Molecule Information

General Information of the Molecule (ID: Mol04362)

• Name: Dual specificity protein kinase TTK (TTK) ,Homo sapiens
• Synonyms: Phosphotyrosine picked threonine-protein kinase
• Molecule Type: Protein
• Gene Name: TTK
• Gene ID: 7272
• Sequence:
  MESEDLSGRELTIDSIMNKVRDIKNKFKNEDLTDELSLNKISADTTDNSGTVNQIMMMAN
  NPEDWLSLLLKLEKNSVPLSDALLNKLIGRYSQAIEALPPDKYGQNESFARIQVRFAEL
  K AIQEPDDARDYFQMARANCKKFAFVHISFAQFELSQGNVKKSKQLLQKAVERGAVPLE
  ML EIALRNLNLQKKQLLSEEEKKNLSASTVLTAQESFSGSLGHLQNRNNSCDSRGQTTK
  ARF LYGENMPPQDAEIGYRNSLRQTNKTKQSCPFGRVPVNLLNSPDCDVKTDDSVVPCF
  MKRQ TSRSECRDLVVPGSKPSGNDSCELRNLKSVQNSHFKEPLVSDEKSSELIITDSIT
  LKNKT ESSLLAKLEETKEYQEPEVPESNQKQWQSKRKSECINQNPAASSNHWQIPELAR
  KVNTEQ KHTTFEQPVFSVSKQSPPISTSKWFDPKSICKTPSSNTLDDYMSCFRTPVVKN
  DFPPACQ LSTPYGQPACFQQQQHQILATPLQNLQVLASSSANECISVKGRIYSILKQIG
  SGGSSKVF QVLNEKKQIYAIKYVNLEEADNQTLDSYRNEIAYLNKLQQHSDKIIRLYDY
  EITDQYIYM VMECGNIDLNSWLKKKKSIDPWERKSYWKNMLEAVHTIHQHGIVHSDLKP
  ANFLIVDGML KLIDFGIANQMQPDTTSVVKDSQVGTVNYMPPEAIKDMSSSRENGKSKS
  KISPKSDVWSL GCILYYMTYGKTPFQQIINQISKLHAIIDPNHEIEFPDIPEKDLQDVL
  KCCLKRDPKQRI SIPELLAHPYVQIQTHPVNQMAKGTTEEMKYVLGQLVGLNSPNSILK
  AAKTLYEHYSGGE SHNSSSSKTFEKKRGKK
• Function: Involved in mitotic spindle assembly checkpoint signaling, aprocess that delays anaphase until chromosomes are bioriented on thespindle, and in the repair of incorrect mitotic kinetochore-spindlemicrotubule attachments . Phosphorylates MAD1L1 to promote the mitotic spindleassembly checkpoint . PhosphorylatesCDCA8/Borealin leading to enhanced AURKB activity at the kinetochore. Phosphorylates SKA3 at 'Ser-34' leading todissociation of the SKA complex from microtubules and destabilizationof microtubule-kinetochore attachments .Phosphorylates KNL1, KNTC1 and autophosphorylates .Phosphorylates MCRS1 which enhances recruitment of KIF2A to the minusend of spindle microtubules and promotes chromosome alignment. {ECO:0000269|PubMed:18243099,ECO:0000269|PubMed:28441529, ECO:0000269|PubMed:29162720,ECO:0000269|PubMed:30785839}.
• Uniprot ID: TTK_HUMAN
• Ensembl ID: ENSG0000011274210
• HGNC ID: HGNC:12401

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma multiforme [ICD-11: 2A00.03] [1]

• Resistant Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

Preclinical Drug(s) 1 drug(s) in total

BAY1217389

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma multiforme [ICD-11: 2A00.03] [1]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Sensitive Drug: BAY1217389
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

References

• Ref 1: TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma. BMC Cancer. 2022 Jul 18;22(1):786.