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O95382 (M3K6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 132. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 6

EC=2.7.11.25
Alternative name(s):
Apoptosis signal-regulating kinase 2
Gene names
Name:MAP3K6
Synonyms:ASK2, MAPKKK6, MEKK6
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1288 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of a protein kinase signal transduction cascade. Activates the JNK, but not ERK or p38 kinase pathways. Ref.1 Ref.5

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Activated by phosphorylation on Thr-806. Catalytically active only when complexed with MAP3K5, with MAP3K5 supporting the stability and the active configuration of MAP3K6 and MAP3K6 activating MAP3K5 by direct phosphorylation. Ref.1

Subunit structure

Binds both upstream activators and downstream substrates in multimolecular complexes.

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Contains 1 protein kinase domain.

Sequence caution

The sequence AAD05304.1 differs from that shown. Reason: Erroneous initiation.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O95382-1)

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: O95382-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-277: Missing.
     1065-1074: RLRAQGLGPA → WMNGEDKGSF
     1075-1288: Missing.
Note: No experimental confirmation available.
Isoform 3 (identifier: O95382-3)

The sequence of this isoform differs from the canonical sequence as follows:
     161-168: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 12881288Mitogen-activated protein kinase kinase kinase 6
PRO_0000086251

Regions

Domain648 – 906259Protein kinase
Nucleotide binding654 – 6629ATP By similarity
Coiled coil1004 – 102926 Potential
Coiled coil1166 – 120540 Potential

Sites

Active site7711Proton acceptor By similarity
Binding site6771ATP By similarity

Amino acid modifications

Modified residue8061Phosphothreonine By similarity
Modified residue9841Phosphoserine Ref.6 Ref.7 Ref.8
Modified residue11291Phosphoserine Ref.6 Ref.8
Modified residue11491Phosphoserine Ref.8

Natural variations

Alternative sequence1 – 277277Missing in isoform 2.
VSP_026201
Alternative sequence161 – 1688Missing in isoform 3.
VSP_026202
Alternative sequence1065 – 107410RLRAQGLGPA → WMNGEDKGSF in isoform 2.
VSP_026203
Alternative sequence1075 – 1288214Missing in isoform 2.
VSP_026204
Natural variant4551T → I. Ref.1 Ref.3
Corresponds to variant rs1138294 [ dbSNP | Ensembl ].
VAR_032832
Natural variant4991R → C.
Corresponds to variant rs11247641 [ dbSNP | Ensembl ].
VAR_046050
Natural variant5441R → W. Ref.10
Corresponds to variant rs55671988 [ dbSNP | Ensembl ].
VAR_046051
Natural variant6221N → K. Ref.4 Ref.10
Corresponds to variant rs35659744 [ dbSNP | Ensembl ].
VAR_032833
Natural variant6681R → G. Ref.10
Corresponds to variant rs55869163 [ dbSNP | Ensembl ].
VAR_046052
Natural variant6731R → L. Ref.10
Corresponds to variant rs56359841 [ dbSNP | Ensembl ].
VAR_046053
Natural variant8691P → T in a breast cancer sample; somatic mutation. Ref.9
VAR_035629
Natural variant9251S → L in a breast pleomorphic lobular carcinoma sample; somatic mutation. Ref.10
VAR_046054
Natural variant9681T → I in an ovarian endometrioid cancer sample; somatic mutation. Ref.10
VAR_046055
Natural variant9691S → N. Ref.3
Corresponds to variant rs17856498 [ dbSNP | Ensembl ].
VAR_032834
Natural variant10611A → T. Ref.10
Corresponds to variant rs55990440 [ dbSNP | Ensembl ].
VAR_046056
Natural variant12331G → A.
Corresponds to variant rs17162549 [ dbSNP | Ensembl ].
VAR_046057

Experimental info

Sequence conflict435 – 4406MQYYWD → ALWVPV in AAI29952. Ref.3
Sequence conflict435 – 4406MQYYWD → HTWVPV in AAI29951. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 3, 2009. Version 3.
Checksum: 013AF3729698080F

FASTA1,288142,596
        10         20         30         40         50         60 
MAGPCPRSGA ERAGSCWQDP LAVALSRGRQ LAAPPGRGCA RSRPLSVVYV LTREPQPGLE 

        70         80         90        100        110        120 
PREGTEAEPL PLRCLREACA QVPRPRPPPQ LRSLPFGTLE LGDTAALDAF YNADVVVLEV 

       130        140        150        160        170        180 
SSSLVQPSLF YHLGVRESFS MTNNVLLCSQ ADLPDLQALR EDVFQKNSDC VGSYTLIPYV 

       190        200        210        220        230        240 
VTATGRVLCG DAGLLRGLAD GLVQAGVGTE ALLTPLVGRL ARLLEATPTD SCGYFRETIR 

       250        260        270        280        290        300 
RDIRQARERF SGPQLRQELA RLQRRLDSVE LLSPDIIMNL LLSYRDVQDY SAIIELVETL 

       310        320        330        340        350        360 
QALPTCDVAE QHNVCFHYTF ALNRRNRPGD RAKALSVLLP LVQLEGSVAP DLYCMCGRIY 

       370        380        390        400        410        420 
KDMFFSSGFQ DAGHREQAYH WYRKAFDVEP SLHSGINAAV LLIAAGQHFE DSKELRLIGM 

       430        440        450        460        470        480 
KLGCLLARKG CVEKMQYYWD VGFYLGAQIL ANDPTQVVLA AEQLYKLNAP IWYLVSVMET 

       490        500        510        520        530        540 
FLLYQHFRPT PEPPGGPPRR AHFWLHFLLQ SCQPFKTACA QGDQCLVLVL EMNKVLLPAK 

       550        560        570        580        590        600 
LEVRGTDPVS TVTLSLLEPE TQDIPSSWTF PVASICGVSA SKRDERCCFL YALPPAQDVQ 

       610        620        630        640        650        660 
LCFPSVGHCQ WFCGLIQAWV TNPDSTAPAE EAEGAGEMLE FDYEYTETGE RLVLGKGTYG 

       670        680        690        700        710        720 
VVYAGRDRHT RVRIAIKEIP ERDSRFSQPL HEEIALHRRL RHKNIVRYLG SASQGGYLKI 

       730        740        750        760        770        780 
FMEEVPGGSL SSLLRSVWGP LKDNESTISF YTRQILQGLG YLHDNHIVHR DIKGDNVLIN 

       790        800        810        820        830        840 
TFSGLLKISD FGTSKRLAGI TPCTETFTGT LQYMAPEIID QGPRGYGKAA DIWSLGCTVI 

       850        860        870        880        890        900 
EMATGRPPFH ELGSPQAAMF QVGMYKVHPP MPSSLSAEAQ AFLLRTFEPD PRLRASAQTL 

       910        920        930        940        950        960 
LGDPFLQPGK RSRSPSSPRH APRPSDAPSA SPTPSANSTT QSQTFPCPQA PSQHPPSPPK 

       970        980        990       1000       1010       1020 
RCLSYGGTSQ LRVPEEPAAE EPASPEESSG LSLLHQESKR RAMLAAVLEQ ELPALAENLH 

      1030       1040       1050       1060       1070       1080 
QEQKQEQGAR LGRNHVEELL RCLGAHIHTP NRRQLAQELR ALQGRLRAQG LGPALLHRPL 

      1090       1100       1110       1120       1130       1140 
FAFPDAVKQI LRKRQIRPHW MFVLDSLLSR AVRAALGVLG PEVEKEAVSP RSEELSNEGD 

      1150       1160       1170       1180       1190       1200 
SQQSPGQQSP LPVEPEQGPA PLMVQLSLLR AETDRLREIL AGKEREYQAL VQRALQRLNE 

      1210       1220       1230       1240       1250       1260 
EARTYVLAPE PPTALSTDQG LVQWLQELNV DSGTIQMLLN HSFTLHTLLT YATRDDLIYT 

      1270       1280 
RIRGGMVCRI WRAILAQRAG STPVTSGP 

« Hide

Isoform 2 [UniParc].

Checksum: 8EA06171D8396464
Show »

FASTA79788,674
Isoform 3 [UniParc].

Checksum: C9763EC2F44C5790
Show »

FASTA1,280141,648

References

« Hide 'large scale' references
[1]"Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1."
Takeda K., Shimozono R., Noguchi T., Umeda T., Morimoto Y., Naguro I., Tobiume K., Saitoh M., Matsuzawa A., Ichijo H.
J. Biol. Chem. 282:7522-7531(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, ENZYME REGULATION, INTERACTION WITH MAP3K5, VARIANT ILE-455.
[2]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"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 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 435-1288 (ISOFORMS 1/3), VARIANTS ILE-455 AND ASN-969.
Tissue: Skin.
[4]Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 89-1288 (ISOFORM 3), VARIANT LYS-622.
Tissue: Brain.
[5]"MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5."
Wang X.S., Diener K., Tan T.-H., Yao Z.
Biochem. Biophys. Res. Commun. 253:33-37(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 197-1288, FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH MAP3K5.
[6]"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-984 AND SER-1129, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-984, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[8]"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-984; SER-1129 AND SER-1149, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"The consensus coding sequences of human breast and colorectal cancers."
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. expand/collapse author list , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E.
Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] THR-869.
[10]"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. expand/collapse author list , 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] TRP-544; LYS-622; GLY-668; LEU-673; LEU-925; ILE-968 AND THR-1061.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB167411 mRNA. Translation: BAD12485.1.
FO393419 Genomic DNA. No translation available.
BC015914 mRNA. Translation: AAH15914.1.
BC129950 mRNA. Translation: AAI29951.1.
BC129951 mRNA. Translation: AAI29952.1.
AB208805 mRNA. Translation: BAD92042.1.
AF100318 mRNA. Translation: AAD05304.1. Different initiation.
CCDSCCDS299.1. [O95382-1]
RefSeqNP_004663.3. NM_004672.3. [O95382-1]
XP_005246086.1. XM_005246029.2. [O95382-3]
UniGeneHs.194694.

3D structure databases

ProteinModelPortalO95382.
SMRO95382. Positions 605-950.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114524. 5 interactions.
IntActO95382. 7 interactions.
MINTMINT-7997495.
STRING9606.ENSP00000350195.

Chemistry

BindingDBO95382.
ChEMBLCHEMBL1163123.
GuidetoPHARMACOLOGY2081.

PTM databases

PhosphoSiteO95382.

Proteomic databases

MaxQBO95382.
PaxDbO95382.
PRIDEO95382.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000357582; ENSP00000350195; ENSG00000142733. [O95382-1]
ENST00000374040; ENSP00000363152; ENSG00000142733. [O95382-3]
ENST00000493901; ENSP00000419591; ENSG00000142733. [O95382-1]
GeneID9064.
KEGGhsa:9064.
UCSCuc001bny.1. human. [O95382-1]
uc001bnz.1. human. [O95382-2]
uc009vsw.1. human. [O95382-3]

Organism-specific databases

CTD9064.
GeneCardsGC01M027681.
H-InvDBHIX0000314.
HGNCHGNC:6858. MAP3K6.
HPAHPA051192.
MIM604468. gene.
neXtProtNX_O95382.
PharmGKBPA30602.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG006305.
InParanoidO95382.
KOK04425.
OMAKMQYYWD.
PhylomeDBO95382.
TreeFamTF105115.

Enzyme and pathway databases

BRENDA2.7.11.25. 2681.
SignaLinkO95382.

Gene expression databases

ArrayExpressO95382.
BgeeO95382.
CleanExHS_MAP3K6.
GenevestigatorO95382.

Family and domain databases

InterProIPR025136. DUF4071.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR013761. SAM/pointed.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF13281. DUF4071. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF47769. SSF47769. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi9064.
NextBio33967.
PROO95382.
SOURCESearch...

Entry information

Entry nameM3K6_HUMAN
AccessionPrimary (citable) accession number: O95382
Secondary accession number(s): A2ACE8 expand/collapse secondary AC list , A2VDG4, A2VDG5, Q59HF4, Q5SSD4, Q75PK3, Q96B75
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: November 3, 2009
Last modified: July 9, 2014
This is version 132 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM