P45985 (MP2K4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Dual specificity mitogen-activated protein kinase kinase 4
Short name=MAP kinase kinase 4
Short name=MAPKK 4
EC=2.7.12.2

Alternative name(s):
JNK-activating kinase 1
MAPK/ERK kinase 4
Short name=MEK 4
SAPK/ERK kinase 1
Short name=SEK1
Stress-activated protein kinase kinase 1
Short name=SAPK kinase 1
Short name=SAPKK-1
Short name=SAPKK1
c-Jun N-terminal kinase kinase 1
Short name=JNKK

Gene names

Name:	MAP2K4
Synonyms:	JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	399 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14. Ref.2
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Activated in response to a variety of cellular stresses, including UV and gamma-irradiation, heat shock, hyperosmolarity, T-cell receptor stimulation, peroxide and inflammatory cytokines. Also activated by developmental cues. MAP2K4/MKK4 is activated by the majority of MKKKs, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2, MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK. Ref.11
Subunit structure	Interacts with SPAG9 By similarity. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3, MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with ARRB1, ARRB2 and MAPK8IP3/JIP3. Ref.11 Ref.13 Ref.14 Ref.15 Ref.18
Subcellular location	Cytoplasm By similarity. Nucleus By similarity.
Tissue specificity	Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.
Domain	The DVD domain (residues 364-387) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation. Ref.15 Ref.16 The D domain (residues 34-52) contains a conserved docking site and is required for the binding to MAPK substrates. Ref.15 Ref.16
Post-translational modification	Activated by phosphorylation on Ser-257 and Thr-261 by MAP kinase kinase kinases (MAP3Ks).
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
Biological process	Apoptosis Stress response
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Traceable author statement. Source: Reactome MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cellular response to mechanical stimulus Inferred from expression pattern PubMed 19593445. Source: UniProtKB innate immune response Traceable author statement. Source: Reactome toll-like receptor 10 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 5 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 9 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR1:TLR2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor TLR6:TLR2 signaling pathway Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein kinase activity Traceable author statement Ref.2. Source: ProtInc 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	3	EBI-447868,EBI-49776

Alternative products

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

Isoform 1 (identifier: P45985-1)

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 2 (identifier: P45985-2)

The sequence of this isoform differs from the canonical sequence as follows:
     39-39: G → GFQINFCEKAQS

Note: No experimental confirmation available.

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

Region

37 – 52

16

D domain

Region

364 – 387

24

DVD domain

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.17

Modified residue

257

1

Phosphoserine; by MAP3K Ref.20

Modified residue

261

1

Phosphothreonine; by MAP3K

Natural variations

Alternative sequence

39

1

G → GFQINFCEKAQS in isoform 2.

VSP_038838

Natural variant

16

1

S → R. Ref.10
Corresponds to variant rs17855590 [ dbSNP | Ensembl ].

VAR_062963

Natural variant

142

1

Q → L in a lung squamous cell carcinoma sample; somatic mutation. Ref.26

VAR_040818

Natural variant

154

1

R → W in a colorectal adenocarcinoma sample; somatic mutation. Ref.26

VAR_040819

Natural variant

234

1

N → I in an ovarian serous carcinoma sample; somatic mutation. Ref.26

VAR_040820

Natural variant

251

1

S → N in a metastatic melanoma sample; somatic mutation. Ref.26

VAR_040821

Natural variant

279

1

A → T in a colorectal adenocarcinoma sample; somatic mutation. Ref.26

VAR_040822

Experimental info

Sequence conflict

118

1

K → R in CAG38801. Ref.4

Sequence conflict

179

1

E → G in BAG35884. Ref.6

Sequence conflict

356

1

P → L in AAH60764. Ref.10

Secondary structure

1

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399

Helix Strand Turn

Details...

