Reviewed, UniProtKB/Swiss-Prot P53779 (MK10_HUMAN)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase 10
    EC=2.7.11.24
Alternative name(s):
    Stress-activated protein kinase JNK3
    c-Jun N-terminal kinase 3
    MAP kinase p49 3F12

Gene names

Name:	MAPK10
Synonyms:	JNK3, JNK3A, PRKM10

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	464 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Responds to activation by environmental stress and pro-inflammatory cytokines by phosphorylating a number of transcription factors, primarily components of AP-1 such as c-Jun and ATF2 and thus regulates AP-1 transcriptional activity. Required for stress-induced neuronal apoptosis and the pathogenesis of glutamate excitotoxicity By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium. Ref.6
Enzyme regulation	Activated by threonine and tyrosine phosphorylation by two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K7 phosphorylates MAPK10 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. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by HDAC9. Ref.9
Subunit 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.
Subcellular location	Cytoplasm.
Tissue specificity	Specific to a subset of neurons in the nervous system. Present in the hippocampus and areas, cerebellum, striatum, brain stem, and weakly in the spinal cord. Very weak expression in testis and kidney.
Domain	The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification	Dually phosphorylated on Thr-221 and Tyr-223, which activates the enzyme. Weakly autophosphorylated on threonine and tyrosine residues in vitro. Ref.6 Ref.10
Involvement in disease	A chromosomal rearrangement involving MAPK10 is a cause of epileptic encephalopathy Lennox-Gastaut type [MIM:606369]. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.
Mass spectrometry	Molecular mass is 44070 Da from positions 1 - 464. Determined by ESI. Ref.6

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Chromosomal rearrangement
Disease	Epilepsy
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	JNK cascade Ref.2 Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW JUN kinase activity Ref.2 Inferred from sequence or structural similarity. Source: UniProtKB MAP kinase kinase activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Note: A similar low level of binding to substrates is observed for isoform alpha-1 and isoform alpha-2. However, there is no correlation between binding and phosphorylation, which is achieved about at the same efficiency by all isoforms.

Isoform Alpha-2 (identifier: P53779-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Alpha-1 (identifier: P53779-2)

The sequence of this isoform differs from the canonical sequence as follows:
     418-464: GAAVNSSESLPPSSSVNDISSMSTDQTLASDTDSSLEASAGPLGCCR → AQVQQ

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 464

464

Mitogen-activated protein kinase 10

PRO_0000186277

Regions

Domain

64 – 359

296

Protein kinase

Nucleotide binding

70 – 78

9

ATP

Motif

221 – 223

3

TXY

Sites

Active site

189

1

Proton acceptor

Binding site

93

1

ATP

Amino acid modifications

Modified residue

221

1

Phosphothreonine Ref.6

Modified residue

223

1

Phosphotyrosine Ref.6 Ref.10

Natural variations

Alternative sequence

418 – 464

47

GAAVN…LGCCR → AQVQQ in isoform Alpha-1.

VSP_004839

Secondary structure

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464

Helix Strand Turn

Details...

