TTK (TTK Protein Kinase)
Dual-specificity protein kinase essential for mitotic checkpoint and chromosome segregation
Gene Information Card
| Symbol | TTK |
|---|---|
| Full Name | TTK protein kinase |
| Gene Type | Protein coding |
| Chromosomal Location | 6q14.1 |
| NCBI Gene ID | 7272 ncbi.nlm.nih.gov/gene/7272 |
| Ensembl ID | ENSG00000112742 |
| UniProt ID | P33981 |
| OMIM ID | 604092 |
| HGNC ID | 12401 |
| Aliases | MPS1, MPS1L1, PYT |
Description
The TTK gene encodes a dual-specificity protein kinase that phosphorylates proteins on serine, threonine, and tyrosine residues. TTK (also known as MPS1) is a key component of the spindle assembly checkpoint (SAC), ensuring proper chromosome segregation during mitosis. It localizes to kinetochores and is required for mitotic checkpoint activation in response to unattached kinetochores. Overexpression of TTK is observed in many cancers and is associated with poor prognosis, making it a target for anticancer kinase inhibitors.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast cancer | TTK overexpression promotes aneuploidy and tumor progression; high expression correlates with poor survival. | PMID: 25855791, COSMIC |
| Colorectal cancer | TTK amplification and overexpression drive chromosomal instability and metastasis. | PMID: 26831776, COSMIC |
| Lung cancer | TTK upregulation associated with aggressive phenotype and resistance to chemotherapy. | PMID: 29127120, COSMIC |
| Ovarian cancer | TTK overexpression linked to poor prognosis and platinum resistance. | PMID: 27587529, COSMIC |
| Hepatocellular carcinoma | TTK high expression promotes cell proliferation and correlates with advanced stage. | PMID: 30258072, COSMIC |
| Glioblastoma | TTK overexpression contributes to tumor growth and radioresistance. | PMID: 29323277, COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 38.2 | High |
| Bone marrow | 12.5 | Medium |
| Lymph node | 10.1 | Medium |
| Spleen | 8.9 | Medium |
| Thymus | 7.4 | Medium |
| Brain | 1.2 | Low |
| Heart | 0.8 | Low |
| Liver | 0.5 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 15.3 | High expression; mitotic checkpoint dependent |
| MCF7 (breast cancer) | 12.1 | High expression; associated with proliferation |
| A549 (lung cancer) | 10.8 | High expression; linked to poor prognosis |
| HCT116 (colorectal cancer) | 11.5 | High expression; required for SAC function |
| K562 (leukemia) | 9.2 | Medium expression |
| HEK293 (embryonic kidney) | 4.5 | Low expression; non-transformed |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1084C>T (p.Arg362Trp) | Missense | <0.1% | Unknown functional effect; reported in COSMIC |
| c.1720G>A (p.Glu574Lys) | Missense | <0.1% | Located in kinase domain; potential loss of function |
| c.2113G>A (p.Val705Met) | Missense | <0.1% | Reported in cancer samples; uncertain significance |
| Amplification | Copy number gain | 5-10% in breast/ovarian | Overexpression; drives aneuploidy and tumor progression |
Mutation functional classification
Loss of Function (LOF)
Rare missense mutations in the kinase domain (e.g., p.Glu574Lys) may impair kinase activity and mitotic checkpoint function, leading to increased chromosomal instability.
Gain of Function (GOF)
Gene amplification and overexpression in multiple cancers result in hyperactive TTK signaling, promoting mitotic checkpoint bypass and aneuploidy.
Dominant Negative (DN)
No well-characterized dominant-negative mutations reported in TTK.
View complete mutation data：
Gene Ontology (GO)
| • GO:0004672 (GO:0004672) | • GO:0004674 (GO:0004674) |
| • GO:0004713 (GO:0004713) | • GO:0005524 (GO:0005524) |
| • GO:0000775 (GO:0000775) | • GO:0000776 (GO:0000776) |
| • GO:0000777 (GO:0000777) | • GO:0005819 (GO:0005819) |
| • GO:0007059 (GO:0007059) | • GO:0007094 (GO:0007094) |
| • GO:0031577 (GO:0031577) | • GO:0051301 (GO:0051301) |
| • GO:1904667 (GO:1904667) |
Pathways
• Spindle assembly checkpoint signaling (Reactome R-HSA-69618)
• Cell cycle
• mitotic (Reactome R-HSA-69278)
• M Phase (Reactome R-HSA-68886)
• Resolution of Sister Chromatid Cohesion (Reactome R-HSA-2500257)
Protein Summary
TTK (MPS1) is a 857-amino acid dual-specificity protein kinase with an N-terminal kinase domain and a C-terminal regulatory region. It phosphorylates key mitotic regulators including BUB1, BUBR1, and MAD1 to activate the spindle assembly checkpoint. TTK also autophosphorylates for full activity. Its overexpression in cancers promotes chromosomal instability and tumor progression, while its essential role in mitosis makes it a promising therapeutic target. Several small-molecule inhibitors (e.g., reversine, CFI-402257) are in preclinical and clinical development.
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