Beta strand

85 – 88

4

Beta strand

93 – 95

3

Beta strand

101 – 103

3

Beta strand

107 – 110

4

Beta strand

112 – 121

10

Turn

122 – 124

3

Beta strand

127 – 134

8

Helix

139 – 153

15

Beta strand

164 – 169

6

Beta strand

171 – 178

8

Beta strand

182 – 184

3

Helix

185 – 194

10

Helix

202 – 223

22

Helix

232 – 234

3

Beta strand

235 – 237

3

Beta strand

243 – 245

3

Beta strand

249 – 251

3

Beta strand

267 – 270

4

Helix

272 – 274

3

Helix

287 – 302

16

Beta strand

312 – 314

3

Beta strand

316 – 321

6

Helix

338 – 347

10

Helix

352 – 354

3

Helix

358 – 361

4

Helix

365 – 372

8

Helix

377 – 387

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 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
	Isoform 2 [UniParc]. Checksum: 097F8966398DD6C0	FASTA	410	45,584
	10 20 30 40 50 60 MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGF QINFCEKAQS KRKALKLNFA 70 80 90 100 110 120 NPPFKSTARF TLNPNPTGVQ NPHIERLRTH SIESSGKLKI SPEQHWDFTA EDLKDLGEIG 130 140 150 160 170 180 RGAYGSVNKM VHKPSGQIMA VKRIRSTVDE KEQKQLLMDL DVVMRSSDCP YIVQFYGALF 190 200 210 220 230 240 REGDCWICME LMSTSFDKFY KYVYSVLDDV IPEEILGKIT LATVKALNHL KENLKIIHRD 250 260 270 280 290 300 IKPSNILLDR SGNIKLCDFG ISGQLVDSIA KTRDAGCRPY MAPERIDPSA SRQGYDVRSD 310 320 330 340 350 360 VWSLGITLYE LATGRFPYPK WNSVFDQLTQ VVKGDPPQLS NSEEREFSPS FINFVNLCLT 370 380 390 400 410 KDESKRPKYK ELLKHPFILM YEERAVEVAC YVCKILDQMP ATPSSPMYVD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Brain.
[2]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]	"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] (ISOFORM 1).
[6]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain and Thalamus.
[7]	NIEHS SNPs program Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[8]	"DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage." Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., Chang J.L. , Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C. Nature 440:1045-1049(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	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 (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ARG-16. Tissue: Brain and Testis.
[11]	"MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6." Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R., Lassam N.J. EMBO J. 15:7026-7035(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION, ENZYME REGULATION, INTERACTION WITH MAP3K11/MLK3.
[12]	"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] [Europe PMC] [Abstract] Cited for: CLEAVAGE BY ANTHRAX LETHAL FACTOR.
[13]	"Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3." McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T., Davis R.J., Lefkowitz R.J. Science 290:1574-1577(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ARRB2.
[14]	"Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade." Matsuura H., Nishitoh H., Takeda K., Matsuzawa A., Amagasa T., Ito M., Yoshioka K., Ichijo H. J. Biol. Chem. 277:40703-40709(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAPK8IP3/JIP3.
[15]	"A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates." Ho D.T., Bardwell A.J., Abdollahi M., Bardwell L. J. Biol. Chem. 278:32662-32672(2003) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN, INTERACTION WITH MAPK8/JNK1; MAPK9/JNK2; MAPK10/JNK3; MAPK11 AND MAPK14.
[16]	"Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases." Takekawa M., Tatebayashi K., Saito H. Mol. Cell 18:295-306(2005) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN.
[17]	"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] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[18]	"A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex." Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C., Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S. FEBS Lett. 583:3310-3316(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ARRB1 AND ARRB2.
[19]	"Differential regulation and properties of MAPKs." Raman M., Chen W., Cobb M.H. Oncogene 26:3100-3112(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ENZYME REGULATION.
[20]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, MASS SPECTROMETRY.
[21]	"Diverse physiological functions of MKK4 and MKK7 during early embryogenesis." Asaoka Y., Nishina H. J. Biochem. 148:393-401(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[22]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[23]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[24]	"The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7." Haeusgen W., Herdegen T., Waetzig V. Eur. J. Cell Biol. 90:536-544(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON REGULATION, REVIEW ON FUNCTION.
[25]	"Crystal structures of MKK4 kinase domain reveal that substrate peptide binds to an allosteric site and induces an auto-inhibition state." Matsumoto T., Kinoshita T., Kirii Y., Yokota K., Hamada K., Tada T. Biochem. Biophys. Res. Commun. 400:369-373(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 80-399.
[26]	"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] [Europe PMC] [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