Beta strand

47 – 53

7

Beta strand

56 – 61

6

Beta strand

64 – 72

9

Beta strand

74 – 83

10

Turn

84 – 87

4

Beta strand

88 – 97

10

Helix

98 – 100

3

Helix

102 – 117

16

Beta strand

126 – 130

5

Turn

136 – 138

3

Beta strand

141 – 147

7

Beta strand

150 – 152

3

Helix

153 – 157

5

Helix

163 – 182

20

Helix

192 – 194

3

Beta strand

195 – 197

3

Beta strand

203 – 205

3

Helix

232 – 235

4

Helix

244 – 258

15

Helix

268 – 279

12

Turn

284 – 286

3

Helix

287 – 289

3

Helix

292 – 299

8

Helix

309 – 312

4

Helix

323 – 339

17

Turn

344 – 346

3

Helix

350 – 354

5

Turn

357 – 359

3

Helix

360 – 362

3

Helix

365 – 368

4

Helix

389 – 398

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha-2 [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 2E20C05EB89CDA66	FASTA	464	52,585
	10 20 30 40 50 60 MSLHFLYYCS EPTLDVKIAF CQGFDKQVDV SYIAKHYNMS KSKVDNQFYS VEVGDSTFTV 70 80 90 100 110 120 LKRYQNLKPI GSGAQGIVCA AYDAVLDRNV AIKKLSRPFQ NQTHAKRAYR ELVLMKCVNH 130 140 150 160 170 180 KNIISLLNVF TPQKTLEEFQ DVYLVMELMD ANLCQVIQME LDHERMSYLL YQMLCGIKHL 190 200 210 220 230 240 HSAGIIHRDL KPSNIVVKSD CTLKILDFGL ARTAGTSFMM TPYVVTRYYR APEVILGMGY 250 260 270 280 290 300 KENVDIWSVG CIMGEMVRHK ILFPGRDYID QWNKVIEQLG TPCPEFMKKL QPTVRNYVEN 310 320 330 340 350 360 RPKYAGLTFP KLFPDSLFPA DSEHNKLKAS QARDLLSKML VIDPAKRISV DDALQHPYIN 370 380 390 400 410 420 VWYDPAEVEA PPPQIYDKQL DEREHTIEEW KELIYKEVMN SEEKTKNGVV KGQPSPSGAA 430 440 450 460 VNSSESLPPS SSVNDISSMS TDQTLASDTD SSLEASAGPL GCCR
	Isoform Alpha-1. Checksum: FCC8C11954481C04	FASTA	422	48,554
	10 20 30 40 50 60 MSLHFLYYCS EPTLDVKIAF CQGFDKQVDV SYIAKHYNMS KSKVDNQFYS VEVGDSTFTV 70 80 90 100 110 120 LKRYQNLKPI GSGAQGIVCA AYDAVLDRNV AIKKLSRPFQ NQTHAKRAYR ELVLMKCVNH 130 140 150 160 170 180 KNIISLLNVF TPQKTLEEFQ DVYLVMELMD ANLCQVIQME LDHERMSYLL YQMLCGIKHL 190 200 210 220 230 240 HSAGIIHRDL KPSNIVVKSD CTLKILDFGL ARTAGTSFMM TPYVVTRYYR APEVILGMGY 250 260 270 280 290 300 KENVDIWSVG CIMGEMVRHK ILFPGRDYID QWNKVIEQLG TPCPEFMKKL QPTVRNYVEN 310 320 330 340 350 360 RPKYAGLTFP KLFPDSLFPA DSEHNKLKAS QARDLLSKML VIDPAKRISV DDALQHPYIN 370 380 390 400 410 420 VWYDPAEVEA PPPQIYDKQL DEREHTIEEW KELIYKEVMN SEEKTKNGVV KGQPSPSAQV QQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"p493F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system." Mohit A.A., Martin J.H., Miller C.A. Neuron 14:67-78(1995) [PubMed: 7826642] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-1). Tissue: Hippocampus.
[2]	"Selective interaction of JNK protein kinase isoforms with transcription factors." Gupta S., Barrett T., Whitmarsh A.J., Cavanagh J., Sluss H.K., Derijard B., Davis R.J. EMBO J. 15:2760-2770(1996) [PubMed: 8654373] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA-1 AND ALPHA-2). Tissue: Brain.
[3]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-2). Tissue: Brain.
[6]	"Activation of JNK3 alpha 1 requires both MKK4 and MKK7: kinetic characterization of in vitro phosphorylated JNK3 alpha 1." Lisnock J., Griffin P., Calaycay J., Frantz B., Parsons J., O'Keefe S.J., LoGrasso P. Biochemistry 39:3141-3148(2000) [PubMed: 10715136] [Abstract] Cited for: PARTIAL PROTEIN SEQUENCE, REGULATION BY MAP2K4 AND MAP2K7, PHOSPHORYLATION AT THR-221 AND TYR-223, COFACTOR, MASS SPECTROMETRY.
[7]	"Characterization of a novel human sperm-associated antigen 9 (SPAG9) having structural homology with c-Jun N-terminal kinase-interacting protein." Jagadish N., Rana R., Selvi R., Mishra D., Garg M., Yadav S., Herr J.C., Okumura K., Hasegawa A., Koyama K., Suri A. Biochem. J. 389:73-82(2005) [PubMed: 15693750] [Abstract] Cited for: INTERACTION WITH SPAG9.
[8]	"Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy." Shoichet S.A., Duprez L., Hagens O., Waetzig V., Menzel C., Herdegen T., Schweiger S., Dan B., Vamos E., Ropers H.-H., Kalscheuer V.M. Hum. Genet. 118:559-567(2006) [PubMed: 16249883] [Abstract] Cited for: CHROMOSOMAL REARRANGEMENT, INVOLVEMENT IN EPILEPTIC ENCEPHALOPATHY LENNOX-GASTAUT TYPE.
[9]	"Neuroprotection by histone deacetylase-related protein." Morrison B.E., Majdzadeh N., Zhang X., Lyles A., Bassel-Duby R., Olson E.N., D'Mello S.R. Mol. Cell. Biol. 26:3550-3564(2006) [PubMed: 16611996] [Abstract] Cited for: INTERACTION WITH HDAC9, ENZYME REGULATION.
[10]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-223, MASS SPECTROMETRY.
[11]	"Crystal structure of JNK3: a kinase implicated in neuronal apoptosis." Xie X., Gu Y., Fox T., Coll J.T., Fleming M.A., Markland W., Caron P.R., Wilson K.P., Su M.S.-S. Structure 6:983-991(1998) [PubMed: 9739089] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 40-402.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

