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Updated November 2019

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Nomenclature

Short Name:
ASK1
Full Name:
Mitogen-activated protein kinase kinase kinase 5
Alias:
  • Apoptosis signal regulating kinase 1
  • MAP3K5
  • MAPK/ERK kinase kinase 5
  • MAPKKK5
  • MEK kinase 5
  • MEKK5
  • Apoptosis signal-regulating kinase 1
  • ASK-1
  • Kinase ASK1
  • M3K5

Classification

Type:
Protein-serine/threonine kinase
Group:
STE
Family:
STE11
SubFamily:
NA
 
 

Specific Links

BioCarta Entry: mapk pathway
Entrez-Gene Entry: 4217
Entrez-Protein Entry: NP_005914
OMIM Entry: 602448
PhosphoNET Entry: Q99683
UniProt Entry: Q99683
Kinexus Products: ASK1
Apoptosis signal regulating protein-serine kinase 1 S1033 phosphosite-specific antibody AB-PK524
Apoptosis signal regulating protein-serine kinase 1 T838 phosphosite-specific antibody AB-PK525
Apoptosis signal regulating protein-serine kinase 1 (T836-G841, human) pT838 phosphopeptide - Powder PE-04ALO99
Apoptosis signal regulating protein-serine kinase 1 (A1030-E1036, human) pS1033 phosphopeptide - Powder PE-04ALQ95
Apoptosis signal regulating protein-serine kinase 1 (N832-Y845, human) pT836+pT838+pT842 phosphopeptide - Powder PE-04ART60

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):
154,537
# Amino Acids:
1374
# mRNA Isoforms:
2
mRNA Isoforms:
154,537 Da (1374 AA; Q99683); 69,839 Da (621 AA; Q99683-2)
4D Structure:
Homodimer when inactive. Binds both upstream activators and downstream substrates in multimolecular complexes. Associates with and inhibited by HIV-1 Nef. Interacts with DAB2IP and PPM1L. Interacts with ARRB2.
1D Structure:
Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence
 
3D Image (rendered using PV Viewer):

PDB ID
2CLQ

Subfamily Alignment
subfamily domain
 
Domain Distribution:
Start End Domain
680 938 Pkinase
1244 1285 Coiled-coil
 

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
○ Apoptosis signal regulating protein-serine kinase 1 S1033 phosphosite-specific antibody AB-PK524
○ Apoptosis signal regulating protein-serine kinase 1 T838 phosphosite-specific antibody AB-PK525
○ Apoptosis signal regulating protein-serine kinase 1 (T836-G841, human) pT838 phosphopeptide - Powder PE-04ALO99
○ Apoptosis signal regulating protein-serine kinase 1 (A1030-E1036, human) pS1033 phosphopeptide - Powder PE-04ALQ95
○ Apoptosis signal regulating protein-serine kinase 1 (N832-Y845, human) pT836+pT838+pT842 phosphopeptide - Powder PE-04ART60
 

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K946.
Serine phosphorylated:

S82, S83-, S115, S461, S821, S958, S964, S966-, S986, S1029-, S1033, S1240.
Sumoylated:
K535, K1083, K1114.
Threonine phosphorylated:

T528, T813+, T825, T838+, T842-, T1109, T1326.
Tyrosine phosphorylated:

Y570, Y574, Y718-, Y798, Y814, Y982.
 

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
    75

    818

    29

    829

  • adrenal
    49

    529

    15

    155

  • bladder
    9

    101

    30

    62

  • brain
    39

    428

    113

    453

  • breast
    76

    823

    25

    599

  • cervix
    14

    152

    82

    167

  • colon
    21

    232

    31

    359

  • heart
    44

    483

    63

    841

  • intestine
    65

    703

    17

    526

  • kidney
    11

    116

    100

    83

  • liver
    7

    81

    49

    79

  • lung
    58

    635

    191

    691

  • lymphnode
    11

    118

    52

    59

  • ovary
    29

    317

    12

    178

  • pancreas
    19

    204

    43

    130

  • pituitary
    83

    900

    15

    553

  • prostate
    15

    160

    140

    138

  • salivarygland
    6

    69

    38

    62

  • skeletalmuscle"
    7

    75

    108

    45

  • skin
    67

    727

    109

    741

  • spinalcord
    21

    233

    41

    122

  • spleen
    13

    147

    45

    96

  • stomach
    14

    152

    40

    94

  • testis
    10

    110

    39

    66

  • thymus
    9

    97

    41

    86

  • thyroid
    46

    500

    79

    661

  • tonsil
    11

    121

    55

    58

  • trachea
    9

    98

    39

    55

  • uterus
    9

    99

    39

    67

  • reticulocytes"
    5

    59

    28

    44

  • t-lymphocytes
    82

    898

    24

    756

  • b-lymphocytes
    55

    598

    36

    591

  • neutrophils
    20

    219

    72

    391

  • macrophages
    100

    1089

    57

    860

  • sperm
    48

    523

    35

    1746

 

