Nomenclature
Short Name:
MEKK2
Full Name:
Mitogen-activated protein kinase kinase kinase 2
Alias:
- EC 2.7.11.25
- Kinase MEKK2
- MAPKKK2
- MEK kinase 2
- MEKK 2
- MEKK2B
- M3K2
- MAP/ERK kinase kinase 2
- MAP3K2
- MAPK/ERK kinase kinase 2
Classification
Type:
Protein-serine/threonine kinase
Group:
STE
Family:
STE11
SubFamily:
NA
Structure
Mol. Mass (Da):
69741
# Amino Acids:
619
# mRNA Isoforms:
1
mRNA Isoforms:
69,741 Da (619 AA; Q9Y2U5)
4D Structure:
Self-associates. Binds both upstream activators and downstream substrates in multimolecular complexes. Interacts (via the kinase catalytic domain) with STK38.
1D Structure:
Subfamily Alignment
Domain Distribution:
Kinexus Products
Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
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Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Methylated:
K260.
Serine phosphorylated:
S26, S153, S159, S163, S164, S239, S248, S297, S300, S302, S311, S312, S315, S331, S344, S347, S349, S493, S505, S514+, S520+.
Threonine phosphorylated:
T158, T283, T290, T337, T432, T516, T522+, T524-.
Tyrosine phosphorylated:
Y169, Y240, Y250.
Ubiquitinated:
K385, K602.
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:
34
1208
46
1189
1
34
13
47
1.2
42
11
20
7
238
176
699
23
823
53
579
3
96
82
222
2
88
65
158
57
2040
36
4076
13
470
10
471
5
193
119
341
2
54
26
45
20
718
118
587
1.2
43
22
16
1.3
47
6
24
1.2
44
22
48
1.1
40
32
65
6
205
169
168
1.3
46
16
30
2
84
101
95
20
729
186
654
1.3
45
22
49
2
62
24
81
1.1
39
12
19
1.1
40
16
24
2
73
22
122
19
663
120
849
2
54
25
26
1
35
16
25
1.1
40
16
26
1.5
53
56
46
29
1027
18
674
100
3562
52
7000
9
335
116
674
22
797
156
641
2
87
87
180
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
99.8
100
100
-
-
100
-
-
98
-
-
-
98.8
99.1
99
-
-
-
95.8
97.9
96
-
-
96
-
-
-
49.1
50.7
-
91
95.3
92
-
-
88
-
-
83
-
-
-
-
-
-
-
-
-
-
-
-
39.5
49.1
-
-
-
-
-
-
-
-
-
-
-
-
-
25.2
42.4
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Binding Proteins
Examples of known interacting proteins
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| No. | Name – UniProt ID |
|---|---|
| 1 | MAP2K4 - P45985 |
| 2 | WNK1 - Q9H4A3 |
| 3 | NFKBIA - P25963 |
| 4 | YWHAZ - P63104 |
| 5 | YWHAE - P62258 |
| 6 | YWHAH - Q04917 |
Regulation
Activation:
Activated by phosphorylation on Thr-524
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
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 |
|---|
| ANKRD3 (RIPK4) | P57078 | T184 | SMDGLFGTIAYLPPE | + |
| MEK5 (MAP2K5, MKK5) | Q13163 | S311 | VSTQLVNSIAKTYVG | + |
| MEK5 (MAP2K5, MKK5) | Q13163 | T315 | LVNSIAKTYVGTNAY | + |
| 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
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
Comments:
Methylation of the protein increases MAP kinase signalling and promotes Ras-driven carcinomas.
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: Bladder carcinomas (%CFC= +78, p<0.002); and Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +452, p<0.045). The COSMIC website notes an up-regulated expression score for MEKK2 in diverse human cancers of 332, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 54 for this protein kinase in human cancers was 0.9-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: 0.05 % in 25370 diverse cancer specimens. This rate is only -34 % 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: 0.27 % in 602 endometrium cancers tested; 0.21 % in 1093 large intestine cancers tested.
Frequency of Mutated Sites:
None > 3 in 20,653 cancer specimens
Comments:
Only 5 deletions, 1 insertion and no complex mutations are noted on the COSMIC website.