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Updated November 2019

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Nomenclature

Short Name:
TTK
Full Name:
Dual specificity protein kinase TTK
Alias:
  • Cancer/testis antigen 96
  • CT96
  • Mps1
  • MPS1L1
  • Phosphotyrosine picked threonine-protein kinase
  • PYT; TTK protein kinase
  • EC 2.7.12.1
  • ESK
  • Esk1
  • FLJ38280

Classification

Type:
Protein-serine/threonine kinase
Group:
Other
Family:
TTK
SubFamily:
NA
 
 

Specific Links

Entrez-Gene Entry: 7272
Entrez-Protein Entry: NP_003309
GeneCards Entry: MPS1L1
KinBASE Entry: TTK
OMIM Entry: 604092
Pfam Entry: P33981
PhosphoNET Entry: P33981
Phosphosite Plus Entry: 779
ScanSite Entry: P33981
Source Entry: TTK
UCSD-Nature Entry: A000882
UniProt Entry: P33981
Kinexus Products: TTK
Dual specificity protein kinase TTK T676 phosphosite-specific antibody AB-PK842
Dual specificity protein kinase TTK Y833+Y836 phosphosite-specific antibody AB-PK843
TTKSubtide - TTK protein kinase substrate peptide - Powder PE-01BJR90
Dual specificity protein kinase TTK (D674-K680, human) pT676 phosphopeptide - Powder PE-04AQF99
Dual specificity protein kinase TTK (K830-G839, human) pY833+pY836 phosphopeptide - Powder PE-04AQH99

General Links

ClustalW2
GPS-Cuckoo
Human Protein Atlas
Kinase.com
Kinase Research
Kinasource
Kinomer
Netphorest
NetworKIN
Phosida
PhosphoElm
Protein Blast
ScanSite
String

Structure

Mol. Mass (Da):
97072
# Amino Acids:
857
# mRNA Isoforms:
2
mRNA Isoforms:
97,072 Da (857 AA; P33981); 96,944 Da (856 AA; P33981-2)
4D Structure:
NA
1D Structure:
Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence
 
3D Image (rendered using PV Viewer):

PDB ID
3HMN

Subfamily Alignment
subfamily domain
 
Domain Distribution:
Start End Domain
161 184 Coiled-coil
525 791 Pkinase
 

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
○ Dual specificity protein kinase TTK T676 phosphosite-specific antibody AB-PK842
○ Dual specificity protein kinase TTK Y833+Y836 phosphosite-specific antibody AB-PK843
○ TTKSubtide - TTK protein kinase substrate peptide - Powder PE-01BJR90
○ Dual specificity protein kinase TTK (D674-K680, human) pT676 phosphopeptide - Powder PE-04AQF99
○ Dual specificity protein kinase TTK (K830-G839, human) pY833+pY836 phosphopeptide - Powder PE-04AQH99
 

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K852, K853.
Methylated:
K19, K385, R467.
Serine phosphorylated:

S3, S7, S15, S37, S80, S108, S214, S216, S218, S258, S281, S291, S317, S321, S333, S345, S353, S362, S363, S382, S393, S433, S436, S440, S455, S464, S582+, S618, S677+, S742+, S821, S824, S837, S845, S847.
Threonine phosphorylated:

T12, T33, T46, T210, T288+, T351, T360, T371, T453, T458, T468, T564, T594, T675-, T676+, T686+, T795, T805, T806-, T849.
Tyrosine phosphorylated:

Y131, Y255, Y374, Y462, Y811+, Y833, Y836.
Ubiquitinated:
K86, K372, K385, K538, K546, K696, K810, K827, K848.
 

