Reviewed, UniProtKB/Swiss-Prot P45985 (MP2K4_HUMAN)

Names and origin

Protein names

Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 4
      Short name=MAP kinase kinase 4
    EC=2.7.12.2
Alternative name(s):
    JNK-activating kinase 1
    c-Jun N-terminal kinase kinase 1
      Short name=JNKK
    SAPK/ERK kinase 1
      Short name=SEK1

Gene names

Name:	MAP2K4
Synonyms:	JNKK1, MKK4, PRKMK4, SERK1

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

General annotation (Comments)

Function	Dual specificity kinase that activates the JUN kinases MAPK8 (JNK1) and MAPK9 (JNK2) as well as MAPK14 (p38) but not MAPK1 (ERK2) or MAPK3 (ERK1).
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts with SPAG9 By similarity.
Tissue specificity	Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
Post-translational modification	Activated by phosphorylation on Ser/Thr by MAP kinase kinase kinases By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Gene Ontology (GO)
Biological process	JNK cascade Ref.1 Traceable author statement. Source: ProtInc protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MAP3K1	Q13233	2	EBI-447868,EBI-49776
MAPK8	P45983	1	EBI-447868,EBI-286483
TRIB1	Q96RU8	1	EBI-447868,EBI-492555

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 399	399	Dual specificity mitogen-activated protein kinase kinase 4		PRO_0000086381
Regions
	Domain	102 – 367	266	Protein kinase
	Nucleotide binding	108 – 116	9	ATP By similarity
	Compositional bias	5 – 19	15	Gly/Ser-rich
Sites
	Active site	229	1	Proton acceptor By similarity
	Binding site	131	1	ATP By similarity
	Site	45 – 46	2	Cleavage; by anthrax lethal factor
	Site	58 – 59	2	Cleavage; by anthrax lethal factor
Amino acid modifications
	Modified residue	90	1	Phosphoserine Ref.7
Natural variations
	Natural variant	142	1	Q → L in a lung squamous cell carcinoma sample; somatic mutation. Ref.9		VAR_040818
	Natural variant	154	1	R → W in a colorectal adenocarcinoma sample; somatic mutation. Ref.9		VAR_040819
	Natural variant	234	1	N → I in an ovarian serous carcinoma sample; somatic mutation. Ref.9		VAR_040820
	Natural variant	251	1	S → N in a metastatic melanoma sample; somatic mutation. Ref.9		VAR_040821
	Natural variant	279	1	A → T in a colorectal adenocarcinoma sample; somatic mutation. Ref.9		VAR_040822

Sequences

	Sequence		Length	Mass (Da)
	P45985-1 [UniParc]. Last modified November 1, 1995. Version 1. Checksum: A472537F2F26770B	FASTA	399	44,288
	10 20 30 40 50 60 MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN PPFKSTARFT 70 80 90 100 110 120 LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE DLKDLGEIGR GAYGSVNKMV 130 140 150 160 170 180 HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD VVMRSSDCPY IVQFYGALFR EGDCWICMEL 190 200 210 220 230 240 MSTSFDKFYK YVYSVLDDVI PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS 250 260 270 280 290 300 GNIKLCDFGI SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL 310 320 330 340 350 360 ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK DESKRPKYKE 370 380 390 LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2." Lin A., Minden A., Martinetto H., Claret F.-X., Lange-Carter C., Mercurio F., Johnson G.L., Karin M. Science 268:286-290(1995) [PubMed: 7716521] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"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: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene." Su G.H., Hilgers W., Shekher M.C., Tang D.J., Yeo C.J., Hruban R.H., Kern S.E. Cancer Res. 58:2339-2342(1998) [PubMed: 9622070] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	NIEHS SNPs program Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor." Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C. Biochem. J. 352:739-745(2000) [PubMed: 11104681] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[7]	"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 SCALE ANALYSIS] AT SER-90, MASS SPECTROMETRY.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-142; TRP-154; ILE-234; ASN-251 AND THR-279.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases
EMBLGenBankDDBJ	U17743 mRNA. Translation: AAC50127.1. L36870 mRNA. Translation: AAC41719.1. AF070090 , AF070080, AF070081, AF070082, AF070083, AF070084, AF070085, AF070086, AF070087, AF070088, AF070089 Genomic DNA. Translation: AAC24130.1. BT019676 mRNA. Translation: AAV38482.1. DQ015703 Genomic DNA. Translation: AAY22176.1.
IPI	IPI00024674.
PIR	I38901.
RefSeq	NP_003001.1.
UniGene	Hs.514681
3D structure databases
HSSP	HSSP built from PDB template 1F3M based on UniProtKB Q13153.
ModBase	Search...
Protein-protein interaction databases
IntAct	P45985. 5 interactions.
PTM databases
PhosphoSite	P45985.
Proteomic databases
PRIDE	P45985.
Genome annotation databases
Ensembl	ENSG00000065559. Homo sapiens. [Contig view]
GeneID	6416.
KEGG	hsa:6416.
NMPDR	fig|9606.3.peg.13149.
Organism-specific databases
GeneCards	GC17P011864.
H-InvDB	HIX0027148.
HGNC	HGNC:6844. MAP2K4.
HPA	CAB007751.
MIM	601335. gene.
PharmGKB	PA30589.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P45985.
HOVERGEN	P45985.
OMA	P45985. NILMDRR.
Enzyme and pathway databases
BRENDA	2.7.12.2. 247.
Pathway_Interaction_DB	anthraxpathway. Cellular roles of Anthrax toxin. ceramidepathway. Ceramide signaling pathway. ephrinbrevpathway. Ephrin B reverse signaling. faspathway. FAS signaling pathway (CD95). fcer1pathway. Fc-epsilon receptor I signaling in mast cells. il6_7pathway. IL6-mediated signaling events. tcrjnkpathway. JNK signaling in the CD4+ TCR pathway. ar_tf_pathway. Regulation of Androgen receptor activity. p38alphabetapathway. Regulation of p38-alpha and p38-beta. met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met). trail_pathway. TRAIL signaling pathway. lymphangiogenesis_pathway. VEGFR3 signaling in lymphatic endothelium.
Gene expression databases
ArrayExpress	P45985.
Bgee	P45985.
CleanEx	HS_MAP2K4.
Family and domain databases
InterPro	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]
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	24922.
PMAP-CutDB	P45985.
SOURCE	Search...

Entry information

Entry name

MP2K4_HUMAN

Accession

Primary (citable) accession number: P45985
Secondary accession number(s): Q5U0B8

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	June 16, 2009
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)