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L36870 mRNA. Translation: AAC41719.1.
U17743 mRNA. Translation: AAC50127.1.
AF070090 , AF070080, AF070081, AF070082, AF070083, AF070084, AF070085, AF070086, AF070087, AF070088, AF070089 Genomic DNA. Translation: AAC24130.1.
CR536564 mRNA. Translation: CAG38801.1.
BT019676 mRNA. Translation: AAV38482.1.
AK131544 mRNA. Translation: BAG54774.1.
AK313053 mRNA. Translation: BAG35884.1.
DQ015703 Genomic DNA. Translation: AAY22176.1.
AC005244 Genomic DNA. No translation available.
AC005410 Genomic DNA. No translation available.
CH471108 Genomic DNA. Translation: EAW89975.1.
CH471108 Genomic DNA. Translation: EAW89974.1.
CH471108 Genomic DNA. Translation: EAW89976.1.
BC036032 mRNA. Translation: AAH36032.1.
BC060764 mRNA. Translation: AAH60764.1.

IPI

IPI00024674.
IPI00942214.

PIR

I38901.

RefSeq

NP_003001.1. NM_003010.2.

UniGene

Hs.514681.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3ALN	X-ray	2.30	A/B/C	80-399	[»]
3ALO	X-ray	2.60	A	80-399	[»]
3VUT	X-ray	3.50	A/B	80-399	[»]

ProteinModelPortal

P45985.

ModBase

Search...

Protein-protein interaction databases

IntAct

P45985. 4 interactions.

MINT

MINT-151438.

STRING

9606.ENSP00000262445.

PTM databases

PhosphoSite

P45985.

Polymorphism databases

DMDM

1170596.

Proteomic databases

PaxDb

P45985.

PRIDE

P45985.

Protocols and materials databases

DNASU

6416.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000353533; ENSP00000262445; ENSG00000065559.
ENST00000415385; ENSP00000410402; ENSG00000065559.

GeneID

6416.

KEGG

hsa:6416.

UCSC

uc002gnj.3. human.
uc002gnk.3. human.

Organism-specific databases

CTD

6416.

GeneCards

GC17P011864.

HGNC

HGNC:6844. MAP2K4.

HPA

CAB007751.

MIM

601335. gene.

neXtProt

NX_P45985.

PharmGKB

PA30589.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOVERGEN

HBG108518.

InParanoid

P45985.

KO

K04430.

OMA

GITLMEV.

OrthoDB

EOG479F76.

PhylomeDB

P45985.

Enzyme and pathway databases

BRENDA

2.7.12.2. 2681.

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.

Reactome

REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.

SignaLink

P45985.

Gene expression databases

Bgee

P45985.

CleanEx

HS_MAP2K4.

Genevestigator

P45985.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P45985.

ChEMBL

CHEMBL2897.

ChiTaRS

MAP2K4. human.

EvolutionaryTrace

P45985.

GenomeRNAi

6416.

NextBio

24922.

PMAP-CutDB

P45985.

SOURCE

Search...

Entry information

Entry name

MP2K4_HUMAN

Accession

Primary (citable) accession number: P45985
Secondary accession number(s): B2R7N7 , B3KYB2, D3DTS5, Q5U0B8, Q6FHX4, Q6P9H2, Q6PIE6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	November 1, 1995
Last modified:	May 29, 2013
This is version 136 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.