KinaseNET

Nomenclature

Short Name:

ZC1

Full Name:

Mitogen-activated protein kinase kinase kinase kinase 4

Alias:

EC 2.7.11.1
M4K4
MAP4K4
MAPK kinase kinase kinase 4
MAPK/ERK kinase kinase kinase 4
MEK kinase kinase 4; MEKKK 4; MEKKK4; Mitogen-activated protein kinase kinase kinase kinase 4; Nck interacting kinase; NIK
FLH21957
Hepatocyte progenitor kinase-like/germinal center kinase-like kinase
HGK
HPK/GCK-like kinase HGK

Classification

Type:

Protein-serine/threonine kinase

Group:

STE

Family:

STE20

SubFamily:

MSN

Specific Links

Entrez-Protein Entry:	NP_663719
GeneCards Entry:	HGK
Pfam Entry:	O95819
PhosphoNET Entry:	O95819
Phosphosite Plus Entry:	2496
ScanSite Entry:	O95819
Source Entry:	MAP4K4
UniProt Entry:	O95819
Kinexus Products:	ZC1 Mitogen-activated protein kinase kinase kinase kinase 4 pan-specific antibody AB-NK300-1 Mitogen-activated protein kinase kinase kinase kinase 4 T187 phosphosite-specific antibody AB-PK653 Mitogen-activated protein kinase kinase kinase kinase 4 (A2-D20, human) peptide - Powder PE-01BFM99T Mitogen-activated protein kinase kinase kinase kinase 4 (R184-G190, human) pT187 phosphopeptide - Powder PE-04ALN99

General Links

Structure

Mol. Mass (Da):

142,101

# Amino Acids:

1239

# mRNA Isoforms:

mRNA Isoforms:

150,913 Da (1319 AA; O95819-3); 142,101 Da (1239 AA; O95819); 141,929 Da (1242 AA; O95819-5); 138,418 Da (1211 AA; O95819-2); 133,401 Da (1165 AA; O95819-4)

4D Structure:

Interacts with the SH3 domain of the adapter proteins Nck By similarity. Interacts (via its CNH regulatory domain) with ATL1 (via the N-terminal region).

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

4U3Y

Subfamily Alignment

Domain Distribution:

Start	End	Domain
25	289	Pkinase
359	379	Coiled-coil
384	492	Coiled-coil
926	1213	CNH

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 kinase 4 pan-specific antibody AB-NK300-1
○	Mitogen-activated protein kinase kinase kinase kinase 4 T187 phosphosite-specific antibody AB-PK653
○	Mitogen-activated protein kinase kinase kinase kinase 4 (A2-D20, human) peptide - Powder PE-01BFM99T
○	Mitogen-activated protein kinase kinase kinase kinase 4 (R184-G190, human) pT187 phosphopeptide - Powder PE-04ALN99

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Serine phosphorylated:

S5, S175+, S264, S324, S326, S464, S523, S536, S550, S580, S598, S600, S602, S604, S629, S631, S639, S644, S649, S656, S677, S679, S680, S681, S683, S684, S686, S688, S692, S696, S698, S700, S708, S709, S710, S712, S715, S717, S791, S800, S801, S805, S811, S823, S830, S842, S852, S853, S854, S855, S868, S870, S871, S877, S900, S913, S995, S1224.

Threonine phosphorylated:

T35, T59, T124, T181+, T187+, T191-, T319, T351, T576, T627, T628, T809, T828, T834, T840, T846, T857, T873, T874, T876, T907, T915, T1146, T1230.

Tyrosine phosphorylated:

Y36, Y86, Y132, Y193-, Y321, Y323, Y467, Y520, Y560, Y992, Y1143, Y1227.

Ubiquitinated:

K285, K1010, K1198.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

100

1338

50

1117
2

26

21

17
18

239

28

294
53

707

191

794
61

817

55

609
6

76

101

53
8

102

64

269
62

836

68

1580
30

398

20

375
6

82

152

143
15

207

52

332
53

711

215

657
20

274

50

391
6

75

15

56
10

140

47

232
2

29

30

20
15

198

274

1816
12

162

40

227
11

144

142

232
60

806

191

638
71

951

46

1234
13

180

50

226
17

222

30

283
37

493

40

1409
21

278

46

348
57

760

129

1427
20

265

56

387
10

128

40

166
13

180

40

238
10

136

56

180
57

764

24

625
39

526

57

683
10

137

145

244
65

872

130

722
21

282

92

583

Evolution

Species Conservation

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

100

100

100
73.6

82.9

95
20.8

29.1

96
-

-

93.5
-

-

-
63.8

74.2

93
-

-

-
65.4

75.4

92
25.6

40.8

94
-

-

-
-

-

-
21

29

94
20

28.8

93
21.2

29.8

87
-

-

-
-

-

44
-

-

-
49.5

62.6

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	NCK1 - P16333
2	SLC9A1 - P19634
3	GBP3 - Q9H0R5
4	RAP2A - P10114
5	MAP3K7 - O43318
6	ITGB1 - P05556
7	DOK1 - Q99704
8	CASP8 - Q14790
9	BRCA1 - P38398

Regulation

Activation:

Inhibition:

Synthesis:

Degradation:

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

Bosutinib	Kd = 8.2 nM	5328940	288441	22037378
AST-487	Kd = 15 nM	11409972	574738	18183025
Lestaurtinib	Kd = 23 nM	126565		22037378
Staurosporine	Kd = 24 nM	5279		18183025
Alsterpaullone	IC50 < 25 nM	5005498	50894	22037377
Cdk1/2 Inhibitor III	IC50 < 25 nM	5330812	261720	22037377
Gö6976	IC50 < 25 nM	3501	302449	22037377
JAK3 Inhibitor VI	IC50 < 25 nM	16760524		22037377
K-252a; Nocardiopsis sp.	IC50 < 25 nM	3813	281948	22037377
PKR Inhibitor; Negative Control	IC50 < 25 nM	16760619		22037377
SB218078	IC50 < 25 nM	447446	289422	22037377
SU11652	IC50 < 25 nM	24906267	13485	22037377
KW2449	Kd = 33 nM	11427553	1908397	22037378
Alsterpaullone; 2-Cyanoethyl	IC50 > 50 nM	16760286	260138	22037377
Flt-3 Inhibitor II	IC50 > 50 nM	11601743	377193	22037377
IDR E804	IC50 > 50 nM	6419764	1802727	22037377
Kenpaullone	IC50 > 50 nM	3820	296586	22037377
PKR Inhibitor	IC50 > 50 nM	6490494	235641	22037377
TWS119	IC50 > 50 nM	9549289	405759	22037377
VEGFR2 Kinase Inhibitor II	IC50 > 50 nM	5329155	88606	22037377
Doramapimod	Kd = 90 nM	156422	103667	18183025
A674563	Kd = 140 nM	11314340	379218	22037378
Sunitinib	Kd = 140 nM	5329102	535	18183025
AG-E-60384	IC50 > 150 nM	6419741	413188	22037377
ALX-270-403-M001	IC50 > 150 nM			22037377
BML-275	IC50 > 150 nM	11524144	478629	22037377
GSK-3 Inhibitor IX	IC50 > 150 nM	5287844	409450	22037377
GSK-3 Inhibitor XIII	IC50 > 150 nM	6419766	359482	22037377
Nintedanib	Kd = 150 nM	9809715	502835	22037378
SU9516	IC50 > 150 nM	5289419	258805	22037377
Syk Inhibitor	IC50 > 150 nM	6419747	104279	22037377
VEGFR2 Kinase Inhibitor IV	IC50 > 150 nM	5329468	92461	22037377
Dovitinib	Kd = 160 nM	57336746		18183025
Foretinib	Kd = 190 nM	42642645	1230609	22037378
BCP9000906	IC50 > 250 nM	5494425	21156	22037377
Fasudil	IC50 > 250 nM	3547	38380	22037377
Flt-3 Inhibitor III	IC50 > 250 nM	11772958		22037377
Gö6983	IC50 > 250 nM	3499	261491	22037377
GSK-3 Inhibitor X	IC50 > 250 nM	6538818	430226	22037377
GSK-3b Inhibitor XI	IC50 > 250 nM	10020713	272629	22037377
GTP-14564	IC50 > 250 nM	3385203	406375	22037377
H-89	IC50 > 250 nM	449241	104264	22037377
Indirubin-3′-monoxime	IC50 > 250 nM	5326739		22037377
PP1 Analog II; 1NM-PP1	IC50 > 250 nM	5154691	573578	22037377
STO609	IC50 > 250 nM	51371511		22037377
SU11274	IC50 > 250 nM	9549297	261641	22037377
Tpl2 Kinase Inhibitor	IC50 > 250 nM	9549300		22037377
SU14813	Kd = 260 nM	10138259	1721885	22037378
PHA-665752	Kd = 280 nM	10461815	450786	22037378
Neratinib	Kd = 330 nM	9915743	180022	22037378
Pelitinib	Kd = 330 nM	6445562	607707	18183025
Axitinib	Kd = 350 nM	6450551	1289926	22037378
BPIQ-I	IC50 = 500 nM	2427		22037377
Dasatinib	IC50 = 500 nM	11153014	1421	22037377
JNJ-10198409	IC50 = 500 nM	9797370	120077	22037377
LY364947	IC50 = 500 nM	447966	261454	22037377
PD169316	IC50 = 500 nM	4712	17331	22037377
Rho Kinase Inhibitor III; Rockout	IC50 = 500 nM	644354	380071	22037377
Semaxinib	IC50 = 500 nM	5329098	276711	22037377
SU6656	IC50 = 500 nM	5353978	605003	22037377
Syk Inhibitor II	IC50 = 500 nM	16760670		22037377
Brivanib	Kd = 590 nM	11234052	377300	22037378
N-Benzoylstaurosporine	Kd = 650 nM	56603681	608533	22037378
NVP-TAE684	Kd = 970 nM	16038120	509032	22037378
1;9-Pyrazoloanthrone	IC50 > 1 µM	8515	7064	22037377
A 443654	IC50 < 1 µM	10172943	379300	19465931
AG1296	IC50 > 1 µM	2049	71191	22037377
AG1478	IC50 > 1 µM	2051	7917	22037377
Aloisine A	IC50 > 1 µM	5326843	75680	22037377
Aloisine; RP106	IC50 > 1 µM	44350092	126343	22037377
Bisindolylmaleimide I	IC50 > 1 µM	2396	7463	22037377
Bisindolylmaleimide IV	IC50 > 1 µM	2399	266487	22037377
BML-277	IC50 > 1 µM	9969021	179583	22037377
BMS-690514	Kd = 1 µM	11349170		21531814
Compound 56	IC50 > 1 µM	2857	29197	22037377
FR180204	IC50 > 1 µM	11493598	259551	22037377
IC261	IC50 > 1 µM	3674	576349	22037377
IKK-2 Inhibitor IV	IC50 > 1 µM	9903786	257167	22037377
IRAK-1-4 Inhibitor I	IC50 > 1 µM	11983295	379787	22037377
MNK1 Inhibitor	IC50 > 1 µM	11644425	1240885	22037377
PKCb Inhibitor	IC50 > 1 µM	6419755	366266	22037377
SB590885	IC50 = 1 µM	11465183	477989
TBCA	IC50 > 1 µM	1095828		22037377
VEGFR2 Kinase Inhibitor I	IC50 > 1 µM	6419834	86943	22037377
WHI-P154	IC50 > 1 µM	3795	473773	22037377
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
RAF265	Kd = 1.3 µM	11656518	558752	18183025
Vandetanib	Kd = 1.4 µM	3081361	24828	18183025
Cediranib	Kd = 2 µM	9933475	491473	22037378
Momelotinib	IC50 > 2 µM	25062766		19295546
Pazopanib	Kd = 2.2 µM	10113978	477772	22037378
GDC0879	Kd = 2.3 µM	11717001	525191	22037378
Tozasertib	Kd = 2.4 µM	5494449	572878	18183025
PP121	IC50 < 2.5 µM	24905142		18849971
Quizartinib	Kd = 2.5 µM	24889392	576982	19654408
SB203580	Kd = 3.7 µM	176155	10	18183025
Sorafenib	Kd = 4.8 µM	216239	1336	18183025

Disease Linkage

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= +96, p<0.003); Clear cell renal cell carcinomas (cRCC) (%CFC= +68, p<0.016); Colorectal adenocarcinomas (early onset) (%CFC= +76, p<0.0002); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +71, p<(0.0003); Skin fibrosarcomas (%CFC= +126, p<0.001); Skin squamous cell carcinomas (%CFC= +74, p<0.008); and Uterine fibroids (%CFC= +110, p<0.0002). The COSMIC website notes an up-regulated expression score for ZC1 in diverse human cancers of 431, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 29 for this protein kinase in human cancers was 0.5-fold of the average score of 60 for the human protein kinases.

Mutagenesis Experiments:

Insertional mutagenesis studies in mice support 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 24998 diverse cancer specimens. This rate is only -12 % 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: 0.4 % in 1128 large intestine cancers tested; 0.3 % in 807 skin cancers tested; 0.19 % in 590 stomach cancers tested; 0.16 % in 602 endometrium cancers tested; 0.08 % in 1810 lung cancers tested; 0.08 % in 1302 breast cancers tested.

Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: S259L (6).

Comments:

Only 6 deletions, 2 insertions and no complex mutations are noted on the COSMIC website.

COSMIC Entry:

MAP4K4

OMIM Entry:

604666

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

Serine phosphorylated:

Threonine phosphorylated:

Tyrosine 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:

Protein Kinase Specificity

Matrix Type:

Domain #:

Inhibitors

Based on in vitro and/or in vivo phosphorylation data

Disease Linkage

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: