KinaseNET

Nomenclature

Short Name:

JNK3

Full Name:

Mitogen-activated protein kinase 10

Alias:

C-Jun N-terminal kinase 3
EC 2.7.11.24
MAPK10
MK10
P493F12
FLJ12099; FLJ33785; P493F12; PRKM10; p54bSAPK; Stress-activated protein kinase JNK3
JNK3A
JNK3-alpha-2
Kinase JNK3
MAP kinase p49 3F12

Classification

Type:

Protein-serine/threonine kinase

Group:

CMGC

Family:

MAPK

SubFamily:

JNK

Specific Links

Entrez-Gene Entry:	5602
Entrez-Protein Entry:	NP_002744
GeneCards Entry:	JNK3
KinBASE Entry:	JNK3
OMIM Entry:	602897
Pfam Entry:	P53779
PhosphoNET Entry:	P53779
Phosphosite Plus Entry:	713
Protein Data Bank Entry:	1JNK
ScanSite Entry:	P53779
Source Entry:	MAPK10
UCSD-Nature Entry:	A001298
UniProt Entry:	P53779
Kinexus Products:	JNK3 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-2 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-3 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-4 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (A305-P319, human) peptide - Powder PE-01AXQ99 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (K26-S40, human) peptide - Powder PE-01AXR90 Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (M1-D15, human) peptide - Powder PE-01AXS95 JNKSubtide - JNK1 (MAPK8) protein kinase substrate peptide - Powder PE-01BHT95 Mitogen-activated protein kinase 10 (M220-T226, human) pY223 phosphopeptide - Powder PE-04AWD00 JNKSelectideA - JNK1 protein kinase substrate peptide - Powder PE-14CAD90

General Links

Structure

Mol. Mass (Da):

52,585

# Amino Acids:

464

# mRNA Isoforms:

mRNA Isoforms:

52,585 Da (464 AA; P53779); 48,554 Da (422 AA; P53779-2); 48,128 Da (426 AA; P53779-3); 31,933 Da (277 AA; P53779-4)

4D Structure:

Interacts with MAPKBP1 By similarity. Binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway. Interacts with HDAC9. Interacts with ARRB2; the interaction enhances MAPK10 activation by MAP3K5.

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

4KKE

Subfamily Alignment

Domain Distribution:

Start	End	Domain
64	359	Pkinase

Kinexus Products

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

hiddentext

○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-2
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-3
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 pan-specific antibody AB-NK197-4
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (A305-P319, human) peptide - Powder PE-01AXQ99
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (K26-S40, human) peptide - Powder PE-01AXR90
○	Jun N-terminus protein-serine kinase (stress-activated protein kinase (SAPKb)) 3 (M1-D15, human) peptide - Powder PE-01AXS95
○	JNKSubtide - JNK1 (MAPK8) protein kinase substrate peptide - Powder PE-01BHT95
○	Mitogen-activated protein kinase 10 (M220-T226, human) pY223 phosphopeptide - Powder PE-04AWD00
○	JNKSelectideA - JNK1 protein kinase substrate peptide - Powder PE-14CAD90

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Palmitoylated:

C462, C463.

Serine phosphorylated:

S193, S217-, S330, S417.

Threonine phosphorylated:

T131-, T216+, T221+, T226-, T281.

Tyrosine phosphorylated:

Y223+.

Ubiquitinated:

