Nomenclature
Short Name:
ASK2
Full Name:
Mitogen-activated protein kinase kinase kinase 6
Alias:
- Apoptosis signal regulating kinase 2
- MAPKKK6
- MEKK6
- MEK kinase 6
- EC 2.7.11.25
- Kinase MAP3K6
- M3K6
- MAP3K6
Classification
Type:
Protein-serine/threonine kinase
Group:
STE
Family:
STE11
SubFamily:
NA
Specific Links
Structure
Mol. Mass (Da):
142596
# Amino Acids:
1288
# mRNA Isoforms:
3
mRNA Isoforms:
142,596 Da (1288 AA; O95382); 141,648 Da (1280 AA; O95382-3); 88,674 Da (797 AA; O95382-2);
4D Structure:
Binds both upstream activators and downstream substrates in multimolecular complexes.
1D Structure:
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|---|---|
| 648 | 906 | Pkinase |
| 728 | 748 | Coiled-coil |
| 899 | 909 | Coiled-coil |
Kinexus Products
Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Serine phosphorylated:
S367, S896, S912, S917, S964, S984, S1129, S1149, S1281.
Threonine phosphorylated:
T801+, T804+, T806+, T810-, T899.
Tyrosine phosphorylated:
Y717.
Ubiquitinated:
K540, K773, K910, K999.
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:
87
1321
28
1228
1
16
10
14
7
104
25
63
12
177
113
525
37
564
31
529
6
97
61
156
0.6
9
35
7
36
556
42
1253
12
177
10
172
3
51
81
69
5
75
36
66
46
706
99
633
3
49
36
31
1.1
17
6
18
4
63
33
65
2
24
17
17
18
281
107
223
18
277
30
1100
2
37
79
37
43
649
107
592
4
65
32
85
5
79
34
78
5
73
26
59
17
259
30
1173
7
103
32
101
46
697
81
1423
5
82
39
58
4
67
30
66
7
100
30
79
3
43
28
38
63
965
18
692
100
1527
31
2735
46
705
77
1126
40
608
78
522
3
41
48
34
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
99.5
99.6
100
96.2
97.2
-
-
-
89
-
-
80
77.9
81
89
87.1
91
-
87.1
91
88
-
-
87.5
-
-
-
46.6
62.9
-
46.4
63
64
-
-
-
44.5
61.6
-
-
-
-
-
-
-
-
-
-
-
-
-
39.4
56.3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Regulation
Activation:
Activated by phosphorylation on Thr-806 in the kinase activation loop. Catalytically active only when complexed with MAP3K5, with MAP3K5 supporting the stability and the active configuration of MAP3K6 and MAP3K6 activating MAP3K5 by direct phosphorylation.
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
Protein Kinase Specificity
Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites
Matrix Type:
Predicted from the application of the Kinexus Kinase Substrate Predictor Version 2.0 algorithm, which was trained with over 10,000 kinase-protein substrate pairs and 8,000 kinase-peptide substrate pairs.
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 |
|---|
Disease Linkage
General Disease Association:
Cancer
Specific Cancer Types:
Familial gastric cancer (FGC)
Comments:
ASK2 may be a tumour suppressor protein (TSP). However, its extremely low rate of mutation in human tumours indicates that it may also act as a tumour requiring protein (TRP). MAP3K6 can form a heterocomplex with MAP3K5 (ASK1) to act as a proapoptotic signal and tumour suppressor protein. The P946L, F849Sfs*142, P958T, D200Y and V207G variants have been linked to familial gastric cancer, and they were predicted to be variants that lead to either a decrease in function or dominant negative phenotype. Studies with mouse models also indicate that MAP3K6 acts as a tumour suppressor.
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= -56, p<0.003); Brain glioblastomas (%CFC= -85, p<0.068); Breast epithelial cell carcinomas (%CFC= +68, p<0.08); Cervical cancer stage 2B (%CFC= -93); Clear cell renal cell carcinomas (cRCC) (%CFC= +151, p<0.021); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -89, p<0.0009); Oral squamous cell carcinomas (OSCC) (%CFC= -60, p<0.001); and Skin fibrosarcomas (%CFC= -83). The COSMIC website notes an up-regulated expression score for ASK2 in diverse human cancers of 343, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 34 for this protein kinase in human cancers was 0.6-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.
Mutation Rate in All Cancers:
Percent mutation rates per 100 amino acids length in human cancers: 0 % in 25490 diverse cancer specimens. This rate is -97 % lower than the average rate of 0.075 % calculated for human protein kinases in general. Such a very low frequency of mutation in human cancers is consistent with this protein kinase playing a role as a tumour requiring protein (TRP).
Frequency of Mutated Sites:
None > 1 in 20,773 cancer specimens
Comments:
Only 4 deletions, 4 insertions, and 2 complex mutations are noted on the COSMIC website.