KinaseNET

Nomenclature

Short Name:

MLK3

Full Name:

Mitogen-activated protein kinase kinase kinase 11

Alias:

EC 2.7.11.25
Kinase MLK3
Mitogen activated protein kinase kinase kinase 11
Mixed lineage kinase 3
MLK-3
SPRK
M3K11
MAP3K11
MAPKKK11
MEKK11

Classification

Type:

Protein-serine/threonine kinase

Group:

TKL

Family:

MLK

SubFamily:

MLK

Specific Links

BioCarta Entry:	mapk pathway
Entrez-Gene Entry:	4296
Entrez-Protein Entry:	NP_002410
GeneCards Entry:	SPRK
KinBASE Entry:	MLK3
OMIM Entry:	600050
Pfam Entry:	Q16584
PhosphoNET Entry:	Q16584
Phosphosite Plus Entry:	623
Source Entry:	MAP3K11
UCSD-Nature Entry:	A001551
UniProt Entry:	Q16584
Kinexus Products:	MLK3 Mixed-lineage protein-serine kinase 3; Mitogen-activated protein kinase kinase kinase 11 S281 phosphosite-specific antibody AB-PK718 Mixed-lineage protein-serine kinase 3; Mitogen-activated protein kinase kinase kinase 11 T277+S281 phosphosite-specific antibody AB-PK870 Mixed-lineage protein-serine kinase 3 / Mitogen-activated protein kinase kinase kinase 11 (T278-G284, human) pS281 phosphopeptide - Powder PE-04AOB85 Mixed-lineage protein-serine kinase 3 / Mitogen-activated protein kinase kinase kinase 11 (W274-G280, human) pT277+pS281 phosphopeptide - Powder PE-04AQV65

General Links

Structure

Mol. Mass (Da):

92,688

# Amino Acids:

847

# mRNA Isoforms:

mRNA Isoforms:

92,688 Da (847 AA; Q16584); 65,344 Da (590 AA; Q16584-2)

4D Structure:

Homodimer; undergoes dimerization during activation.

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

Subfamily Alignment

Domain Distribution:

Start	End	Domain
41	105	SH3
117	376	TyrKc
396	441	Coiled-coil
403	424	Leucine zipper 1
438	459	Leucine zipper 2
117	384	Pkinase

Kinexus Products

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

hiddentext

○	Mixed-lineage protein-serine kinase 3; Mitogen-activated protein kinase kinase kinase 11 S281 phosphosite-specific antibody AB-PK718
○	Mixed-lineage protein-serine kinase 3; Mitogen-activated protein kinase kinase kinase 11 T277+S281 phosphosite-specific antibody AB-PK870
○	Mixed-lineage protein-serine kinase 3 / Mitogen-activated protein kinase kinase kinase 11 (T278-G284, human) pS281 phosphopeptide - Powder PE-04AOB85
○	Mixed-lineage protein-serine kinase 3 / Mitogen-activated protein kinase kinase kinase 11 (W274-G280, human) pT277+pS281 phosphopeptide - Powder PE-04AQV65

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Methylated:

R512.

Serine phosphorylated:

S11, S35, S281+, S394, S493, S507, S524, S548, S555, S556, S654, S674, S693, S705, S724, S727, S740, S746, S748, S758, S770, S789, S793, S815.

Threonine phosphorylated:

T277+, T477, T526, T677, T702, T708, T738, T752, T755.

Ubiquitinated:

K264.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

62

667

28

762
15

159

13

164
10

111

11

95
25

263

81

456
70

750

21

684
12

133

52

184
41

433

33

668
61

651

34

1367
67

720

10

614
45

478

66

583
19

207

28

166
61

653

143

647
17

178

22

113
12

129

11

110
12

133

25

110
10

102

14

94
21

223

199

1074
9

101

20

77
11

115

59

79
57

606

79

549
17

185

23

201
33

351

26

509
10

107

20

76
10

110

18

134
19

207

23

210
86

914

54

1506
12

126

25

75
11

121

19

101
11

121

19

108
30

326

14

93
100

1069

18

656
49

522

26

663
5

54

69

101
69

735

57

638
9

101

35

51

Evolution

Species Conservation

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

100

100

100
99.4

99.6

99
98.3

98.8

98
-

-

94.5
-

-

100
82.6

83.7

93
-

-

-
94.4

95.4

95
93.8

95.4

94
-

-

-
-

-

-
-

-

-
43.3

56.6

-
46.5

58.7

-
-

-

-
30.3

43.8

-
35.6

49.2

-
20.6

35.7

-
-

-

-
-

-

-
-

-

-
-

-

36
-

-

36
-

-

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	CDC42 - P60953
2	SH3RF1 - Q7Z6J0
3	CHUK - O15111
4	MAP4K1 - Q92918
5	DLG4 - P78352
6	AKT1 - P31749
7	MAP4K2 - Q12851
8	IKBKB - O14920
9	RHOG - P84095
10	MAP2K4 - P45985
11	MAP3K12 - Q12852
12	CDC37 - Q16543
13	HSP90AA1 - P07900
14	HSP90AA2 - Q14568
15	MAPK8IP1 - Q9UQF2

Regulation

Activation:

Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation. Phosphorylation at Thr-277 and Ser-281 increases phosphotransferase activity.

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

MLK3	Q16584	T277	LAREWHKTTQMSAAG	+
MLK3	Q16584	S281	WHKTTQMSAAGTYAW	+
HPK1	Q92918	S281	WHKTTQMSAAGTYAW	+
Akt1	P31749	S674	PGRERGESPTTPPTP	?

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

MKK3 (MAP2K3, MEK3)	P46734	S218	ISGYLVDSVAKTMDA	+
MKK3 (MAP2K3, MEK3)	P46734	T222	LVDSVAKTMDAGCKP	+
MKK4 (MAP2K4, MEK4)	P45985	S257	ISGQLVDSIAKTRDA	+
MKK4 (MAP2K4, MEK4)	P45985	T261	LVDSIAKTRDAGCRP	+
MKK7 (MAP2K7, MEK7)	O14733	S271	ISGRLVDSKAKTRSA	+
MKK7 (MAP2K7, MEK7)	O14733	T275	LVDSKAKTRSAGCAA	+
MLK3 (MAP3K11)	Q16584	S281	WHKTTQMSAAGTYAW	+
MLK3 (MAP3K11)	Q16584	T277	LAREWHKTTQMSAAG	+

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

TTT-3002	IC50 < 4 nM
BCP9000822	IC50 = 10 nM	5278396	222102
R406	Kd = 11 nM	11984591		22037378
K-252a; Nocardiopsis sp.	IC50 = 13 nM	3813	281948	17266195
N-Benzoylstaurosporine	Kd = 17 nM	56603681	608533	18183025
Lestaurtinib	Kd = 18 nM	126565		22037378
Staurosporine	Kd = 20 nM	5279		18183025
Cdk1/2 Inhibitor III	IC50 < 25 nM	5330812	261720	22037377
Gö6976	IC50 < 25 nM	3501	302449	22037377
SB218078	IC50 < 25 nM	447446	289422	22037377
Amgen TBK 1 inhibitor (Compound II)	IC50 < 40 nM
BX795	IC50 < 40 nM	10077147	577784
GSK-3 Inhibitor IX	IC50 < 40 nM	5287844	409450
Wyeth PDK1 Inhibitor Compound 1	IC50 < 40 nM
K-252c	IC50 = 49 nM	3815	16958	17266195
Alsterpaullone	IC50 > 50 nM	5005498	50894	22037377
ALX-270-403-M001	IC50 > 50 nM			22037377
Bosutinib	IC50 > 50 nM	5328940	288441	22037377
IDR E804	IC50 > 50 nM	6419764	1802727	22037377
JAK3 Inhibitor VI	IC50 > 50 nM	16760524		22037377
NU6140	IC50 > 50 nM	10202471	1802728	22037377
PKCb Inhibitor	IC50 > 50 nM	6419755	366266	22037377
Syk Inhibitor	IC50 > 50 nM	6419747	104279	22037377
CEP5104	IC50 = 55 nM	23378546	460989	18714982
CEP6331	IC50 = 65 nM	9823787	460990	18714982
BI-D1870	IC50 < 100 nM	25023738	573107
Curcumin	IC50 < 100 nM	5281767	116438
IKK-3 inhibitor IX	IC50 < 100 nM	11626927	373751
IPA-3	IC50 < 100 nM	521106	472940
K00596a	IC50 < 100 nM	9549298	200027
MRT67307	IC50 = 100 nM	44464263
Purvalanol B	IC50 = 100 nM	448991	23254
Ro-31-8220	IC50 < 100 nM	5083	6291
Semaxinib	IC50 = 100 nM	5329098	276711
Staurosporine aglycone	IC50 < 100 nM	3035817	281948
Aloisine A	IC50 > 150 nM	5326843	75680	22037377
Alsterpaullone; 2-Cyanoethyl	IC50 > 150 nM	16760286	260138	22037377
Dovitinib	IC50 > 150 nM	57336746		22037377
Flt-3 Inhibitor II	IC50 > 150 nM	11601743	377193	22037377
GSK-3 Inhibitor XIII	IC50 > 150 nM	6419766	359482	22037377
Indirubin-3′-monoxime	IC50 > 150 nM	5326739		22037377
Pazopanib	IC50 > 150 nM	10113978	477772	22037377
PKR Inhibitor	IC50 > 150 nM	6490494	235641	22037377
SB202190	IC50 > 150 nM	5353940	278041	22037377
STO609	IC50 > 150 nM	51371511		22037377
SU11652	IC50 > 150 nM	24906267	13485	22037377
VEGFR2 Kinase Inhibitor II	IC50 > 150 nM	5329155	88606	22037377
KW2449	Kd = 230 nM	11427553	1908397	22037378
Aloisine; RP106	IC50 > 250 nM	44350092	126343	22037377
GSK-3 Inhibitor X	IC50 > 250 nM	6538818	430226	22037377
IKK-2 Inhibitor IV	IC50 > 250 nM	9903786	257167	22037377
Purvalanol A	IC50 > 250 nM	456214	23327	22037377
CHEMBL1240703	Kd = 270 nM	52945601	1240703	19654408
Foretinib	Kd = 340 nM	42642645	1230609	22037378
KIN 112	IC50 < 400 nM
PP242	IC50 < 400 nM	25243800
Sunitinib	IC50 < 400 nM	5329102	535
Syk Inhibitor IV	IC50 < 400 nM	10200390
NVP-TAE684	Kd = 420 nM	16038120	509032	22037378
Compound 52	IC50 = 500 nM	2856		22037377
JNJ-7706621	IC50 = 500 nM	5330790	191003	22037377
Kenpaullone	IC50 = 500 nM	3820	296586	22037377
Tozasertib	IC50 = 500 nM	5494449	572878	22037377
TWS119	IC50 = 500 nM	9549289	405759	22037377
VEGFR2 Kinase Inhibitor I	IC50 = 500 nM	6419834	86943	22037377
VEGFR2 Kinase Inhibitor IV	IC50 = 500 nM	5329468	92461	22037377
CZC-25146	IC50 < 600 nM
Nintedanib	Kd = 700 nM	9809715	502835	22037378
GSK650394A	IC50 < 800 nM	25022668	558642
GW441756 hydrochloride	IC50 < 800 nM	16219400
LDN193189	IC50 < 800 nM	25195294	513147
SU6656	IC50 < 800 nM	5353978	605003
Syk Inhibitor II	IC50 < 800 nM	16760670
1;9-Pyrazoloanthrone	IC50 > 1 µM	8515	7064	22037377
AG-E-60384	IC50 > 1 µM	6419741	413188	22037377
AG1478	IC50 = 1 µM	2051	7917
BCP9000906	IC50 > 1 µM	5494425	21156	22037377
Bisindolylmaleimide I	IC50 > 1 µM	2396	7463	22037377
Bisindolylmaleimide IV	IC50 > 1 µM	2399	266487	22037377
BML-275	IC50 = 1 µM	11524144	478629
Chelerythrine	IC50 < 1 µM	72311
GW 843682X	IC50 = 1 µM	9826308	514499
IRAK-1-4 Inhibitor I	IC50 = 1 µM	11983295	379787
JNKIN7	IC50 = 1 µM	57340685
PDK1/Akt/Flt Dual Pathway Inhibitor	IC50 > 1 µM	5113385	599894	22037377
PKR Inhibitor; Negative Control	IC50 > 1 µM	16760619		22037377
Ruxolitinib	IC50 = 1 µM	25126798	1789941
Src Kinase Inhibitor I	IC50 > 1 µM	1474853	97771	22037377
SU9516	IC50 > 1 µM	5289419	258805	22037377
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
SU14813	Kd = 1.7 µM	10138259	1721885	18183025
SureCN373973	Kd < 2.5 µM	9818573	30678	19035792
GSK461364A	IC50 > 3 µM	15983966	1908394
HG-9-91-01	IC50 > 3 µM
TG101348	Kd = 3.1 µM	16722836	1287853	22037378
AST-487	Kd = 4 µM	11409972	574738	22037378
Quercetagetin	IC50 < 4 µM	5281680	413552
(5Z)-7-Oxozeaenol	IC50 > 4.5 µM		1077979
BMS-690514	Kd < 4.5 µM	11349170		21531814
GDC-0941	IC50 > 4.5 µM	17755052	521851
Tofacitinib	IC50 > 4.5 µM	9926791	221959

