the p53-MDM2 interaction and abrogating MDM2-mediated p53 ubiquitination; this phosphorylation stabilizes p53 and activates p21 and Lats2 after spindle disruption; phospho-mimetic T18D rescues tetraploid checkpoint defects of p53-depleted cells, while T18A does not. In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, phospho-mimetic/deficient mutants, cell cycle analysis Molecular and Cellular Biology High 19332559
2009 CHK2 phosphorylates TTK/hMps1 at Thr288, stabilizing TTK in response to DNA damage; CHK2 knockdown or inhibition abolishes this TTK stabilization; TTK T288A mutant re-expressed in TTK-knockdown cells causes defective G2/M arrest, establishing a CHK2→TTK feedback loop. siRNA knockdown, CHK2 inhibitor, phospho-specific antibody, mutant re-expression, cell cycle analysis Oncogene Medium 19151762
2012 MPS1/Mph1 phosphorylates KNL1/Spc7 at MELT repeat sequences; this phosphorylation recruits the Bub1-Bub3 complex to the kinetochore in vitro, which is required for SAC activation (Mad1-Mad2-Mad3 localization) and chromosome alignment; non-phosphorylatable spc7-12A abolishes Bub1-Bub3 kinetochore targeting, while phospho-mimetic spc7-12E forces their localization even without Mph1. In vitro kinase assay, in vitro binding assay, phospho-mimetic/non-phosphorylatable mutants, fluorescence microscopy in fission yeast and human cells Nature Cell Biology High 22521786 22660415
2012 Mph1 kinase activity (fission yeast) is required for Mad2 and Mad3 to stably bind the APC/C; a kinase-dead Mph1 allele is checkpoint-defective, and APC/C-associated Mad2 and Mad3 levels are dramatically reduced; specific phosphorylation sites in Mad2 regulate its binding to Cdc20-APC/C. Kinase-dead allele analysis, APC/C immunoprecipitation/mass spectrometry, Mad2 phospho-site mutagenesis in S. pombe Current Biology High 22281223
2012 Kinetochore recruitment of Mph1 is essential and upstream in the SAC hierarchy in fission yeast; an Mph1 mutant that cannot localize to kinetochores abolishes SAC signaling, and artificial kinetochore tethering of this mutant restores signaling; Mph1 and Aurora kinase Ark1 are at the top of a three-layered SAC protein recruitment hierarchy, with Bub1/Bub3 in the middle and Mad3/Mad1-Mad2 at the bottom. Separation-of-function mutants, forced kinetochore tethering (Mph1-Ndc80 fusion), fluorescence microscopy, genetic epistasis in S. pombe Journal of Cell Science High 22184248 22825872
2015 TTK/hMps1 phosphorylates MDM2 in response to oxidative stress, promoting histone H2B ubiquitination and chromatin decompaction, which facilitates oxidative DNA damage repair and ATR-CHK1 (but not ATM-CHK2) signaling; rescue with WT but not phospho-deficient MDM2 confirms TTK-dependent MDM2 phosphorylation is required. In vitro kinase assay, siRNA knockdown, H2B ubiquitination assay, DNA damage foci analysis, phospho-deficient mutant rescue Nucleic Acids Research High 26531827
2015 TTK inhibition impairs homologous recombination repair (HR) by decreasing Rad51 foci formation; re-expression of wild-type TTK rescues both radioresistance and HR repair, but kinase-dead TTK does not, establishing that TTK kinase activity is required for HR. Genetic knockdown, kinase-dead mutant re-expression, Rad51 foci immunofluorescence, clonogenic survival assays, in vivo xenograft The Journal of Clinical Investigation High 31961339
2016 The Ndc80 hairpin region acts as a kinetochore platform for Mph1/MPS1 recruitment in fission yeast; the ndc80-AK01 point mutation within the hairpin eliminates kinetochore localization of all SAC components including Mph1; artificial tethering of Mph1 to kinetochores in ndc80-AK01 cells fully restores checkpoint signaling. Point mutagenesis of Ndc80, forced kinetochore tethering, fluorescence microscopy, checkpoint assays in S. pombe Cell Cycle Medium 26900649
2017 TTK inhibitor NTRC 0066-0 inhibits phosphorylation of the TTK substrate KNL1 in cell lines and in mice, and induces chromosome missegregation; X-ray crystal structures of multiple TTK inhibitors reveal that the most potent compounds induce a shift of the glycine-rich loop by binding the catalytic lysine (Lys553), a 'lysine trap' that disrupts the catalytic machinery. X-ray crystallography, cellular phosphorylation assays (KNL1), antiproliferative assays, thermal stability experiments Journal of Molecular Biology High 28539250
2018 USP9X directly interacts with TTK and deubiquitinates TTK via K48 ubiquitin chain, stabilizing TTK protein; USP9X knockdown reduces TTK protein levels, and this axis promotes NSCLC cell proliferation, migration, and tumorigenesis. Quantitative proteomics, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vivo xenograft Theranostics Medium 29721084
2018 Disruption of APC/C complex members confers resistance to TTK inhibitor CFI-402257; genome-wide CRISPR/Cas9 screens identified APC/C components as mediators of TTKi resistance; validated by CRISPR/Cas9 and siRNA, consistent with the APC/C promoting mitotic exit downstream of SAC inactivation by TTK inhibition. Genome-wide CRISPR/Cas9 screen, siRNA validation, cell viability and cell cycle assays in TNBC lines Proceedings of the National Academy of Sciences of the USA High 29378962
2022 The first irreversible covalent MPS1/TTK inhibitor (RMS-07) was developed targeting a cysteine in the kinase hinge region; covalent binding was validated by mass spectrometry and X-ray crystal structure, confirming the binding site and selectivity mechanism. X-ray crystallography, mass spectrometry, cellular target engagement assays, antiproliferative assays Journal of Medicinal Chemistry High 35167750
2023 BMAL1 transcriptionally controls TTK as a circadian-controlled gene; TTK phosphorylates MDM2, which in turn regulates H2B monoubiquitination (H2Bub1); H2Bub1 feeds back to regulate BMAL1 expression, forming a BMAL1–TTK–MDM2–H2Bub1 positive loop that maintains osteogenic capacity of BM-MSCs. ChIP (BMAL1 on TTK promoter), western blot, phosphorylation assay, rAAV9 in vivo rescue in aging mice Molecular Therapy. Nucleic Acids Medium 36910712

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 MPS1/Mph1 phosphorylates the kinetochore protein KNL1/Spc7 to recruit SAC components. Nature cell biology 291 22660415
2012 Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Current biology : CB 242 22521786
2009 Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination. Genes & development 218 19136626
2013 TTK/hMPS1 is an attractive therapeutic target for triple-negative breast cancer. PloS one 120 23700430
1992 Expression of TTK, a novel human protein kinase, is associated with cell proliferation. The Journal of biological chemistry 107 1639825
2017 Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proceedings of the National Academy of Sciences of the United States of America 101 28270606
1998 Mph1, a member of the Mps1-like family of dual specificity protein kinases, is required for the spindle checkpoint in S. pombe. Journal of cell science 101 9601094
2015 Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model. Annals of oncology : official journal of the European Society for Medical Oncology 95 26153498
2018 Leader of the SAC: molecular mechanisms of Mps1/TTK regulation in mitosis. Open biology 87 30111590
2009 Interplay between the Smc5/6 complex and the Mph1 helicase in recombinational repair. Proceedings of the National Academy of Sciences of the United States of America 82 19995966
2015 TTK activates Akt and promotes proliferation and migration of hepatocellular carcinoma cells. Oncotarget 81 26418879
2004 TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. The Journal of biological chemistry 81 15618221
2004 Yeast MPH1 gene functions in an error-free DNA damage bypass pathway that requires genes from Homologous recombination, but not from postreplicative repair. Genetics 80 15126389
2014 Key role of dual specificity kinase TTK in proliferation and survival of pancreatic cancer cells. British journal of cancer 77 25137017
2011 Drosophila BTB/POZ domains of "ttk group" can form multimers and selectively interact with each other. Journal of molecular biology 77 21821048
2018 Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America 71 29378962
2020 TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. The Journal of clinical investigation 67 31961339
2013 Heteroduplex DNA position defines the roles of the Sgs1, Srs2, and Mph1 helicases in promoting distinct recombination outcomes. PLoS genetics 66 23516370
2018 TTK promotes mesenchymal signaling via multiple mechanisms in triple negative breast cancer. Oncogenesis 65 30206215
2018 A novel USP9X substrate TTK contributes to tumorigenesis in non-small-cell lung cancer. Theranostics 64 29721084
2005 Saccharomyces cerevisiae MPH1 gene, required for homologous recombination-mediated mutation avoidance, encodes a 3' to 5' DNA helicase. The Journal of biological chemistry 62 15634678
2000 MPH1, a yeast gene encoding a DEAH protein, plays a role in protection of the genome from spontaneous and chemically induced damage. Genetics 60 10880470
2009 TTK/hMps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at Thr18. Molecular and cellular biology 59 19332559
2014 Template switching during break-induced replication is promoted by the Mph1 helicase in Saccharomyces cerevisiae. Genetics 58 24496010
2016 HLF/miR-132/TTK axis regulates cell proliferation, metastasis and radiosensitivity of glioma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 27522003
2011 Processing of DNA structures via DNA unwinding and branch migration by the S. cerevisiae Mph1 protein. DNA repair 52 21880555
2017 TTK Inhibitors as a Targeted Therapy for CTNNB1 (β-catenin) Mutant Cancers. Molecular cancer therapeutics 51 28751540
2022 CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America 50 35914158
2017 The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen. Journal of medicinal chemistry 50 28991472
2012 Mph1 kinetochore localization is crucial and upstream in the hierarchy of spindle assembly checkpoint protein recruitment to kinetochores. Journal of cell science 48 22825872
2017 Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity. Journal of molecular biology 47 28539250
2017 The Smc5/6 complex regulates the yeast Mph1 helicase at RNA-DNA hybrid-mediated DNA damage. PLoS genetics 47 29281624
2015 Molecular basis underlying resistance to Mps1/TTK inhibitors. Oncogene 47 26364596
1994 Cell cycle dependent regulation of the protein kinase TTK. Oncogene 47 8302607
2021 TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway. Cell death & disease 45 34876569
2015 Discovery of imidazo[1,2-b]pyridazine derivatives: selective and orally available Mps1 (TTK) kinase inhibitors exhibiting remarkable antiproliferative activity. Journal of medicinal chemistry 41 25625617
2014 Expression and function analysis of mitotic checkpoint genes identifies TTK as a potential therapeutic target for human hepatocellular carcinoma. PloS one 41 24905462
2009 The cell cycle checkpoint kinase CHK2 mediates DNA damage-induced stabilization of TTK/hMps1. Oncogene 41 19151762
2002 The Drosophila transcription factor tramtrack (TTK) interacts with Trithorax-like (GAGA) and represses GAGA-mediated activation. Nucleic acids research 41 12384587
2015 The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents. Journal of medicinal chemistry 40 25763473
2008 TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress. Oncogene 40 18794806
1999 A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog protein, is highly conserved, and interacts with RAE28/mph1 in vitro. Differentiation; research in biological diversity 38 10653359
2019 Silencing TTK expression inhibits the proliferation and progression of prostate cancer. Experimental cell research 37 31605696
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
2015 Requirement for human Mps1/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation. Nucleic acids research 37 26531827
2020 TTK regulates proliferation and apoptosis of gastric cancer cells through the Akt-mTOR pathway. FEBS open bio 35 32530571
2017 Targeting dual specificity protein kinase TTK attenuates tumorigenesis of glioblastoma. Oncotarget 34 29423030
2001 Mitotic checkpoint genes hBUB1, hBUB1B, hBUB3 and TTK in human bladder cancer, screening for mutations and loss of heterozygosity. Carcinogenesis 33 11323402
2016 Sgs1 and Mph1 Helicases Enforce the Recombination Execution Checkpoint During DNA Double-Strand Break Repair in Saccharomyces cerevisiae. Genetics 32 27075725
2016 Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer. Scientific reports 32 27618777
2014 Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides. Bioorganic & medicinal chemistry 32 25043312
2012 The Mph1 helicase can promote telomere uncapping and premature senescence in budding yeast. PloS one 32 22848695
2011 Centromere-tethered Mps1 pombe homolog (Mph1) kinase is a sufficient marker for recruitment of the spindle checkpoint protein Bub1, but not Mad1. Proceedings of the National Academy of Sciences of the United States of America 32 22184248
2020 Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells. Cancer science 31 32478948
2013 Scaffold-focused virtual screening: prospective application to the discovery of TTK inhibitors. Journal of chemical information and modeling 31 23672464
2012 Kinase activity of fission yeast Mph1 is required for Mad2 and Mad3 to stably bind the anaphase promoting complex. Current biology : CB 31 22281223
2020 DNA Helicase Mph1FANCM Ensures Meiotic Recombination between Parental Chromosomes by Dissociating Precocious Displacement Loops. Developmental cell 30 32386601
2017 Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability. PloS one 30 28380042
2012 Rad5-dependent DNA repair functions of the Saccharomyces cerevisiae FANCM protein homolog Mph1. The Journal of biological chemistry 29 22696213
2017 Stable aneuploid tumors cells are more sensitive to TTK inhibition than chromosomally unstable cell lines. Oncotarget 28 28415765
2012 Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors. Bioorganic & medicinal chemistry letters 28 22632936
2017 Novel pyrrolopyrimidines as Mps1/TTK kinase inhibitors for breast cancer. Bioorganic & medicinal chemistry 27 28259529
2017 Whole-Exome Sequencing Identifies the 6q12-q16 Linkage Region and a Candidate Gene, TTK, for Pulmonary Nontuberculous Mycobacterial Disease. American journal of respiratory and critical care medicine 27 28777004
2020 Rad9/53BP1 promotes DNA repair via crossover recombination by limiting the Sgs1 and Mph1 helicases. Nature communications 26 32576832
2017 Acceleration of osteoblast differentiation by a novel osteogenic compound, DMP-PYT, through activation of both the BMP and Wnt pathways. Scientific reports 26 28814721
2016 Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance. Genes & development 25 26966248
1994 IL-2-induced expression of TTK, a serine, threonine, tyrosine kinase, correlates with cell cycle progression. Journal of immunology (Baltimore, Md. : 1950) 25 8254211
2016 Association between polymorphisms in segregation genes BUB1B and TTK and gastric cancer risk. Radiology and oncology 24 27679546
2004 TTK kinase is essential for the centrosomal localization of TACC2. FEBS letters 24 15304323
2020 MiR-582-5p Inhibits Bladder Cancer-Genesis by Suppressing TTK Expression. Cancer management and research 22 33244270
2009 The MPH1 gene of Saccharomyces cerevisiae functions in Okazaki fragment processing. The Journal of biological chemistry 22 19181670
2023 Therapeutic targeting of the TPX2/TTK network in colorectal cancer. Cell communication and signaling : CCS 21 37770979
2022 Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor. Journal of medicinal chemistry 21 35167750
2021 Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel. Molecular therapy. Methods & clinical development 21 33665229
2010 Mph1 requires mismatch repair-independent and -dependent functions of MutSalpha to regulate crossover formation during homologous recombination repair. Nucleic acids research 21 20047969
2009 Mutational analysis of TTK gene in gastric and colorectal cancers with microsatellite instability. Cancer research and treatment 21 20057968
2003 Dynamic distribution of TTK in HeLa cells: insights from an ultrastructural study. Cell research 21 14728800
2024 Annexin A2 combined with TTK accelerates esophageal cancer progression via the Akt/mTOR signaling pathway. Cell death & disease 20 38658569
2021 TTK is a potential therapeutic target for cisplatin-resistant ovarian cancer. Journal of ovarian research 20 34598710
2023 BID expression determines the apoptotic fate of cancer cells after abrogation of the spindle assembly checkpoint by AURKB or TTK inhibitors. Molecular cancer 19 37443114
2010 Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress. Yeast (Chichester, England) 19 19918932
2021 In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1. International journal of molecular sciences 18 34072728
2023 Integrated multi-omics analyses and functional validation reveal TTK as a novel EMT activator for endometrial cancer. Journal of translational medicine 17 36829176
2020 Pyrido[2, 3-d]pyrimidin-7(8H)-ones as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. European journal of medicinal chemistry 17 33248853
2016 Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1. Genes & development 17 26966246
2016 Binding of the Fkh1 Forkhead Associated Domain to a Phosphopeptide within the Mph1 DNA Helicase Regulates Mating-Type Switching in Budding Yeast. PLoS genetics 17 27257873
2000 Tumour necrosis factor alpha enhances the expression of hydroxyl lyase, cytoplasmic antiproteinase-2 and a dual specificity kinase TTK in human chondrocyte-like cells. Cytokine 17 10671299
2022 Combined 3D-QSAR, molecular docking and dynamics simulations studies to model and design TTK inhibitors. Frontiers in chemistry 16 36405310
2016 MTE1 Functions with MPH1 in Double-Strand Break Repair. Genetics 16 26920759
2016 Identification of RSK and TTK as Modulators of Blood Vessel Morphogenesis Using an Embryonic Stem Cell-Based Vascular Differentiation Assay. Stem cell reports 16 27618721
2019 TTK contributes to tumor growth and metastasis of clear cell renal cell carcinoma by inducing cell proliferation and invasion. Neoplasma 14 31607131
2015 A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity. Bioorganic & medicinal chemistry 14 25801152
2023 BMAL1-TTK-H2Bub1 loop deficiency contributes to impaired BM-MSC-mediated bone formation in senile osteoporosis. Molecular therapy. Nucleic acids 13 36910712
2022 TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma. BMC cancer 13 35850753
2021 TTK inhibitor promotes radiosensitivity of liver cancer cells through p21. Biochemical and biophysical research communications 13 33689884
2021 Tumour suppressor role of microRNA-335-5p in esophageal squamous cell carcinoma by targeting TTK (Mps1). Experimental and molecular pathology 13 34953918
2019 Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy. Journal of medicinal chemistry 13 30998356
2018 LMO1 functions as an oncogene by regulating TTK expression and correlates with neuroendocrine differentiation of lung cancer. Oncotarget 13 30038707
2016 The hairpin region of Ndc80 is important for the kinetochore recruitment of Mph1/MPS1 in fission yeast. Cell cycle (Georgetown, Tex.) 13 26900649
2016 Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK. Bioorganic & medicinal chemistry letters 13 27335255

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