Evolution

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

    100

    100
  • tableheader
    99.3

    99.4

    100
  • tableheader
    44.9

    61.4

    99
  • tableheader
    -

    -

    96
  • tableheader
    -

    -

    97
  • tableheader
    68

    73.1

    97
  • tableheader
    -

    -

    -
  • tableheader
    94.2

    95.8

    95
  • tableheader
    92.7

    94.4

    94
  • tableheader
    -

    -

    -
  • tableheader
    84.4

    87.8

    -
  • tableheader
    80.4

    87

    89
  • tableheader
    -

    -

    77
  • tableheader
    71.8

    84.1

    74
  • tableheader
    -

    -

    -
  • tableheader
    40.7

    58.2

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    44.7

    60.8

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
 

Binding Proteins

Examples of known interacting proteins
hiddentext
No. Name – UniProt ID
1 YWHAZ - P63104
2 PDCD6 - O75340
3 GADD45B - O75293
4 IGF1R - P08069
5 ERN1 - O75460
6 AHRR - A9YTQ3
7 AKT1 - P31749
8 RAF1 - P04049
9 QARS - P47897
10 CDC25A - P30304
11 RB1CC1 - Q8TDY2
12 YWHAE - P62258
13 YWHAH - Q04917
14 GSTP1 - P09211
15 MAPK8IP3 - Q9UPT6
 

Regulation

Activation:
Activated by phosphorylation at Thr-838 ; Binds to, and stabilizes MAP3K6 and is activated by MAP3K6 by phosphorylation on Thr-838. ; Dephosphorylated and activated by PGAM5.
Inhibition:
Contains an N-terminal autoinhibitory domain. ; inhibited by phosphorylation at Ser-966 and Ser-1033. ; Inhibited by HIV-1 Nef.
Synthesis:
By TNF-alpha.
Degradation:
NA
 

Kinections Map

Click here to download a PPT of the image below
 
Kinections GIF
 

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
AKT3 Q9Y243 S83 ATRGRGSSVGGGSRR -
Akt2 P31751 S83 ATRGRGSSVGGGSRR -
Akt1 P31749 S83 ATRGRGSSVGGGSRR -
ASK1 Q99683 Y718 IPERDSRYSQPLHEE -
JAK2 O60674 Y798 IPERDSRYSQPLHEE
JAK1 P23458 Y798 IPERDSRYSQPLHEE
ASK1 Q99683 T813 GDNVLINTYSGVLKI
ASK1 Q99683 Y814 DNVLINTYSGVLKIS
ASK1 Q99683 T838 GINPCTETFTGTLQY +
PDK1 O15530 T838 GINPCTETFTGTLQY +
ASK1 Q99683 T842 CTETFTGTLQYMAPE -
ASK1 Q99683 S966 NEYLRSISLPVPVLV -
ASK1 Q99683 S1029 DENFEDHSAPPSPEE -
 

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
ASK1 (MAP3K5) Q99683 S1029 DENFEDHSAPPSPEE -
ASK1 (MAP3K5) Q99683 S966 NEYLRSISLPVPVLV -
ASK1 (MAP3K5) Q99683 T813 GDNVLINTYSGVLKI
ASK1 (MAP3K5) Q99683 T838 GINPCTETFTGTLQY +
ASK1 (MAP3K5) Q99683 T842 CTETFTGTLQYMAPE -
ASK1 (MAP3K5) Q99683 Y718 IPERDSRYSQPLHEE -
ASK1 (MAP3K5) Q99683 Y814 DNVLINTYSGVLKIS
Cip1 (p21, CDKN1A) P38936 S97 GGRRPGTSPALLQGT
MKK3 (MAP2K3, MEK3) P46734 S218 ISGYLVDSVAKTMDA +
MKK4 (MAP2K4, MEK4) P45985 S257 ISGQLVDSIAKTRDA +
MKK4 (MAP2K4, MEK4) P45985 T261 LVDSIAKTRDAGCRP +
MKK6 (MAP2K6, MEK6) P52564 S207 ISGYLVDSVAKTIDA +
MKK6 (MAP2K6, MEK6) P52564 T211 LVDSVAKTIDAGCKP +
MKK7 (MAP2K7, MEK7) O14733 S271 ISGRLVDSKAKTRSA +
MKK7 (MAP2K7, MEK7) O14733 T275 LVDSKAKTRSAGCAA +
 