U07620 mRNA. Translation: AAC50101.1.
U34819 mRNA. Translation: AAC50604.1.
U34820 mRNA. Translation: AAC50605.1.
AC096953 Genomic DNA. No translation available.
CH471057 Genomic DNA. Translation: EAX05963.1.
BC035057 mRNA. Translation: AAH35057.1.

IPI

IPI00003148.
IPI00023547.

PIR

S71104.

RefSeq

NP_002744.1.
NP_620446.1.
NP_620447.1.
NP_620448.1.

UniGene

Hs.125503

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1JNK	X-ray	2.30	A	1-423	[»]
1PMN	X-ray	2.20	A	40-401	[»]
1PMQ	X-ray	2.20	A	40-401	[»]
1PMU	X-ray	2.70	A	40-401	[»]
1PMV	X-ray	2.50	A	40-401	[»]
2B1P	X-ray	1.90	A	46-400	[»]
2EXC	X-ray	2.75	X	45-400	[»]
2O0U	X-ray	2.10	A	39-402	[»]
2O2U	X-ray	2.45	A	39-402	[»]
2OK1	X-ray	2.40	A	40-402	[»]
2P33	X-ray	2.40	A	40-402	[»]
2R9S	X-ray	2.40	A/B	46-401	[»]
2WAJ	X-ray	2.40	A	39-402	[»]
2ZDT	X-ray	2.00	A	39-402	[»]
2ZDU	X-ray	2.50	A	39-402	[»]
3CGF	X-ray	3.00	A	40-402	[»]
3CGO	X-ray	3.00	A	40-402	[»]
3DA6	X-ray	2.00	A	39-402	[»]
3FI2	X-ray	2.28	A	39-402	[»]
3FI3	X-ray	2.20	A	39-402	[»]
3FV8	X-ray	2.28	A	39-402	[»]
3G90	X-ray	2.40	X	40-402	[»]
3G9L	X-ray	2.20	X	40-402	[»]
3G9N	X-ray	2.80	A	40-402	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:1015N.

IntAct

P53779. 5 interactions.

PTM databases

PhosphoSite

P53779.

Proteomic databases

PRIDE

P53779.

Genome annotation databases

Ensembl

ENSG00000109339. Homo sapiens. [Contig view]

GeneID

5602.

KEGG

hsa:5602.

Organism-specific databases

GeneCards

GC04M087156.

H-InvDB

HIX0004352.

HGNC

HGNC:6872. MAPK10.

MIM

602897. gene.
606369. phenotype.

PharmGKB

PA30617.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P53779.

HOVERGEN

P53779.

OMA

P53779. EHNKLKX.

Enzyme and pathway databases

BRENDA

2.7.11.24. 247.

Pathway_Interaction_DB

foxopathway. FoxO family signaling.
p75ntrpathway. p75(NTR)-mediated signaling.

Gene expression databases

ArrayExpress

P53779.

Bgee

P53779.

CleanEx

HS_MAPK10.

GermOnline

ENSG00000109339. Homo sapiens.

Family and domain databases

InterPro

IPR008351. JNK_MAPK.
IPR003527. MAP_kinase_CS.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PRINTS

PR01772. JNKMAPKINASE.

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

PROSITE

PS01351. MAPK. 1 hit.
PS00107. PROTEIN_KINASE_ATP. False negative.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

21762.

SOURCE

Search...

Entry information

Entry name

MK10_HUMAN

Accession

Primary (citable) accession number: P53779
Secondary accession number(s): A6NFS3, Q15707, Q49AP1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	November 1, 1997
Last modified:	June 16, 2009
This is version 105 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)