Disease Linkage

General Disease Association:

Neurological and liver disorders

Specific Diseases (Non-cancerous):

HIV-1-associated dementia (HAD); Non-alcoholic steatohepatitis (NASH)

Comments:

The HIV-1 encoded proteins Tat and gp120 are toxic to neurons and activate monocytes and other myeloid cells, which may contribute the clinical manifestation of Human immunodeficiency virus (HIV)-1-associated dementia (HAD) and other HIV-1-associated neurocognitive disorders (HAND). Greater than 50% of patients living with HIV-1 will develop HAND, even with stringent adherence to anti-retroviral therapy. Since over -expression of MLK3 in rat primary rat neurons induces their apoptosis, and selective inhibition of MLK3 protects Tat and gp120-mediated activation of monocytes (with the release of inflammatory cytokines), MLK3 may be a useful target for treatment of HAD and HAND. MLK3 has been implicated as a regulator of disease progression in Non-alcoholic steatohepatitis (NASH), which is one of the most common chronic liver diseases worldwide.

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= +118, p<0.006); Brain glioblastomas (%CFC= +743, p<0.002); Brain oligodendrogliomas (%CFC= +1685, p<0.009); Large B-cell lymphomas (%CFC= +49, p<0.039); Ovary adenocarcinomas (%CFC= +127, p<0.031); Pituitary adenomas (ACTH-secreting) (%CFC= -49); Skin melanomas - malignant (%CFC= +59, p<0.0001); Skin squamous cell carcinomas (%CFC= +47, p<0.026); and T-cell prolymphocytic leukemia (%CFC= +71, p<0.009). The COSMIC website notes an up-regulated expression score for MLK3 in diverse human cancers of 439, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 114 for this protein kinase in human cancers was 1.9-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: 0.07 % in 25371 diverse cancer specimens. This rate is only -11 % 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: 0.43 % in 1093 large intestine cancers tested; 0.37 % in 805 skin cancers tested; 0.24 % in 589 stomach cancers tested; 0.1 % in 1941 lung cancers tested; 0.09 % in 1270 liver cancers tested.

Frequency of Mutated Sites:

None > 3 in 20,655 cancer specimens

Comments:

Only 6 deletions, 1 insertion and no complex mutations are noted on the COSMIC website.

COSMIC Entry:

MAP3K11

OMIM Entry:

600050

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:

Subfamily Alignment

Domain Distribution:

Kinexus Products

hiddentext

Post-translation Modifications

Methylated:

Serine phosphorylated:

Threonine phosphorylated:

Ubiquitinated:

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 Diseases (Non-cancerous):

Comments:

Gene Expression in Cancers:

Mutagenesis Experiments:

Mutation Rate in All Cancers:

Mutation Rate in Specific 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: