KinaseNET

Nomenclature

Short Name:

ZAK

Full Name:

Mitogen-activated protein kinase kinase kinase MLT

Alias:

AZK
mlklak
MLK-like mitogen-activated protein triple kinase
MLT
MLTK
MRK; MRK-beta; Sterile alpha motif and leucine zipper containing kinase AZK
EC 2.7.11.25
HCCS-4
Mixed lineage kinase-related kinase
MLK7

Classification

Type:

Protein-serine/threonine kinase

Group:

TKL

Family:

MLK

SubFamily:

MLK

Specific Links

Entrez-Gene Entry:	51776
Entrez-Protein Entry:	NP_057737
GeneCards Entry:	MRK
KinBASE Entry:	ZAK
Pfam Entry:	Q9NYL2
PhosphoNET Entry:	Q9NYL2
Phosphosite Plus Entry:	799
Source Entry:	B230120H23RIK
UniProt Entry:	Q9NYL2
Kinexus Products:	ZAK Mitogen-activated protein kinase kinase kinase MLT T161+T162 phosphosite-specific antibody AB-PK719 Mitogen-activated protein kinase kinase kinase MLT (H158-S165, human) pT161+pT162 phosphopeptide - Powder PE-04AQP95

General Links

Structure

Mol. Mass (Da):

91,181

# Amino Acids:

800

# mRNA Isoforms:

mRNA Isoforms:

91,155 Da (800 AA; Q9NYL2); 51,582 Da (455 AA; Q9NYL2-2); 35,468 Da (312 AA; Q9NYL2-3)

4D Structure:

Homodimer. Interacts with PKN1 and ZNF33A

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

5HES

Subfamily Alignment

Domain Distribution:

Start	End	Domain
16	277	Pkinase
277	328	Coiled-coil
339	410	SAM
287	308	Leucine zipper

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.

hiddentext

○	Mitogen-activated protein kinase kinase kinase MLT T161+T162 phosphosite-specific antibody AB-PK719
○	Mitogen-activated protein kinase kinase kinase MLT (H158-S165, human) pT161+pT162 phosphopeptide - Powder PE-04AQP95

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Acetylated:

K116, K354, K369, K376, K538, K544.

Methylated:

R670, R683, R693.

Serine phosphorylated:

S2, S3, S7, S136, S155, S165+, S268, S275, S302, S362, S366, S557, S563, S567, S568, S584, S591, S593, S599, S603, S610, S633, S635, S636, S637, S648, S649, S654, S660, S661, S667, S668, S674, S685, S687, S690, S691, S706, S718, S720, S727, S733, S757, S761, S764, S781.

Threonine phosphorylated:

T161+, T162+, T267, T576, T586, T628, T639, T666, T704, T769.

Tyrosine phosphorylated:

Y78, Y84, Y93, Y120, Y673.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

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Evolution

Species Conservation

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

100

100

100
21.8

35.8

99.5
90.2

90.9

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93
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92

94.8

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91.8

95.6

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91.4

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90.1

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75.5

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76.5
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34.6

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60

74.5

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For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	ZNF33A - Q06730
2	MAP2K4 - P45985

Regulation

Activation:

Activated by phosphorylation by PKN1 and autophosphorylation on Thr-161 and Ser-165.

Inhibition:

Synthesis:

Degradation:

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

ZAK	Q9NYL2	T161	ASRFHNHTTHMSLVG	+
ZAK	Q9NYL2	T162	SRFHNHTTHMSLVGT	+
ZAK	Q9NYL2	S165	HNHTTHMSLVGTFPW	+

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

Chk2 (CHEK2)	O96017	T68	SSLETVSTQELYSIP	+
H3.1	P68431	S29	ATKAARKSAPATGGV	+
ZAK (MLTK)	Q9NYL2	S165	HNHTTHMSLVGTFPW	+
ZAK (MLTK)	Q9NYL2	T161	ASRFHNHTTHMSLVG	+
ZAK (MLTK)	Q9NYL2	T162	SRFHNHTTHMSLVGT	+

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 #:

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

AST-487	Kd = 2.3 nM	11409972	574738	18183025
Sorafenib	Kd = 6.3 nM	216239	1336	18183025
Motesanib	Kd = 8 nM	11667893	572881	18183025
Nilotinib	Kd = 11 nM	644241	255863	22037378
PLX4720	Kd = 41 nM	24180719	1230020	22037378
Dasatinib	Kd = 45 nM	11153014	1421	18183025
Foretinib	Kd = 45 nM	42642645	1230609	22037378
BML-275	IC50 > 50 nM	11524144	478629	22037377
TWS119	IC50 > 50 nM	9549289	405759	22037377
Dovitinib	Kd = 63 nM	57336746		18183025
RAF265	Kd = 63 nM	11656518	558752	18183025
Bosutinib	Kd = 80 nM	5328940	288441	22037378
Flt-3 Inhibitor III	IC50 > 150 nM	11772958		22037377
Flt-3 Inhibitor II	IC50 > 250 nM	11601743	377193	22037377
Cdk1/2 Inhibitor III	IC50 = 500 nM	5330812	261720	22037377
JNJ-10198409	IC50 = 500 nM	9797370	120077	22037377
PKR Inhibitor	IC50 = 500 nM	6490494	235641	22037377
KW2449	Kd = 580 nM	11427553	1908397	22037378
TG101348	Kd = 650 nM	16722836	1287853	22037378
Masitinib	Kd = 770 nM	10074640		22037378
BMS-690514	Kd < 800 nM	11349170		21531814
Doramapimod	Kd = 860 nM	156422	103667	18183025
CHEMBL566515	Kd < 1 µM	44478401	566515	19788238
GSK-3 Inhibitor IX	IC50 > 1 µM	5287844	409450	22037377
JAK3 Inhibitor VI	IC50 > 1 µM	16760524		22037377
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
Canertinib	Kd = 1.2 µM	156414	31965	18183025
Pelitinib	Kd = 1.2 µM	6445562	607707	18183025
LY364947	IC50 = 1.4 µM	447966	261454	16539403
Neratinib	Kd = 1.5 µM	9915743	180022	22037378
Barasertib	Kd = 1.7 µM	16007391	215152	18183025
Axitinib	Kd = 2.6 µM	6450551	1289926	22037378
Imatinib	Kd = 2.6 µM	123596	941	18183025
Tozasertib	Kd = 2.8 µM	5494449	572878	18183025
Ki-20227	Kd = 3.3 µM	9869779	1908396	22037378
SB203580	Kd = 4.4 µM	176155	10	18183025
Vatalanib	Kd = 4.4 µM	151194	101253	18183025

Disease Linkage

General Disease Association:

Cancer

Specific Cancer Types:

Cervical cancer

Gene Expression in Cancers:

The COSMIC website notes an up-regulated expression score for ZAK in diverse human cancers of 339, which is 0.7-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. Mutations at amino acid residues 45, 161, 162, and 165 positions can lead to loss of phosphotransferase or autophosphorylation activity.

Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.05 % in 24915 diverse cancer specimens. This rate is only -28 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: L60P (3).

Comments:

Only 3 deletions, 1 insertion, and no complex mutations are noted on the COSMIC website.

COSMIC Entry:

ZAK

OMIM Entry:

609479

Nomenclature

Short Name:

Full Name:

Alias:

Classification

Type:

Group:

Family:

SubFamily:

Specific Links

General Links

Structure

Mol. Mass (Da):

# Amino Acids:

# mRNA Isoforms:

mRNA Isoforms:

4D Structure:

1D Structure:

3D Image (rendered using PV Viewer):

PDB ID

Subfamily Alignment

Domain Distribution:

Kinexus Products

hiddentext

Post-translation Modifications

Acetylated:

Methylated:

Serine phosphorylated:

Threonine phosphorylated:

Tyrosine phosphorylated:

Distribution

Human Tissue Distribution

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

Evolution

Species Conservation

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

Binding Proteins

hiddentext

Regulation

Activation:

Inhibition:

Synthesis:

Degradation:

Known Upstream Kinases

Based on in vitro and/or in vivo phosphorylation data

Known Downstream Substrates

Based on in vitro and/or in vivo phosphorylation data

Protein Kinase Specificity

Matrix Type:

Domain #:

Inhibitors

Based on in vitro and/or in vivo phosphorylation data

Disease Linkage

General Disease Association:

Specific Cancer Types:

Gene Expression in Cancers:

Mutagenesis Experiments:

Mutation Rate in All Cancers:

Frequency of Mutated Sites:

Comments:

COSMIC Entry:

OMIM Entry:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity: