P49185 (MK08_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase 8
Short name=MAP kinase 8
Short name=MAPK 8
EC=2.7.11.24

Alternative name(s):
SAPK gamma
Stress-activated protein kinase JNK1
c-Jun N-terminal kinase 1
p54 gamma

Gene names

Name:	Mapk8
Synonyms:	Jnk1, Prkm8

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	411 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity. Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins. Loss of this interaction abrogates the acetylation required for replication initiation. Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation. Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy. Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons. In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone By similarity. Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH By similarity. Ref.2 Ref.5 Ref.6
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium. Ref.2
Enzyme regulation	Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. Inhibited by dual specificity phosphatases, such as DUSP1. Inhibited by SERPINB3 By similarity. Inhibited by IFN-gamma-induced S-nitrosylation.
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, WWOX and JAMP. Interacts with NFATC4. Interacts (phosphorylated form) with NFE2; the interaction phosphorylates NFE2 in undifferentiated cells. Interacts with MECOM; regulates JNK signaling. Interacts with PIN1; this interaction mediates MAPK8 conformational changes leading to the binding of MAPK8 to its substrates By similarity. Forms a complex with MAPK8IP1 and ARHGEF28. Interacts with STMN2, STMN3 and STMN4. Ref.4 Ref.5
Subcellular location	Cytoplasm. Nucleus By similarity. Note: In the cortical neurons, predominantly cytoplasmic and associated with the Golgi apparatus and endosomal fraction. Ref.5
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 by MAP2K7 and MAP2K4, which activates the enzyme. Phosphorylated by TAOK2 By similarity. Nitrosylated upon IFN-gamma-induced endogenous NO production, which inhibits 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
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein S-nitrosylation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	inflammatory response Inferred from direct assay PubMed 11435459. Source: RGD negative regulation of apoptotic process Inferred from direct assay PubMed 15309413. Source: RGD neuron projection development Inferred from mutant phenotype Ref.5. Source: RGD positive regulation of DNA replication Inferred from mutant phenotype PubMed 9487126. Source: RGD positive regulation of apoptotic process Inferred from expression pattern PubMed 16699462. Source: RGD positive regulation of cell migration Inferred from direct assay PubMed 12853963. Source: RGD positive regulation of microtubule polymerization Inferred from mutant phenotype Ref.5. Source: RGD regulation of transcription, DNA-dependent Inferred from direct assay PubMed 12011047. Source: RGD response to heat Inferred from direct assay PubMed 10772775. Source: RGD response to hydrogen peroxide Inferred from direct assay PubMed 14707549. Source: RGD response to osmotic stress Inferred from direct assay PubMed 10781376. Source: RGD response to steroid hormone stimulus Inferred from expression pattern PubMed 14512437. Source: RGD
Cellular_component	axon part Inferred from direct assay PubMed 9714150. Source: RGD cytosol Traceable author statement. Source: Reactome dendrite cytoplasm Inferred from direct assay PubMed 9714150. Source: RGD mitochondrion Inferred from direct assay PubMed 15504737. Source: RGD nucleus Inferred from direct assay PubMed 10773432PubMed 15504737PubMed 16699462. Source: RGD perikaryon Inferred from direct assay PubMed 9714150. Source: RGD vesicle Inferred from direct assay Ref.5. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 411	411	Mitogen-activated protein kinase 8		PRO_0000186264
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	116	1	S-nitrosocysteine; in inhibited form Ref.3
	Modified residue	183	1	Phosphothreonine; by MAP2K7 By similarity
	Modified residue	185	1	Phosphotyrosine; by MAP2K4 By similarity
	Modified residue	377	1	Phosphoserine By similarity
Experimental info
	Mutagenesis	116	1	C → S: Abolished inhibitory effect of IFN-gamma on JNK1 activity. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P49185 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: 04E388B4F94633D4	FASTA	411	46,807
	10 20 30 40 50 60 MSRSKRDNNF YSVEIADSTF 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 LKILFPGRDY 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 MDLEERTKNG VIRGQPSPLG AAVINGSQHP VSSPSVNDMS SMSTDPTLAS D

References

[1]	"The stress-activated protein kinase subfamily of c-Jun kinases." Kyriakis J.M., Banerjee P., Nikolakaki E., Dai T., Rubie E.A., Ahmad M.F., Avruch J., Woodgett J.R. Nature 369:156-160(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	"Stimulation of 'stress-regulated' mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses." Clerk A., Fuller S.J., Michael A., Sugden P.H. J. Biol. Chem. 273:7228-7234(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, COFACTOR. Tissue: Heart.
[3]	"Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation." Park H.S., Huh S.H., Kim M.S., Lee S.H., Choi E.J. Proc. Natl. Acad. Sci. U.S.A. 97:14382-14387(2000) [PubMed] [Europe PMC] [Abstract] Cited for: S-NITROSYLATION AT CYS-116, MUTAGENESIS OF CYS-116.
[4]	"Cytoplasmic retention sites in p190RhoGEF confer anti-apoptotic activity to an EGFP-tagged protein." Wu J., Zhai J., Lin H., Nie Z., Ge W.-W., Garcia-Bermejo L., Muschel R.J., Schlaepfer W.W., Canete-Soler R. Brain Res. Mol. Brain Res. 117:27-38(2003) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH MAPK8IP1 AND ARHGEF28.
[5]	"JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length." Tararuk T., Ostman N., Li W., Bjorkblom B., Padzik A., Zdrojewska J., Hongisto V., Herdegen T., Konopka W., Courtney M.J., Coffey E.T. J. Cell Biol. 173:265-277(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH MAPK8IP1; STMN2; STMN3 AND STMN4, SUBCELLULAR LOCATION.
[6]	"Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate." Westerlund N., Zdrojewska J., Padzik A., Komulainen E., Bjorkblom B., Rannikko E., Tararuk T., Garcia-Frigola C., Sandholm J., Nguyen L., Kallunki T., Courtney M.J., Coffey E.T. Nat. Neurosci. 14:305-313(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L27129 mRNA. Translation: AAA42111.1.
IPI	IPI00191803.
PIR	S43970.
RefSeq	NP_446281.1. NM_053829.1.
UniGene	Rn.4090.
3D structure databases
ProteinModelPortal	P49185.
SMR	P49185. Positions 7-364.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-1500743.
STRING	10116.ENSRNOP00000027338.
PTM databases
PhosphoSite	P49185.
Proteomic databases
PaxDb	P49185.
PRIDE	P49185.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	116554.
KEGG	rno:116554.
UCSC	RGD:621506. rat.
Organism-specific databases
CTD	5599.
RGD	621506. Mapk8.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233024.
HOVERGEN	HBG014652.
InParanoid	P49185.
KO	K04440.
Enzyme and pathway databases
BRENDA	2.7.11.24. 5301.
Reactome	REACT_111984. Signal Transduction.
Gene expression databases
ArrayExpress	P49185.
Genevestigator	P49185.
GermOnline	ENSRNOG00000020155. Rattus norvegicus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR003527. MAP_kinase_CS. IPR008351. MAPK_JNK. IPR000719. Prot_kinase_cat_dom. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
PRINTS	PR01772. JNKMAPKINASE.
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
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
ChEMBL	CHEMBL5718.

Entry information

Entry name

MK08_RAT

Accession

Primary (citable) accession number: P49185

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	May 29, 2013
This is version 126 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program