K204.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

97

1071

22

811
10

115

13

84
19

212

6

201
56

616

90

614
47

521

23

432
7

83

52

120
25

282

33

455
26

283

35

476
18

204

10

151
16

172

92

174
6

71

24

83
45

502

143

652
8

92

17

50
9

102

11

69
6

63

23

78
13

142

14

116
9

105

338

102
8

91

12

114
7

73

72

76
31

349

84

311
33

371

23

411
8

93

23

98
9

95

15

121
25

282

15

570
6

67

23

92
46

514

59

632
8

86

20

63
11

122

15

131
29

322

15

421
15

165

28

143
42

461

42

186
100

1108

26

2127
19

208

83

442
63

697

57

663
13

146

62

214

Evolution

Species Conservation

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

100

100

100
39

52.6

100
90.1

91.2

100
-

-

100
-

-

-
99.8

99.8

98
-

-

-
98.7

98.9

100
98.7

98.9

99
-

-

-
72.3

75.5

-
70.5

76.5

98
79.7

84.9

98
70.3

77.2

95.5
-

-

-
62.7

70.9

78
-

-

-
59

70.9

70
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
35.3

55.2

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	MAPK8IP3 - Q9UPT6
2	CDK5 - Q00535
3	STMN2 - Q93045
4	MAP2K4 - P45985
5	SH3BP5 - O60239
6	TP53 - P04637
7	MAPKBP1 - O60336
8	DUSP16 - Q9BY84
9	DUSP1 - P28562
10	PLIN2 - Q99541

Regulation

Activation:

Phosphorylation at Thr-221 and Tyr-223, by MAP2K4 and MAP2K7. MAP2K7, increases phosphotransferase activity. MAP2K7 phosphorylates JNK3 on Thr-221 causing a conformational change and a large increase in Vmax. MAP2K4 then phosphorylates Tyr-223 resulting in a further increase in Vmax.

Inhibition:

Phosphorylation at Thr-131 inhibits phosphotransferase activity. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by HDAC9.

Synthesis:

Degradation:

Kinections Map

Click here to download a PPT of the image below

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

CDK5	Q00535	T131	ISLLNVFTPQKTLEE	-
MEK7	O14733	T221	AGTSFMMTPYVVTRY	+
MEK4	P45985	T221	AGTSFMMTPYVVTRY	+
MEK7	O14733	Y223	TSFMMTPYVVTRYYR	+
MEK4	P45985	Y223	TSFMMTPYVVTRYYR	+

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

APLP2	Q06481	T736	VEVDPMLTPEERHLN
APP	P05067	T743	VEVDAAVTPEERHLS
ATF2	P15336	T69	SVIVADQTPTPTRFL	+
ATF2	P15336	T71	IVADQTPTPTRFLKN	+
Bcl-2	P10415	S70	RDPVARTSPLQTPAA
Bcl-2	P10415	S87	AAAGPALSPVPPVVH	+
Bcl-2	P10415	T56	FSSQPGHTPHPAASR	+
Bcl-2	P10415	T74	ARTSPLQTPAAPGAA
Bim	O43521	S69	GPLAPPASPGPFATR
DRPLA	P54259	S734	EEYETPESPVPPARS
Elk-1	P19419	S383	IHFWSTLSPIAPRSP	+
GR	P04150	S226	IDENCLLSPLAGEDD	-
JIP3	Q9UPT6	T269	GQSSAAATPSTTGTK
JIP3	Q9UPT6	T279	TTGTKSNTPTSSVPS
JIP3	Q9UPT6	T290	SVPSAAVTPLNESLQ
Jun (c-Jun)	P05412	S63	KNSDLLTSPDVGLLK	+
Jun (c-Jun)	P05412	S73	VGLLKLASPELERLI	+
MCL1	Q07820	S121	PAADAIMSPEEELDG
MCL1	Q07820	T163	TDGSLPSTPPPAEEE
Myc	P01106	S62	LLPTPPLSPSRRSGL
Myc	P01106	S71	SRRSGLCSPSYVAVT
Myc	P01106	T58	KKFELLPTPPLSPSR
NFAT2	O95644	S172	YRDPSCLSPASSLSS
p53	P04637	S37	NVLSPLPSQAMDDLM	+
Shc1	P29353	S36	TPPEELPSPSASSLG	-
STMN2	Q93045	S62	ELILKPPSPISEAPR
STMN2	Q93045	S73	EAPRTLASPKKKDLS

Protein Kinase Specificity

Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites

Matrix Type:

Experimentally derived from alignment of 22 known protein substrate phosphosites. Note that additional binding sites on JNK substrates with D motifs (consensus=R-P-t-s/r/t-L-p-L or K/r-x-s-L-s-L/i/v-s-l/p) facilitate higher selectivity for phosphorylation by this protein kinase.

