Reviewed, UniProtKB/Swiss-Prot P52564 (MP2K6_HUMAN)

Names and origin

Protein names

Recommended name:
    Dual specificity mitogen-activated protein kinase kinase 6
      Short name=MAP kinase kinase 6
      Short name=MAPKK 6
    EC=2.7.12.2
Alternative name(s):
    MAPK/ERK kinase 6
    SAPKK3

Gene names

Name:	MAP2K6
Synonyms:	MEK6, MKK6, PRKMK6

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	334 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in MAP kinase p38 exclusively.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Probably activated by dual phosphorylation on Ser-207 and Thr-211.
Subunit structure	Interacts with Yersinia yopJ.
Tissue specificity	Isoform 2 is only expressed in skeletal muscle. Isoform 1, on the other hand, is found in skeletal muscle, heart, and in lesser extent in liver or pancreas. Ref.3
Induction	Strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, NGF or EGF.
Post-translational modification	Weakly autophosphorylated. Ref.8 Ref.9 Acetylation of Ser-207 and Thr-211 by Yersinia yopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.
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	Alternative splicing
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	DNA damage induced protein phosphorylation Traceable author statement. Source: ProtInc cell cycle arrest Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase activity Traceable author statement. Source: ProtInc 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
PKN1	Q16512	1	EBI-448135,EBI-602382

Alternative products

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

Isoform 1 (identifier: P52564-1)

Also known as: MKK6b;

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: P52564-2)

Also known as: MKK6;

The sequence of this isoform differs from the canonical sequence as follows:
     1-56: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 334

334

Dual specificity mitogen-activated protein kinase kinase 6

PRO_0000086386

Regions

Domain

53 – 314

262

Protein kinase

Nucleotide binding

59 – 67

9

ATP By similarity

Sites

Active site

179

1

Proton acceptor By similarity

Binding site

82

1

ATP By similarity

Site

14 – 15

2

Cleavage; by anthrax lethal factor

Amino acid modifications

Modified residue

28

1

Phosphothreonine Ref.9

Modified residue

82

1

N6-acetyllysine Ref.11

Modified residue

207

1

O-acetylserine; by Yersinia yopJ; alternate

Modified residue

207

1

Phosphoserine; alternate Ref.8

Modified residue

211

1

O-acetylthreonine; by Yersinia yopJ; alternate

Modified residue

211

1

Phosphothreonine; alternate Ref.8

Natural variations

Alternative sequence

1 – 56

56

Missing in isoform 2.

VSP_004882

Experimental info

Mutagenesis

207

1

S → A: Inactivation.

Mutagenesis

207

1

S → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675.

Mutagenesis

211

1

T → A: Inactivation.

Mutagenesis

211

1

T → E: Constitutive activation according to PubMed:8622669, but not to PubMed:8621675.

Sequence conflict

125

1

V → M in AAB03705. Ref.3

Sequence conflict

125

1

V → M in AAB03708. Ref.3

Secondary structure

1

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334

Helix Strand Turn

Details...

Helix

50 – 52

3

Beta strand

53 – 58

6

Beta strand

67 – 72

6

Beta strand

78 – 84

7

Helix

90 – 104

15

Beta strand

125 – 130

6

Beta strand

133 – 135

3

Helix

136 – 145

10

Turn

152 – 154

3

Helix

158 – 172

15

Helix

182 – 184

3

Beta strand

193 – 196

4

Helix

222 – 225

4

Helix

236 – 242

7

Helix

246 – 252

7

Helix

263 – 272

10

Turn

280 – 282

3

Helix

285 – 294

10

Helix

299 – 301

3

Helix

305 – 308

4

Helix

312 – 319

8

Helix

324 – 331

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (MKK6b) [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 4ECA8014522216AF	FASTA	334	37,492
	10 20 30 40 50 60 MSQSKGKKRN PGLKIPKEAF EQPQTSSTPP RDLDSKACIS IGNQNFEVKA DDLEPIMELG 70 80 90 100 110 120 RGAYGVVEKM RHVPSGQIMA VKRIRATVNS QEQKRLLMDL DISMRTVDCP FTVTFYGALF 130 140 150 160 170 180 REGDVWICME LMDTSLDKFY KQVIDKGQTI PEDILGKIAV SIVKALEHLH SKLSVIHRDV 190 200 210 220 230 240 KPSNVLINAL GQVKMCDFGI SGYLVDSVAK TIDAGCKPYM APERINPELN QKGYSVKSDI 250 260 270 280 290 300 WSLGITMIEL AILRFPYDSW GTPFQQLKQV VEEPSPQLPA DKFSAEFVDF TSQCLKKNSK 310 320 330 ERPTYPELMQ HPFFTLHESK GTDVASFVKL ILGD
	Isoform 2 (MKK6). Checksum: 1EE7FC1B26B11AE4	FASTA	278	31,339
	10 20 30 40 50 60 MELGRGAYGV VEKMRHVPSG QIMAVKRIRA TVNSQEQKRL LMDLDISMRT VDCPFTVTFY 70 80 90 100 110 120 GALFREGDVW ICMELMDTSL DKFYKQVIDK GQTIPEDILG KIAVSIVKAL EHLHSKLSVI 130 140 150 160 170 180 HRDVKPSNVL INALGQVKMC DFGISGYLVD SVAKTIDAGC KPYMAPERIN PELNQKGYSV 190 200 210 220 230 240 KSDIWSLGIT MIELAILRFP YDSWGTPFQQ LKQVVEEPSP QLPADKFSAE FVDFTSQCLK 250 260 270 KNSKERPTYP ELMQHPFFTL HESKGTDVAS FVKLILGD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway." Raingeaud J., Whitmarsh A.J., Barrett T., Derijard B., Davis R.J. Mol. Cell. Biol. 16:1247-1255(1996) [PubMed: 8622669] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS. Tissue: Skeletal muscle.
[2]	"Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade." Stein B., Brady H., Yang M.X., Young D.B., Barbosa M.S. J. Biol. Chem. 271:11427-11433(1996) [PubMed: 8626699] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: T-cell.
[3]	"Characterization of the structure and function of a novel MAP kinase kinase (MKK6)." Han J., Lee J.-D., Jiang Y., Li Z., Feng L., Ulevitch R.J. J. Biol. Chem. 271:2886-2891(1996) [PubMed: 8621675] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, MUTAGENESIS. Tissue: Placenta.
[4]	"A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3." Moriguchi T., Kuroyanagi N., Yamaguchi K., Gotoh Y., Irie K., Kano T., Shirakabe K., Muro Y., Shibuya H., Matsumoto K., Nishida E., Hagiwara M. J. Biol. Chem. 271:13675-13679(1996) [PubMed: 8663074] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[5]	"Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells." Cuenda A., Alonso G., Morrice N., Jones M., Meier R., Cohen P., Nebreda A.R. EMBO J. 15:4156-4164(1996) [PubMed: 8861944] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]	"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 1). Tissue: Urinary bladder.
[7]	"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.
[8]	"Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation." Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J., Orth K. Science 312:1211-1214(2006) [PubMed: 16728640] [Abstract] Cited for: ACETYLATION AT SER-207 AND THR-211, PHOSPHORYLATION AT SER-207 AND THR-211, INACTIVATION BY YERSINIA YOPJ, MASS SPECTROMETRY.
[9]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-28, MASS SPECTROMETRY.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-82, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

U39657 mRNA. Translation: AAC50389.1.
U39656 mRNA. Translation: AAC50388.1.
U49732 mRNA. Translation: AAB05035.1.
U39065 mRNA. Translation: AAB03705.1.
U39064 mRNA. Translation: AAB03708.1.
D87905 mRNA. Translation: BAA13496.1.
X96757 mRNA. Translation: CAA65532.1.
BC012009 mRNA. Translation: AAH12009.1.

IPI

IPI00003814.
IPI00219569.

PIR

S71631.

RefSeq

NP_002749.2.

UniGene

Hs.463978

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3ENM	X-ray	2.35	A/B/C/D	45-332	[»]
3FME	X-ray	2.26	A	47-334	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P52564. 5 interactions.

STRING

P52564.

PTM databases

PhosphoSite

P52564.

Proteomic databases

PRIDE

P52564.

Genome annotation databases

Ensembl

ENST00000359094; ENSP00000351997; ENSG00000108984; Homo sapiens. [Genome view]
ENST00000435374; ENSP00000409228; ENSG00000108984; Homo sapiens. [Genome view]

GeneID

5608.

KEGG

hsa:5608.

UCSC

uc002jij.1. human.

Organism-specific databases

CTD

5608.

GeneCards

GC17P064922.

H-InvDB

HIX0017658.

HGNC

HGNC:6846. MAP2K6.

HPA

CAB007744.

MIM

601254. gene.

PharmGKB

PA30591.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P52564.

HOVERGEN

P52564.

OMA

TESAVAM.

Enzyme and pathway databases

BRENDA

2.7.12.2. 247.

Pathway_Interaction_DB

anthraxpathway. Cellular roles of Anthrax toxin.
il1pathway. IL1-mediated signaling events.
il12_2pathway. IL12-mediated signaling events.
il6_7pathway. IL6-mediated signaling events.
p38_mkk3_6pathway. p38 MAPK signaling pathway.
ar_tf_pathway. Regulation of Androgen receptor activity.
p38alphabetapathway. Regulation of p38-alpha and p38-beta.
p38gammadeltapathway. Signaling mediated by p38-gamma and p38-delta.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Gene expression databases

ArrayExpress

P52564.

Bgee

P52564.

CleanEx

HS_MAP2K6.

Genevestigator

P52564.

GermOnline

ENSG00000108984. Homo sapiens.

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

21798.

PMAP-CutDB

P52564.

SOURCE

Search...

Entry information

Entry name

MP2K6_HUMAN

Accession

Primary (citable) accession number: P52564

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	November 3, 2009
This is version 99 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.