Reviewed, UniProtKB/Swiss-Prot P45983 (MK08_HUMAN)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase 8
    EC=2.7.11.24
Alternative name(s):
    Stress-activated protein kinase JNK1
    c-Jun N-terminal kinase 1
    JNK-46

Gene names

Name:	MAPK8
Synonyms:	JNK1, PRKM8

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	427 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 JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. In T-cells, JNK1 and JNK2 are required for polarized differentiation of T-helper cells into Th1 cells By similarity. Phosphorylates heat shock factor protein 4 (HSF4). JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. Inhibited by dual specificity phosphatases, such as DUSP1.
Subunit structure	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 TP53 and WWOX. Interacts with JAMP. Forms a complex with MAPK8IP1 and RGNEF By similarity.
Domain	The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification	Dually phosphorylated on Thr-183 and Tyr-185, which activates the enzyme.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	JUN phosphorylation Inferred from direct assay. Source: MGI activation of pro-apoptotic gene products Inferred from Experiment. Source: Reactome cell motion Traceable author statement. Source: ProtInc negative regulation of apoptosis Inferred from direct assay. Source: MGI response to UV Inferred from direct assay. Source: MGI response to stress Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro JUN kinase activity Ref.2 Inferred from direct assay. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATF2	P15336	1	EBI-288687,EBI-1170906
JUN	P05412	2	EBI-286483,EBI-852823
JUN	P05412	2	EBI-288687,EBI-852823
MAP2K4	P45985	1	EBI-286483,EBI-447868
MAP2K7	O14733-2	2	EBI-286483,EBI-492627
Mapk8ip1	Q9WVI9-1	1	EBI-286483,EBI-288461	From a different organism.

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 2 (identifier: P45983-1)

Also known as: JNK1-alpha-2;

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 1 (identifier: P45983-2)

Also known as: JNK1-alpha-1;

The sequence of this isoform differs from the canonical sequence as follows:
     380-427: GAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR → AQVQQ

Isoform 3 (identifier: P45983-3)

Also known as: JNK1-beta-1;

The sequence of this isoform differs from the canonical sequence as follows:
     208-208: L → I
     219-230: VCHKILFPGRDY → IKGGVLFPGTDH
     380-427: GAAVINGSQHPSSSSSVNDVSSMSTDPTLASDTDSSLEAAAGPLGCCR → AQVQQ

Isoform 4 (identifier: P45983-4)

Also known as: JNK1-beta-2;

The sequence of this isoform differs from the canonical sequence as follows:
     208-208: L → I
     219-230: VCHKILFPGRDY → IKGGVLFPGTDH

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 427

427

Mitogen-activated protein kinase 8

PRO_0000186262

Regions

Domain

26 – 321

296

Protein kinase

Nucleotide binding

32 – 40

9

ATP By similarity

Motif

183 – 185

3

TXY

Sites

Active site

151

1

Proton acceptor By similarity

Binding site

55

1

ATP By similarity

Amino acid modifications

Modified residue

183

1

Phosphothreonine

Modified residue

185

1

Phosphotyrosine

Modified residue

255

1

Phosphothreonine

Modified residue

258

1

Phosphothreonine

Modified residue

259

1

Phosphotyrosine

Modified residue

357

1

Phosphotyrosine

Modified residue

367

1

Phosphothreonine

Modified residue

377

1

Phosphoserine

Natural variations

Alternative sequence

208

1

L → I in isoform 3 and isoform 4.

VSP_004831

Alternative sequence

219 – 230

12

VCHKI…PGRDY → IKGGVLFPGTDH in isoform 3 and isoform 4.

VSP_004832

Alternative sequence

380 – 427

48

GAAVI…LGCCR → AQVQQ in isoform 1 and isoform 3.

VSP_004833

Natural variant

171

1

G → S in a renal clear cell carcinoma sample; somatic mutation.

VAR_042258

Natural variant

177

1

G → R in a glioblastoma multiforme sample; somatic mutation.

VAR_042259

Experimental info

Mutagenesis

183

1

T → A: Phosphorylation blocked

Mutagenesis

185

1

Y → F: Phosphorylation blocked

Secondary structure

1

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427

Helix Strand Turn

Details...