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

Hesperadin	Kd < 10 nM	10142586	514409	19035792
SureCN7018367	Kd < 10 nM	18792927	450519	19035792
Lestaurtinib	Kd = 12 nM	126565		22037378
Kinome_3027	Ki = 18 nM	11640926	378627	16759099
1;9-Pyrazoloanthrone	Kd = 22 nM	8515	7064	15711537
SB203580	Kd = 35 nM	176155	10	18183025
JNKIN7	IC50 < 40 nM	57340685
JNKIN8	IC50 < 40 nM	57340686
SB202190	Kd = 42 nM	5353940	278041	18183025
KW2449	Kd = 51 nM	11427553	1908397	22037378
JNK Inhibitor VIII	Ki = 52 nM	11624601	210618	18077363
TTT-3002	IC50 < 60 nM
Doramapimod	Kd = 62 nM	156422	103667	15711537
NVP-TAE684	Kd = 67 nM	16038120	509032	22037378
AS601245	IC50 = 70 nM	11422035	191384	17451961
CHEMBL1788116	IC50 = 70 nM	11422034	1788116	15999997
7-hydroxystaurosporine	IC50 > 100 nM	72271	1236539
AT9283	IC50 > 100 nM	24905142		19143567
Staurosporine aglycone	IC50 < 100 nM	3035817	281948
MK5108	IC50 > 103 nM	24748204		20053775
Staurosporine	Kd = 110 nM	5279		18183025
Kinome_2553	IC50 = 120 nM	16007116	377383	16854050
GSK1838705A	Kd = 130 nM	25182616	464552	22037378
AMG-47a	IC50 = 145 nM	16086114	215943	16970394
JNK Inhibitor IX	IC50 = 200 nM	766949	233001	22284361
TG101348	Kd = 200 nM	16722836	1287853	22037378
JNJ-28312141	Kd = 240 nM			22037378
Nintedanib	Kd = 270 nM	9809715	502835	22037378
Gö6976	IC50 > 300 nM	3501	302449
AC1NS4N8	Kd < 400 nM	5353854	101797	19035792
Syk Inhibitor IV	IC50 < 400 nM	10200390
PDK1/Akt/Flt Dual Pathway Inhibitor	IC50 = 500 nM	5113385	599894	22037377
CZC-25146	IC50 < 600 nM
GSK650394A	IC50 > 600 nM	25022668	558642
R406	IC50 < 600 nM	11984591
Momelotinib	IC50 < 750 nM	25062766		19295546
AST-487	Kd = 760 nM	11409972	574738	18183025
VX702	Kd = 780 nM	10341154	1090090	19950901
Amgen TBK 1 inhibitor (Compound II)	IC50 < 800 nM
HG-9-91-01	IC50 < 800 nM
A 443654	IC50 > 900 nM	10172943	379300
GSK-3 Inhibitor IX	IC50 > 900 nM	5287844	409450
Ruboxistaurin	IC50 > 900 nM	153999	91829
HG-10-102-01	IC50 = 1 µM
K00596a	IC50 = 1 µM	9549298	200027
KT5720	IC50 = 1 µM	3844	608532
SGI-1776	IC50 > 1 µM			19734450
Silmitasertib	IC50 > 1 µM	24748573		21174434
SNS314	IC50 > 1 µM	16047143	514582	18678489
Syk Inhibitor	IC50 = 1 µM	6419747	104279
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
Axitinib	Kd = 1.1 µM	6450551	1289926	22037378
BI2536	Kd = 1.1 µM	11364421	513909	22037378
IKK-2 Inhibitor IV	Kd < 1.25 µM	9903786	257167	19035792
SureCN5632345	Kd < 1.25 µM	44593646	515466	19035792
JNJ-7706621	Kd = 1.3 µM	5330790	191003	18183025
Pyrimidylpyrrole, 11e	Ki = 1.4 µM	11634725	583042	19827834
ZINC00135906	IC50 = 1.5 µM	24948986		19035792
Pazopanib	Kd = 1.9 µM	10113978	477772	18183025
SGX523	Kd = 1.9 µM	24779724	1236107	22037378
Afatinib	Kd = 2 µM	10184653	1173655	22037378
Nilotinib	Kd = 2 µM	644241	255863	22037378
Gefitinib	Kd = 2.3 µM	123631	939	15711537
CHEMBL249097	Kd < 2.5 µM	25138012	249097	19035792
GDC0879	Kd = 2.5 µM	11717001	525191	22037378
Neratinib	Kd = 2.5 µM	9915743	180022	22037378
Canertinib	Kd = 2.8 µM	156414	31965	15711537
Tozasertib	Kd = 2.8 µM	5494449	572878	18183025
Wyeth PDK1 Inhibitor Compound 1	IC50 > 3 µM
Aloisine A	IC50 = 3.3 µM	5326843	75680	12519061
SureCN4875304	IC50 > 3.5 µM	46871765		20472445
N-Benzoylstaurosporine	Kd = 3.6 µM	56603681	608533	18183025
SU14813	Kd = 3.6 µM	10138259	1721885	22037378
Foretinib	Kd = 3.9 µM	42642645	1230609	22037378
CHEMBL493169	Ki > 4 µM	44219632	493169	19414255
CHEMBL494221	Ki > 4 µM	5328125	494221	19414255
JNJ-28871063	IC50 > 4 µM	17747413		17975007
Erlotinib	Kd = 4.3 µM	176870	553	22037378
Linifanib	Kd = 4.3 µM	11485656	223360	22037378
Sunitinib	Kd = 4.3 µM	5329102	535	22037378
Alsterpaullone	IC50 > 4.5 µM	5005498	50894
GDC-0941	IC50 > 4.5 µM	17755052	521851
MSC 2032964A	IC50 > 4.5 µM
Rapamycin	IC50 > 4.5 µM	5284616	413
Syk Inhibitor II	IC50 > 4.5 µM	16760670

Disease Linkage

General Disease Association:

Neurological disorders

Specific Diseases (Non-cancerous):

Coffin-Lowry syndrome; Congenital insensitivity to pain with anhidrosis; Anhidrosis; Lennox-Gastaut syndrome; Opioid abuse

Comments:

A single patient with pharmacoresistant epileptic encephalopathy has been found to have chromosomal aberration, translocation t(Y;4)(q11.2;q21) that leads to JNK3 truncation, involving this gene. A 13-year-old boy with delayed psychomotor development and mild intellectual disability without seizures who had a de novo heterozygous balanced translocation, 46,X,t(Y;4)(q12;q21.3), where the breakpoint is at JNK3 gene, and leads to elimination of JNK3 functions.

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: Cervical cancer (%CFC= +97, p<0.0001); Cervical cancer stage 2A (%CFC= -71, p<0.064); Clear cell renal cell carcinomas (cRCC) (%CFC= -45, p<0.007); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -56, p<0.0001); Malignant pleural mesotheliomas (MPM) tumours (%CFC= -48, p<0.001); T-cell prolymphocytic leukemia (%CFC= +83, p<0.066); and Uterine leiomyomas (%CFC= -73, p<0.003).

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 24434 diverse cancer specimens. This rate is only 31 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Frequency of Mutated Sites:

None > 1 in 20,654 cancer specimens

Comments:

No deletions, insertions or complex mutations are noted on the COSMIC website.

COSMIC Entry:

MAPK10_ENST00000359221

OMIM Entry:

602897

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

Palmitoylated:

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:

Kinections Map

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:

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: