Disease relevance of TTK

• Escherichia coli expressing the complete kinase domain of TTK contain markedly elevated levels of phosphoserine and phosphothreonine as well as slightly increased levels of phosphotyrosine [1].
• Direct microinjection of the TTK fraction augmented Tat transactivation of HIV-1 LTR in human primary HS68 fibroblasts [2].
• We report here that the expression levels of two families of receptor type tyrosine kinase genes, elk/erk and esk/TTK are developmentally regulated in rat stomach and highly expressed in human gastric cancer tissues [3].

Psychiatry related information on TTK

• Towards freedom: treatment approaches to drug dependence at TTK Hospital [4].

High impact information on TTK

• TTK/hMps1 directly phosphorylates CHK2 on Thr-68 in vitro [5].
• In support of a possible role in regulating cell cycle progression, TTK message is readily detected in rapidly proliferating tissues in vivo including testes, thymus, bone marrow, and many malignant tumors, but not in benign tissues with a low proliferative rate in vivo [6].
• Thus, TTK expression in T cells appears to be a consequence of IL2-induced cell proliferation [6].
• IL-2-induced expression of TTK, a serine, threonine, tyrosine kinase, correlates with cell cycle progression [6].
• These results were confirmed by cell cycle blockade studies with aphidicolin and nocodazole wherein TTK protein levels are not detected in cells in G1 and are readily detectable in cells in the S and G2 phases of the cell cycle.(ABSTRACT TRUNCATED AT 250 WORDS)[6]

Chemical compound and disease context of TTK

• When expressed in Escherichia coli, TTK can phosphorylate serine, threonine, and tyrosine residues [6].

Biological context of TTK

• Furthermore, ablation of TTK expression using small interfering RNA results not only in reduced CHK2 Thr-68 phosphorylation, but also in impaired growth arrest [5].
• TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68 [5].
• Expression of TTK, a novel human protein kinase, is associated with cell proliferation [1].
• Nevertheless, TTK is highly conserved throughout phylogeny with hybridizing sequences being detected in mammals, fish, and yeast [1].
• We previously reported that Tat-associated T-cell-derived kinase (TTK), purified from human primary T-cells, stimulates Tat-dependent transcription of HIV-1 LTR in vivo [Nekhai, Shukla, Fernandez, Kumar and Lamb (2000) Virology 266, 246-256] [2].

Anatomical context of TTK

• TTK was initially identified by screening of a T cell expression library with anti-phosphotyrosine antibodies [1].
• TTK mRNA is present at relatively high levels in testis and thymus, tissues which contain a large number of proliferating cells, but is not detected in most other benign tissues [1].
• As well, all rapidly proliferating cell lines tested expressed TTK mRNA [1].
• Our recent ultrastructural studies demonstrated a dynamic distribution of TTK, from the kinetochore to the centrosome, as cell enters into anaphase [7].
• Dynamic distribution of TTK in HeLa cells: insights from an ultrastructural study [8].

Associations of TTK with chemical compounds

• Taken together, these findings suggest that expression of TTK, a previously unidentified member of the family of kinases which can phosphorylate serine, threonine, and tyrosine hydroxyamino acids, is associated with cell proliferation [1].
• The kinase activities of TTK are blocked by the adenosine analog 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) as well as by the kinase inhibitor H8 at concentrations known to block transcript elongation [9].
• To determine whether this protein kinase, which we call PYT (for phosphotyrosine picked threonine kinase), was a dual-specificity protein kinase we investigated its substrate specificity when expressed in bacteria [10].
• We mapped the phosphorylation sites in the phosphorylated PYT protein and found only phosphothreonine; 90% of the radioactivity mapped to a threonine in the region autophosphorylated by many protein kinases [10].
• TTK protein and mRNA expression increased in both fresh PBL and T cell blasts concurrently with passage of cells through S phase as indicated by [3H]TdR incorporation and cell cycle analysis of propidium iodide-stained cells [6].
• We suggest that phosphorylation of T468 attenuates the degradation of Mps1 at centrosomes and that preventing this degradation is necessary and sufficient to cause centrosome reduplication in human cells [11].

Enzymatic interactions of TTK

• Here, we show that a centrosomal protein TACC2 is phosphorylated in mitosis by TTK signaling pathway [7].

Regulatory relationships of TTK

• Furthermore, TTK mRNA expression was also induced in human articular chondrocytes treated with TNF-alpha but not in untreated chondrocytes [12].

Other interactions of TTK

• Our results are consistent with a model in which TTK functions upstream from CHK2 in response to DNA damage and suggest possible cross-talk between the spindle assembly checkpoint and the DNA damage checkpoint [5].
• Tat induced the TTK-associated CDK2 kinase to phosphorylate CTD, specifically at Ser-2 residues [2].
• TACC2 was pulled down by wild type TTK but not kinase death mutant, suggesting the potential phosphorylation-mediated interaction between these two proteins [7].
• Since phosphorylation of C-terminal domain (CTD) of RNA polymerase II correlates with its enhanced processivity, we studied the properties of a Tat-associated CTD kinase derived from mitogenically stimulated human primary T lymphocytes (TTK) [9].
• Tumour necrosis factor alpha enhances the expression of hydroxyl lyase, cytoplasmic antiproteinase-2 and a dual specificity kinase TTK in human chondrocyte-like cells [12].

Analytical, diagnostic and therapeutic context of TTK

• Our immunofluorescence studies revealed that both TTK and TACC2 are located to the centrosome [7].
• Using immunoelectron microscopy, here we show that TTK is present at the nuclear pore adjacent complex of interphase HeLa cells [8].
• Relative gene expression level analysis by PCR and by Northern blotting revealed that treatment with TNF-alpha enhanced the expression of PLOD, CAP2 and TTK transcripts which confirmed the results obtained with display gels [12].
• The study group consisted of 500 consecutive patients attending TTK Hospital, a non-governmental organisation involved in rehabilitation of substance users [13].

References