Distribution

Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:
% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:
  • adipose
    71

    1704

    16

    3599

  • adrenal
    0.4

    10

    10

    7

  • bladder
    8

    194

    22

    234

  • brain
    45

    1085

    67

    3881

  • breast
    13

    319

    14

    327

  • cervix
    37

    888

    45

    1973

  • colon
    12

    297

    19

    506

  • heart
    91

    2198

    42

    6448

  • intestine
    10

    242

    10

    237

  • kidney
    1.1

    27

    66

    46

  • liver
    2

    55

    35

    100

  • lung
    13

    318

    125

    454

  • lymphnode
    4

    105

    33

    216

  • ovary
    0.7

    16

    8

    9

  • pancreas
    2

    51

    32

    109

  • pituitary
    0.4

    10

    8

    7

  • prostate
    1.5

    35

    120

    118

  • salivarygland
    6

    154

    29

    260

  • skeletalmuscle"
    1.2

    28

    64

    48

  • skin
    17

    404

    56

    463

  • spinalcord
    3

    61

    31

    76

  • spleen
    4

    99

    32

    112

  • stomach
    13

    309

    31

    388

  • testis
    100

    2413

    29

    3357

  • thymus
    85

    2046

    31

    2840

  • thyroid
    89

    2155

    49

    6475

  • tonsil
    13

    307

    36

    496

  • trachea
    4

    90

    29

    146

  • uterus
    3

    75

    29

    110

  • reticulocytes"
    3

    61

    14

    37

  • t-lymphocytes
    18

    432

    18

    322

  • b-lymphocytes
    14

    328

    21

    396

  • neutrophils
    48

    1151

    55

    1306

  • macrophages
    27

    644

    31

    662

  • sperm
    23

    544

    22

    844

 

Evolution

Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
  • tableheader
    100

    100

    100
  • tableheader
    99.2

    99.7

    99
  • tableheader
    85.8

    87.8

    97
  • tableheader
    -

    -

    87
  • tableheader
    -

    -

    93
  • tableheader
    87.4

    92.7

    87.5
  • tableheader
    -

    -

    -
  • tableheader
    74.3

    84.8

    76
  • tableheader
    76.9

    85.7

    79
  • tableheader
    -

    -

    -
  • tableheader
    64.3

    73.7

    -
  • tableheader
    61.1

    74.5

    64
  • tableheader
    52.8

    68.5

    56
  • tableheader
    41.5

    57

    48.5
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    32
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    23.1

    40.3

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    23

    42.4

    -
  • tableheader
    22.8

    44.6

    -
  • tableheader
    -

    -

    -
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
 

Binding Proteins

Examples of known interacting proteins
hiddentext
No. Name – UniProt ID
1 CDCA8 - Q53HL2
2 TACC2 - O95359
3 TUBB1 - Q9H4B7
4 AZU1 - P20160
5 TUBB2A - Q13885
6 TUBB - P07437
7 CDC20 - Q12834
 

Regulation

Activation:
Phosphorylation of S582, Thr-675, Thr-676, Thr-686, Ser-742 increases phosphotransferase activity.
Inhibition:
Phosphorylation of Thr-806 inhibits phosphotransferase activity.
Synthesis:
NA
Degradation:
NA
 

Known Upstream Kinases

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.
Based on in vitro and/or in vivo phosphorylation data

Kinase Short Name UniProt ID (Human) Phosphosite Location Phosphosite Sequence Effect of Phosphorylation
TTK P33981 T33 KFKNEDLTDELSLNK
TTK P33981 S37 EDLTDELSLNKISAD
TTK P33981 S80 EKNSVPLSDALLNKL
TTK P33981 T288 SPDCDVKTDDSVVPC ?
CHK2 O96017 T288 SPDCDVKTDDSVVPC +
TTK P33981 T360 SITLKNKTESSLLAK
TTK P33981 S363 LKNKTESSLLAKLEE
TTK P33981 S436 VFSVSKQSPPISTSK
TTK P33981 T564 LEEADNQTLDSYRNE
TTK P33981 S582 LNKLQQHSDKIIRLY +
TTK P33981 T675 ANQMQPDTTSVVKDS +
TTK P33981 T676 NQMQPDTTSVVKDSQ +
TTK P33981 S677 QMQPDTTSVVKDSQV +
TTK P33981 T686 VKDSQVGTVNYMPPE +
TTK P33981 S742 QQIINQISKLHAIID +
TTK P33981 T795 HPYVQIQTHPVNQMA
TTK P33981 T805 VNQMAKGTTEEMKYV
TTK P33981 T806 NQMAKGTTEEMKYVL -
TTK P33981 Y811 GTTEEMKYVLGQLVG +
TTK P33981 S821 GQLVGLNSPNSILKA ?
ERK2 P28482 S821 GQLVGLNSPNSILKA ?
ERK1 P27361 S821 GQLVGLNSPNSILKA ?
TTK P33981 S824 VGLNSPNSILKAAKT
TTK P33981 S845 GGESHNSSSSKTFEK
TTK P33981 S847 ESHNSSSSKTFEKKR
TTK P33981 T849 HNSSSSKTFEKKRGK
 

Known Downstream Substrates

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.
Based on in vitro and/or in vivo phosphorylation data

Substrate Short Name UniProt ID (Human) Phosphosite Location Phosphosite Sequence Effect of Phosphorylation
Abl1 P00519 T735 DTEWRSVTLPRDLQS +
Abl1 iso2 P00519-2 T754 DTEWRSVTLPRDLQS +
BLM P54132 S1290 QKYSEWTSPAEDSSP
BLM P54132 S1296 TSPAEDSSPGISLSS
BLM P54132 S144 KKLEFSSSPDSLSTI
Borealin Q96AM3 T169 KRSSRANTVTPAVGR
Borealin Q96AM3 T230 DSKEIFLTVPVGGGE
Borealin Q96AM3 T88 QALEEAATADLDITE
Borealin Q96AM3 T94 ATADLDITEINKLTA
BubR1 (Bub1B) O60566 S1043 WKVGKLTSPGALLFQ
BubR1 (Bub1B) O60566 S435 REAELLTSAEKRAEM
BubR1 (Bub1B) O60566 S543 LSEKKNKSPPADPPR
BubR1 (Bub1B) O60566 S670 TLSIKKLSPIIEDSR ?
Chk2 (CHEK2) O96017 T68 SSLETVSTQELYSIP +
HSPA9B P38646 S65 IDLGTTNSCVAVMEG +
HSPA9B P38646 T62 VVGIDLGTTNSCVAV +
Tau iso8 P10636-8 S208 GSPGTPGSRSRTPSL
Tau iso8 P10636-8 S210 PGTPGSRSRTPSLPT
TTK P33981 S363 LKNKTESSLLAKLEE
TTK P33981 S37 EDLTDELSLNKISAD
TTK P33981 S436 VFSVSKQSPPISTSK
TTK P33981 S582 LNKLQQHSDKIIRLY +
TTK P33981 S677 QMQPDTTSVVKDSQV +
TTK P33981 S742 QQIINQISKLHAIID +
TTK P33981 S80 EKNSVPLSDALLNKL
TTK P33981 S821 GQLVGLNSPNSILKA ?
TTK P33981 S824 VGLNSPNSILKAAKT
TTK P33981 S845 GGESHNSSSSKTFEK
TTK P33981 S847 ESHNSSSSKTFEKKR
TTK P33981 T288 SPDCDVKTDDSVVPC ?
TTK P33981 T33 KFKNEDLTDELSLNK
TTK P33981 T360 SITLKNKTESSLLAK
TTK P33981 T564 LEEADNQTLDSYRNE
TTK P33981 T675 ANQMQPDTTSVVKDS +
TTK P33981 T676 NQMQPDTTSVVKDSQ +
TTK P33981 T686 VKDSQVGTVNYMPPE +
TTK P33981 T795 HPYVQIQTHPVNQMA
TTK P33981 T805 VNQMAKGTTEEMKYV
TTK P33981 T806 NQMAKGTTEEMKYVL -
TTK P33981 T849 HNSSSSKTFEKKRGK
TTK P33981 Y811 GTTEEMKYVLGQLVG +
 

