TTK

Official Full Name

TTK protein kinase

Organism

Homo sapiens

GeneID

7272

Background

This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

Synonyms

ESK; PYT; CT96; MPH1; MPS1; MPS1L1;

Bio Chemical Class

Kinase

Protein Sequence

MESEDLSGRELTIDSIMNKVRDIKNKFKNEDLTDELSLNKISADTTDNSGTVNQIMMMANNPEDWLSLLLKLEKNSVPLSDALLNKLIGRYSQAIEALPPDKYGQNESFARIQVRFAELKAIQEPDDARDYFQMARANCKKFAFVHISFAQFELSQGNVKKSKQLLQKAVERGAVPLEMLEIALRNLNLQKKQLLSEEEKKNLSASTVLTAQESFSGSLGHLQNRNNSCDSRGQTTKARFLYGENMPPQDAEIGYRNSLRQTNKTKQSCPFGRVPVNLLNSPDCDVKTDDSVVPCFMKRQTSRSECRDLVVPGSKPSGNDSCELRNLKSVQNSHFKEPLVSDEKSSELIITDSITLKNKTESSLLAKLEETKEYQEPEVPESNQKQWQSKRKSECINQNPAASSNHWQIPELARKVNTEQKHTTFEQPVFSVSKQSPPISTSKWFDPKSICKTPSSNTLDDYMSCFRTPVVKNDFPPACQLSTPYGQPACFQQQQHQILATPLQNLQVLASSSANECISVKGRIYSILKQIGSGGSSKVFQVLNEKKQIYAIKYVNLEEADNQTLDSYRNEIAYLNKLQQHSDKIIRLYDYEITDQYIYMVMECGNIDLNSWLKKKKSIDPWERKSYWKNMLEAVHTIHQHGIVHSDLKPANFLIVDGMLKLIDFGIANQMQPDTTSVVKDSQVGTVNYMPPEAIKDMSSSRENGKSKSKISPKSDVWSLGCILYYMTYGKTPFQQIINQISKLHAIIDPNHEIEFPDIPEKDLQDVLKCCLKRDPKQRISIPELLAHPYVQIQTHPVNQMAKGTTEEMKYVLGQLVGLNSPNSILKAAKTLYEHYSGGESHNSSSSKTFEKKRGKK

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The TTK gene (Threonine and Tyrosine Kinase), also known as Monopolar Spindle 1 (MPS1), is located on human chromosome 6q13-q21 and encodes a dual-specificity protein kinase. The protein consists of 831 amino acids with an approximate molecular weight of 97 kDa, featuring an N-terminal catalytic domain and a C-terminal regulatory domain. TTK exhibits dual substrate specificity, capable of phosphorylating tyrosine, serine, and threonine residues, which allows it to play multiple roles within cellular signaling networks. TTK is a core component of the Spindle Assembly Checkpoint (SAC), a quality control mechanism ensuring proper chromosome segregation during mitosis.

In cell cycle regulation, TTK phosphorylates several SAC components, including MAD1L1, KNL1, and CDCA8/Borealin, thereby activating checkpoint signaling. When chromosomes are not properly attached to the spindle, TTK is recruited to the centromere region, triggering a "wait signal" that inhibits the activation of the anaphase-promoting complex/cyclosome (APC/C) and delays mitotic progression until all chromosomes are correctly aligned. TTK also participates in correcting improper microtubule-kinetochore attachments to prevent aneuploidy. Its expression is low in normal somatic tissues but higher in highly proliferative tissues such as the testis and placenta, consistent with its essential role in mitosis.

Figure 1. Schematic model of Mps1 functions in the SAC. (Bolanos-Garcia VM, 2025)

TTK expression is tightly cell cycle-regulated, being almost undetectable in G1, increasing during S phase, and peaking at G2/M. This periodic expression is regulated by E2F transcription factors and correlates closely with high proliferation rates in tumor cells. Aberrant TTK overexpression has been observed across various malignancies, and its expression level is associated with tumor aggressiveness and poor prognosis.

Biological Functions and Pathological Significance

TTK plays an indispensable role in maintaining genomic stability. During normal mitosis, it acts as a core amplifier of SAC signaling, phosphorylating MAD1L1 to promote recruitment of the MAD1-MAD2 complex to unattached kinetochores. TTK also phosphorylates SKA3, a component of the spindle-kinetochore-associated complex, causing the SKA complex to dissociate from microtubules, disrupting unstable attachments and allowing proper connections to form. This precise regulation ensures chromosomes achieve bipolar attachment before sister chromatid separation, preventing aneuploidy.

Figure 2. SAC activation pathway. (Zeng Y, et al., 2023)

Another key role of TTK is in centrosome replication. In the late S phase, TTK is recruited to the centrosome and phosphorylates proteins such as CEP152 and CEP192, initiating the centrosome duplication program. Proper control of centrosome replication is essential for cell polarity; TTK dysregulation can lead to centrosome overduplication, multipolar spindle formation, chromosomal missegregation, and genomic instability. Overexpression of TTK in tumor cell lines can induce centrosome amplification and aneuploidy, while TTK inhibitors significantly reduce these abnormal phenotypes.

TTK contributes to tumor development and progression in multiple cancer types. Overexpression of TTK has been detected in lung adenocarcinoma, breast cancer, hepatocellular carcinoma, colon cancer, and urothelial carcinoma. TTK overexpression promotes tumor progression by modulating cell cycle pathways, including G2/M checkpoint and E2F target pathways, as well as metabolic pathways such as glycolysis, highlighting its role in coordinating cell cycle progression and metabolic reprogramming. Functionally, TTK overexpression can enhance anti-apoptotic signaling and suppress apoptotic pathways, supporting tumor cell survival and proliferation. TTK expression is also linked to treatment resistance, suggesting potential as a biomarker for predicting therapeutic response.

Recent studies indicate that TTK is involved in non-cancer pathologies, particularly vascular remodeling. TTK expression is significantly upregulated in vascular smooth muscle cells (VSMCs) during phenotypic switching from contractile to synthetic states, which underlies neointimal formation following vascular injury. Experimental models show that TTK inhibition, whether via conditional knockout or small molecule inhibitors, reduces neointimal hyperplasia and restores contractile markers in VSMCs. Mechanistically, TTK promotes VSMC proliferation and migration while suppressing differentiation through activation of the PI3K/AKT pathway, suggesting it may be a therapeutic target for preventing restenosis.

Therapeutic Potential

Given its pivotal role in mitosis, TTK is a promising target for cancer therapy. Small molecule inhibitors of TTK have been developed to competitively bind the ATP pocket, blocking kinase activity. Preclinical studies show that TTK inhibitors induce chromosomal missegregation and mitotic catastrophe, and they demonstrate synergy with microtubule-targeting agents, supporting potential combination therapies. Early-phase clinical studies have shown that selective TTK inhibition is generally tolerable and can modulate target phosphorylation in patients, providing proof-of-concept for therapeutic activity.

TTK inhibitors also offer new strategies for treating restenosis after angioplasty. Localized delivery systems, such as drug-coated balloons or stents, can achieve high local concentrations while minimizing systemic exposure. Targeted inhibition during the critical proliferation period after vascular injury can suppress neointimal growth and promote VSMC contractile phenotype maintenance. Experimental approaches, including nanoparticle-mediated TTK siRNA delivery, have demonstrated durable inhibition of neointimal hyperplasia in preclinical models, highlighting translational potential.

Reference

Zeng Y, Ren X, Jin P, et al. Development of MPS1 Inhibitors: Recent Advances and Perspectives. J Med Chem. 2023 Dec 28;66(24):16484-16514.
Bolanos-Garcia VM. Mps1 kinase functions in mitotic spindle assembly and error correction. Trends Biochem Sci. 2025 May;50(5):438-453.

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