Protein Kinase Specificity

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

Kinections GIF
Matrix Type:
Experimentally derived from alignment of 18 known protein substrate phosphosites and 70 peptides phosphorylated by recombinant ASK1 in vitro tested in-house by Kinexus.
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
Cdk1/2 Inhibitor III IC50 < 25 nM 5330812 261720 22037377
K-252a; Nocardiopsis sp. IC50 < 25 nM 3813 281948 22037377
Staurosporine IC50 = 37 nM 5279 18524589
TTT-3002 IC50 < 40 nM
Lestaurtinib Kd = 70 nM 126565 22037378
AT9283 IC50 > 100 nM 24905142 19143567
MSC 2032964A IC50 = 100 nM
Hymenialdisine IC50 = 150 nM 3035462 18524589
Syk Inhibitor IC50 < 400 nM 6419747 104279
1;9-Pyrazoloanthrone IC50 = 500 nM 8515 7064 22037377
Gö6976 IC50 = 500 nM 3501 302449 22037377
Wyeth PDK1 Inhibitor Compound 1 IC50 < 600 nM
GSK-3 Inhibitor IX IC50 > 900 nM 5287844 409450
GSK650394A IC50 > 900 nM 25022668 558642
MK5108 IC50 > 1 µM 24748204 20053775
PKR Inhibitor IC50 > 1 µM 6490494 235641 22037377
SB218078 IC50 > 1 µM 447446 289422 22037377
Silmitasertib IC50 > 1 µM 24748573 21174434
SNS314 IC50 > 1 µM 16047143 514582 18678489
WZ3146 Kd > 1 µM 44607360 20033049
WZ4002 Kd > 1 µM 44607530 20033049
Hesperadin Kd < 1.25 µM 10142586 514409 19035792
PF-3644022 IC50 < 2 µM
Staurosporine aglycone IC50 < 2 µM 3035817 281948
IKK-2 Inhibitor IV IC50 < 4 µM 9903786 257167
JNJ-28871063 IC50 > 4 µM 17747413 17975007
Amgen TBK 1 inhibitor (Compound II) IC50 > 4.5 µM
GW441756 hydrochloride IC50 > 4.5 µM 16219400
Ruxolitinib IC50 > 4.5 µM 25126798 1789941
Semaxinib IC50 > 4.5 µM 5329098 276711
Sunitinib IC50 > 4.5 µM 5329102 535
 

Disease Linkage

General Disease Association:

Cancer
Specific Cancer Types:
Melanomas
Comments:
ASK1 appears to be a tumour suppressor protein (TSP)The active form of the protein kinase normally acts to inhibit tumour cell proliferation. Mutations in the MAP3K5 gene have been observed in cancer patients, indicating a role for the protein in cancer pathology. For example, 24% of melanoma cell lines were found to contain mutations in the coding-regions of either MAP3K5 or the closely related kinase MAP3K9. Some of these mutations were found in the kinase catalytic domain, which were predicted to affect the catalytic activity of MAP3K5. In addition, loss of heterozygosity in MAP3K5 was observed in 85% of melanoma specimens, indicating that the previously observed mutations result in the loss-of-function in the protein. In vitro assays of MAP3K5 with an I780F substitution, the most commonly observed mutant form of the kinase, showed reduced phosphotransferase activity when compared to wild-type MAP3K5. It appears to be a tumour-suppressor protein with an important role in the prevention of cancer development.
 
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= +46, p<0.0007); Bladder carcinomas (%CFC= +95, p<0.0009); Cervical cancer stage 2B (%CFC= -64, p<0.081); Colon mucosal cell adenomas (%CFC= +53, p<0.0001); Oral squamous cell carcinomas (OSCC) (%CFC= +103, p<0.0001); Papillary thyroid carcinomas (PTC) (%CFC= +77, p<0.1); Pituitary adenomas (aldosterone-secreting) (%CFC= -57, p<0.0002); Skin melanomas - malignant (%CFC= -66, p<0.002); Skin squamous cell carcinomas (%CFC= +92, p<0.01); T-cell prolymphocytic leukemia (%CFC= -50, p<0.005); Uterine leiomyomas from fibroids (%CFC= -55, p<0.0002); and Vulvar intraepithelial neoplasia (%CFC= +75, p<0.0001). The COSMIC website notes an up-regulated expression score for ASK1 in diverse human cancers of 287, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 40 for this protein kinase in human cancers was 0.7-fold of the average score of 60 for the human protein kinases.
Mutagenesis Experiments:

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.
Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25403 diverse cancer specimens. This rate is only -14 % lower 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: 0.38 % in 805 skin cancers tested; 0.27 % in 602 endometrium cancers tested; 0.26 % in 1093 large intestine cancers tested; 0.15 % in 500 urinary tract cancers tested; 0.1 % in 1942 lung cancers tested; 0.06 % in 1466 breast cancers tested.
Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: S53S (11).
Comments:
Only 4 deletions, 3 insertions, and 2 complex mutations are noted on the COSMIC website.
 
COSMIC Entry:
MAP3K5
OMIM Entry:
602448
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