Protein Kinase Specificity

Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites

Kinections GIF
Matrix Type:
Experimentally derived from alignment of 42 known protein substrate phosphosites.
Domain #:
1
 

Inhibitors

For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's
Based on in vitro and/or in vivo phosphorylation data
Compound Name KD, Ki or IC50 (nM) PubChem ID ChEMBL ID PubMed ID
Lestaurtinib Kd = 6.5 nM 126565 22037378
TTT-3002 IC50 < 8 nM
Hesperadin Kd < 10 nM 10142586 514409 19035792
Nintedanib Kd = 22 nM 9809715 502835 22037378
JNJ-28312141 Kd = 34 nM 22037378
NVP-TAE684 Kd = 50 nM 16038120 509032 22037378
Staurosporine Kd = 61 nM 5279 18183025
Sunitinib Kd = 63 nM 5329102 535 18183025
GSK1838705A Kd = 76 nM 25182616 464552 22037378
1;9-Pyrazoloanthrone Kd = 98 nM 8515 7064 15711537
KW2449 Kd = 110 nM 11427553 1908397 22037378
K-252a; Nocardiopsis sp. IC50 > 150 nM 3813 281948 22037377
Pazopanib Kd = 150 nM 10113978 477772 18183025
SU14813 Kd = 180 nM 10138259 1721885 18183025
JNJ-7706621 Kd = 190 nM 5330790 191003 18183025
AST-487 Kd = 230 nM 11409972 574738 18183025
PKR Inhibitor IC50 > 250 nM 6490494 235641 22037377
N-Benzoylstaurosporine Kd = 350 nM 56603681 608533 18183025
AC1NS4N8 Kd < 400 nM 5353854 101797 19035792
Staurosporine aglycone IC50 < 400 nM 3035817 281948
Syk Inhibitor IV IC50 < 400 nM 10200390
Foretinib Kd = 430 nM 42642645 1230609 22037378
TG101348 Kd = 450 nM 16722836 1287853 22037378
Ruxolitinib Kd = 480 nM 25126798 1789941 22037378
IDR E804 IC50 = 500 nM 6419764 1802727 22037377
JAK3 Inhibitor VI IC50 = 500 nM 16760524 22037377
NU6140 IC50 = 500 nM 10202471 1802728 22037377
Purvalanol B IC50 < 600 nM 448991 23254
Ro-31-8220 IC50 < 800 nM 5083 6291
GSK-3 Inhibitor IX IC50 > 900 nM 5287844 409450
BCP9000906 IC50 > 1 µM 5494425 21156 22037377
BX795 IC50 = 1 µM 10077147 577784
Cdk1/2 Inhibitor III IC50 > 1 µM 5330812 261720 22037377
Curcumin IC50 = 1 µM 5281767 116438
Gö6976 IC50 > 1 µM 3501 302449 22037377
Indirubin-3′-monoxime IC50 > 1 µM 5326739 22037377
K00596a IC50 = 1 µM 9549298 200027
PP242 IC50 = 1 µM 25243800
Purvalanol A IC50 = 1 µM 456214 23327
R406 IC50 = 1 µM 11984591
SU11652 IC50 > 1 µM 24906267 13485 22037377
SU6656 IC50 = 1 µM 5353978 605003
SU9516 IC50 > 1 µM 5289419 258805 22037377
Syk Inhibitor IC50 = 1 µM 6419747 104279
Wyeth PDK1 Inhibitor Compound 1 IC50 = 1 µM
WZ3146 Kd > 1 µM 44607360 20033049
WZ4002 Kd > 1 µM 44607530 20033049
Doramapimod Kd = 1.2 µM 156422 103667 15711537
CHEMBL249097 Kd < 1.25 µM 25138012 249097 19035792
LKB1(AAK1 dual inhibitor) Kd < 1.25 µM 44588117 516312 19035792
Roscovitine Kd = 1.6 µM 160355 14762 18183025
BI2536 Kd = 2.5 µM 11364421 513909 22037378
SB203580 Kd = 2.5 µM 176155 10 18183025
Amgen TBK 1 inhibitor (Compound II) IC50 > 3 µM
IPA-3 IC50 < 3 µM 521106 472940
IRAK-4 kinase inhibitor b IC50 > 3 µM
JNKIN8 IC50 > 3 µM 57340686
XMD8-92 IC50 < 3 µM 46843772 1673046 20832753
Sorafenib Kd = 3.5 µM 216239 1336 18183025
SureCN4875304 IC50 > 3.5 µM 46871765 20472445
Erlotinib Kd = 3.7 µM 176870 553 22037378
Axitinib Kd = 3.9 µM 6450551 1289926 22037378
GDC-0941 IC50 > 4.5 µM 17755052 521851
HG-9-91-01 IC50 > 4.5 µM
JNKIN7 IC50 > 4.5 µM 57340685
MRT67307 IC50 > 4.5 µM 44464263
SB202190 Kd = 4.5 µM 5353940 278041 18183025
Syk Inhibitor II IC50 > 4.5 µM 16760670
 

Disease Linkage

General Disease Association:

Cancer
Specific Cancer Types:
Pancreatic ductal adenocarcinomas (PDAC); Triple negative breast cancer (TNBC); Gastric cancer
Comments:
TTK is linked to pancreatic ductal adenocarcinoma (PDAC), which is a pancreatic cancer with high mortality rates. TTK is important in the growth and proliferation of PDAC cancer cells. Triple Negative Breast Cancer (TNBC) is a highly aggressive form of cancer and TTK is consistently upregulated in TNBC tissues.
 
Gene Expression in Cancers:

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= +235, p<0.019); Bladder carcinomas (%CFC= +109, p<0.058); Brain glioblastomas (%CFC= -48, p<0.002); Breast non-basal-like cancer (BLC) (%CFC= +109, p<0.0001); Breast sporadic basal-like cancer (BLC) (%CFC= +167, p<0.0001); Cervical epithelial cancer (%CFC= -50, p<0.025); Colon mucosal cell adenomas (%CFC= +151, p<0.0001); Gastric cancer (%CFC= +85, p<0.0004); Large B-cell lymphomas (%CFC= +46, p<0.007); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +83, p<0.055); Oral squamous cell carcinomas (OSCC) (%CFC= +141, p<0.033); Ovary adenocarcinomas (%CFC= +828, p<0.002); and Vulvar intraepithelial neoplasia (%CFC= +424, p<0.0001). The COSMIC website notes an up-regulated expression score for TTK in diverse human cancers of 543, which is 1.2-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 7 for this protein kinase in human cancers was 0.1-fold of the average score of 60 for the human protein kinases.
Mutagenesis Experiments:

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. The phosphotransferase activity of TTK can be lost with a D664A or T686A mutation.
Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.1 % in 25316 diverse cancer specimens. This rate is only 31 % higher than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:

Highest percent mutation rates per 100 amino acids length in human cancers: 0.9 % in 1093 large intestine cancers tested; 0.47 % in 589 stomach cancers tested; 0.33 % in 602 endometrium cancers tested; 0.19 % in 1755 lung cancers tested.
Frequency of Mutated Sites:

None > 6 in 20,528 cancer specimens
Comments:
Over 60 deletions (37 at R854fs*>4 and 12 at K857fs*? located at the C-terminus), 2 insertions, and no complex mutations are noted on the COSMIC website.
 
COSMIC Entry:
TTK
OMIM Entry:
604092
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