Nomenclature
Short Name:
MLK4
Full Name:
Mitogen-activated protein kinase kinase kinase
Alias:
- EC 2.7.11.25
- M3KL4
- Mixed lineage kinase 4
Classification
Type:
Protein-serine/threonine kinase
Group:
TKL
Family:
MLK
SubFamily:
MLK
Structure
Mol. Mass (Da):
113,957
# Amino Acids:
1036
# mRNA Isoforms:
3
mRNA Isoforms:
113,957 Da (1036 AA; Q5TCX8); 63,040 Da (570 AA; Q5TCX8-2); 52,817 Da (483 AA; Q5TCX8-3)
4D Structure:
Homodimer
1D Structure:
3D Image (rendered using PV Viewer):
PDB ID
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|---|---|
| 38 | 102 | SH3 |
| 124 | 398 | TyrKc |
| 418 | 490 | Coiled-coil |
| 425 | 446 | Leucine zipper 1 |
| 460 | 481 | Leucine zipper 2 |
| 124 | 400 | Pkinase |
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
Serine phosphorylated:
S105, S111, S114, S115, S455, S514, S517, S528, S542, S543, S546, S561, S597, S614, S618, S621, S650, S773, S895, S920.
Threonine phosphorylated:
T142+, T307-, T592, T604, T622, T719.
Tyrosine phosphorylated:
Y47, Y96, Y669, Y724.
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:
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Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
49.1
63.9
99
95
96.1
95.5
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81
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44.7
57.8
80
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69.5
76.9
71
45.7
58.2
73
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70
47.2
62.5
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64
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31.2
45.2
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20.4
35.8
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34
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33
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For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Regulation
Activation:
Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation
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
Disease Linkage
General Disease Association:
Cancer
Specific Cancer Types:
Colorectal cancer (CRC)
Comments:
Mutations in MLK4 have been linked to Colorectal cancer (CRC).
Gene Expression in Cancers:
The COSMIC website notes an up-regulated expression score for MLK4 in diverse human cancers of 672, which is 1.5-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 13 for this protein kinase in human cancers was 0.2-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: 0.1 % in 24973 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: 0.21 % in 866 skin cancers tested; 0.09 % in 1305 large intestine cancers tested; 0.08 % in 127 biliary tract cancers tested; 0.07 % in 273 cervix cancers tested; 0.05 % in 603 endometrium cancers tested; 0.05 % in 590 stomach cancers tested; 0.05 % in 548 urinary tract cancers tested; 0.04 % in 710 oesophagus cancers tested; 0.04 % in 1512 liver cancers tested; 0.03 % in 1326 breast cancers tested; 0.02 % in 441 autonomic ganglia cancers tested; 0.02 % in 1634 lung cancers tested; 0.01 % in 885 prostate cancers tested; 0.01 % in 2083 central nervous system cancers tested; 0.01 % in 1276 kidney cancers tested.
Frequency of Mutated Sites:
Most frequent mutations with the number of reports indicated in brackets: A450D (5); R575* (4); A293V (4); E314K (4); E396K (4); .
Comments:
Only 5 deletions, 4 insertions and no complex mutations are noted on the COSMIC website.