Beta strand

10 – 15

6

Beta strand

18 – 23

6

Beta strand

26 – 45

20

Turn

46 – 49

4

Beta strand

50 – 59

10

Helix

64 – 79

16

Beta strand

88 – 92

5

Turn

98 – 100

3

Beta strand

105 – 109

5

Beta strand

112 – 114

3

Helix

115 – 118

4

Helix

125 – 143

19

Turn

144 – 146

3

Turn

154 – 156

3

Beta strand

157 – 159

3

Beta strand

165 – 167

3

Helix

194 – 197

4

Helix

206 – 220

15

Helix

230 – 241

12

Helix

246 – 250

5

Helix

254 – 260

7

Helix

271 – 274

4

Helix

277 – 279

3

Helix

288 – 301

14

Helix

306 – 308

3

Helix

312 – 317

6

Turn

319 – 321

3

Helix

322 – 324

3

Helix

327 – 330

4

Helix

351 – 361

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 2 (JNK1-alpha-2) [UniParc]. Last modified November 1, 1997. Version 2. Checksum: 94FB6BE0358B9B60	FASTA	427	48,296
	10 20 30 40 50 60 MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 70 80 90 100 110 120 FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 130 140 150 160 170 180 MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTAGTSF 190 200 210 220 230 240 MMTPYVVTRY YRAPEVILGM GYKENVDLWS VGCIMGEMVC HKILFPGRDY IDQWNKVIEQ 250 260 270 280 290 300 LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 310 320 330 340 350 360 MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 370 380 390 400 410 420 MDLEERTKNG VIRGQPSPLG AAVINGSQHP SSSSSVNDVS SMSTDPTLAS DTDSSLEAAA GPLGCCR
	Isoform 1 (JNK1-alpha-1) [UniParc]. Checksum: A7320EF933E9CF85		384	44,229
	10 20 30 40 50 60 MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 70 80 90 100 110 120 FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 130 140 150 160 170 180 MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTAGTSF 190 200 210 220 230 240 MMTPYVVTRY YRAPEVILGM GYKENVDLWS VGCIMGEMVC HKILFPGRDY IDQWNKVIEQ 250 260 270 280 290 300 LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 310 320 330 340 350 360 MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 370 380 MDLEERTKNG VIRGQPSPLA QVQQ
	Isoform 3 (JNK1-beta-1) [UniParc]. Checksum: 76E49A950E64C1A1		384	44,022
	10 20 30 40 50 60 MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 70 80 90 100 110 120 FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 130 140 150 160 170 180 MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTAGTSF 190 200 210 220 230 240 MMTPYVVTRY YRAPEVILGM GYKENVDIWS VGCIMGEMIK GGVLFPGTDH IDQWNKVIEQ 250 260 270 280 290 300 LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 310 320 330 340 350 360 MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 370 380 MDLEERTKNG VIRGQPSPLA QVQQ
	Isoform 4 (JNK1-beta-2) [UniParc]. Checksum: 3F5CC3F6A4F3EF2D		427	48,088
	10 20 30 40 50 60 MSRSKRDNNF YSVEIGDSTF TVLKRYQNLK PIGSGAQGIV CAAYDAILER NVAIKKLSRP 70 80 90 100 110 120 FQNQTHAKRA YRELVLMKCV NHKNIIGLLN VFTPQKSLEE FQDVYIVMEL MDANLCQVIQ 130 140 150 160 170 180 MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTAGTSF 190 200 210 220 230 240 MMTPYVVTRY YRAPEVILGM GYKENVDIWS VGCIMGEMIK GGVLFPGTDH IDQWNKVIEQ 250 260 270 280 290 300 LGTPCPEFMK KLQPTVRTYV ENRPKYAGYS FEKLFPDVLF PADSEHNKLK ASQARDLLSK 310 320 330 340 350 360 MLVIDASKRI SVDEALQHPY INVWYDPSEA EAPPPKIPDK QLDEREHTIE EWKELIYKEV 370 380 390 400 410 420 MDLEERTKNG VIRGQPSPLG AAVINGSQHP SSSSSVNDVS SMSTDPTLAS DTDSSLEAAA GPLGCCR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain." Derijard B., Hibi M., Wu I.-H., Barrett T., Su B., Deng T., Karin M., Davis R.J. Cell 76:1025-1037(1994) [PubMed: 8137421] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal brain.
[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], ALTERNATIVE SPLICING. Tissue: Brain.
[3]	"Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms." Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J., Ulevitch R.J., Davis R.J. Science 267:682-685(1995) [PubMed: 7839144] [Abstract] Cited for: MUTAGENESIS.
[4]	"Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7." Fleming Y., Armstrong C.G., Morrice N., Paterson A., Goedert M., Cohen P. Biochem. J. 352:145-154(2000) [PubMed: 11062067] [Abstract] Cited for: REGULATION BY MAP2K4 AND MAP2K7, COFACTOR.
[5]	"JNK1 physically interacts with WW domain-containing oxidoreductase (WOX1) and inhibits WOX1-mediated apoptosis." Chang N.-S., Doherty J., Ensign A. J. Biol. Chem. 278:9195-9202(2003) [PubMed: 12514174] [Abstract] Cited for: INTERACTION WITH WWOX AND TP53.
[6]	"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.
[7]	"Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26." Hu Y., Mivechi N.F. Mol. Cell. Biol. 26:3282-3294(2006) [PubMed: 16581800] [Abstract] Cited for: FUNCTION, INTERACTION WITH HSF4.
[8]	"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-185, MASS SPECTROMETRY. Tissue: Lung.
[9]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-255; THR-258; TYR-259; TYR-357 AND THR-367, MASS SPECTROMETRY. Tissue: Epithelium.
[10]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-183 AND TYR-185, MASS SPECTROMETRY.
[11]	"Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1." Murata T., Shinozuka Y., Obata Y., Yokoyama K.K. Anal. Biochem. 376:115-121(2008) [PubMed: 18307971] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF JDP2.
[12]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCA