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Q99759 (M3K3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 151. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mitogen-activated protein kinase kinase kinase 3

EC=2.7.11.25
Alternative name(s):
MAPK/ERK kinase kinase 3
Short name=MEK kinase 3
Short name=MEKK 3
Gene names
Name:MAP3K3
Synonyms:MAPKKK3, MEKK3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length626 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators. Ref.1 Ref.8 Ref.9 Ref.10

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Enzyme regulation

Activated by phosphorylation on Thr-530 By similarity.

Subunit structure

Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a complex with MAP2K3, RAC1 and CCM2. Interacts with MAP2K5 and SPAG9. Ref.8 Ref.9 Ref.10

Post-translational modification

Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its activity.

Sequence similarities

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

Contains 1 OPR domain.

Contains 1 protein kinase domain.

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q99759-1)

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: Q99759-2)

The sequence of this isoform differs from the canonical sequence as follows:
     42-42: Q → QKKHNSSSSALLNSPTVTTSSCAGASEKKKFL

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 626626Mitogen-activated protein kinase kinase kinase 3
PRO_0000086245

Regions

Domain44 – 12380OPR
Domain362 – 622261Protein kinase
Nucleotide binding368 – 3769ATP By similarity

Sites

Active site4891Proton acceptor By similarity
Binding site3911ATP By similarity

Amino acid modifications

Modified residue1661Phosphoserine; by SGK1 Ref.7
Modified residue2501Phosphoserine Ref.11 Ref.12
Modified residue3371Phosphoserine; by SGK1 Ref.7 Ref.11 Ref.12 Ref.13
Modified residue3401Phosphoserine Ref.11 Ref.12 Ref.13

Natural variations

Alternative sequence421Q → QKKHNSSSSALLNSPTVTTS SCAGASEKKKFL in isoform 2.
VSP_035967
Natural variant2811V → M. Ref.14
Corresponds to variant rs36109904 [ dbSNP | Ensembl ].
VAR_040685
Natural variant3251A → G.
Corresponds to variant rs34042309 [ dbSNP | Ensembl ].
VAR_037275
Natural variant4351A → G.
Corresponds to variant rs9910858 [ dbSNP | Ensembl ].
VAR_037276

Experimental info

Sequence conflict1351G → E in AAB41729. Ref.1

Secondary structure

................ 626
Helix Strand Turn

Details...

Sequences

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

Last modified November 13, 2007. Version 2.
Checksum: 28129168A57571DD

FASTA62670,898
        10         20         30         40         50         60 
MDEQEALNSI MNDLVALQMN RRHRMPGYET MKNKDTGHSN RQSDVRIKFE HNGERRIIAF 

        70         80         90        100        110        120 
SRPVKYEDVE HKVTTVFGQP LDLHYMNNEL SILLKNQDDL DKAIDILDRS SSMKSLRILL 

       130        140        150        160        170        180 
LSQDRNHNSS SPHSGVSRQV RIKASQSAGD INTIYQPPEP RSRHLSVSSQ NPGRSSPPPG 

       190        200        210        220        230        240 
YVPERQQHIA RQGSYTSINS EGEFIPETSE QCMLDPLSSA ENSLSGSCQS LDRSADSPSF 

       250        260        270        280        290        300 
RKSRMSRAQS FPDNRQEYSD RETQLYDKGV KGGTYPRRYH VSVHHKDYSD GRRTFPRIRR 

       310        320        330        340        350        360 
HQGNLFTLVP SSRSLSTNGE NMGLAVQYLD PRGRLRSADS ENALSVQERN VPTKSPSAPI 

       370        380        390        400        410        420 
NWRRGKLLGQ GAFGRVYLCY DVDTGRELAS KQVQFDPDSP ETSKEVSALE CEIQLLKNLQ 

       430        440        450        460        470        480 
HERIVQYYGC LRDRAEKTLT IFMEYMPGGS VKDQLKAYGA LTESVTRKYT RQILEGMSYL 

       490        500        510        520        530        540 
HSNMIVHRDI KGANILRDSA GNVKLGDFGA SKRLQTICMS GTGMRSVTGT PYWMSPEVIS 

       550        560        570        580        590        600 
GEGYGRKADV WSLGCTVVEM LTEKPPWAEY EAMAAIFKIA TQPTNPQLPS HISEHGRDFL 

       610        620 
RRIFVEARQR PSAEELLTHH FAQLMY 

« Hide

Isoform 2 [UniParc].

Checksum: DF37E5E568FE937E
Show »

FASTA65774,089

References

« Hide 'large scale' references
[1]"Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein kinase/ERK kinase kinase 3 (MEKK) derivative."
Ellinger-Ziegelbauer H.C., Brown K., Kelly K., Siebenlist U.
J. Biol. Chem. 272:2668-2674(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[2]"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. expand/collapse author list , 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 1).
Tissue: Placenta.
[3]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Melanoma.
[4]"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. expand/collapse author list , 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].
[5]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. expand/collapse author list , 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].
[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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain and PNS.
[7]"Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1."
Chun J., Kwon T., Kim D.J., Park I., Chung G., Lee E.J., Hong S.K., Chang S.I., Kim H.Y., Kang S.S.
J. Biochem. 133:103-108(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-166 AND SER-337 BY SGK1.
[8]"PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway."
Nakamura K., Johnson G.L.
J. Biol. Chem. 278:36989-36992(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MAP2K5.
[9]"Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3."
Huang Q., Yang J., Lin Y., Walker C., Cheng J., Liu Z.G., Su B.
Nat. Immunol. 5:98-103(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRAF6.
[10]"A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway."
Bouwmeester T., Bauch A., Ruffner H., Angrand P.-O., Bergamini G., Croughton K., Cruciat C., Eberhard D., Gagneur J., Ghidelli S., Hopf C., Huhse B., Mangano R., Michon A.-M., Schirle M., Schlegl J., Schwab M., Stein M.A. expand/collapse author list , Bauer A., Casari G., Drewes G., Gavin A.-C., Jackson D.B., Joberty G., Neubauer G., Rick J., Kuster B., Superti-Furga G.
Nat. Cell Biol. 6:97-105(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRAF7.
[11]"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-250; SER-337 AND SER-340, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"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-250; SER-337 AND SER-340, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-337 AND SER-340, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[14]"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: VARIANT [LARGE SCALE ANALYSIS] MET-281.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U78876 mRNA. Translation: AAB41729.1.
AK315305 mRNA. Translation: BAG37709.1.
AL834303 mRNA. Translation: CAD38973.1.
AC046185 Genomic DNA. No translation available.
CH471109 Genomic DNA. Translation: EAW94297.1.
CH471109 Genomic DNA. Translation: EAW94298.1.
CH471109 Genomic DNA. Translation: EAW94299.1.
BC090859 mRNA. Translation: AAH90859.1.
BC093672 mRNA. Translation: AAH93672.1.
BC093674 mRNA. Translation: AAH93674.1.
RefSeqNP_002392.2. NM_002401.3.
NP_976226.1. NM_203351.1.
UniGeneHs.29282.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2C60X-ray1.25A37-124[»]
2JRHNMR-A42-126[»]
2O2VX-ray1.83B37-124[»]
2PPHNMR-A42-126[»]
ProteinModelPortalQ99759.
SMRQ99759. Positions 43-122, 325-624.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110379. 33 interactions.
DIPDIP-27521N.
IntActQ99759. 25 interactions.
MINTMINT-272157.
STRING9606.ENSP00000354927.

Chemistry

BindingDBQ99759.
ChEMBLCHEMBL5970.
GuidetoPHARMACOLOGY2078.

PTM databases

PhosphoSiteQ99759.

Polymorphism databases

DMDM160332306.

Proteomic databases

PaxDbQ99759.
PRIDEQ99759.

Protocols and materials databases

DNASU4215.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000361357; ENSP00000354927; ENSG00000198909. [Q99759-2]
ENST00000361733; ENSP00000354485; ENSG00000198909. [Q99759-1]
ENST00000579585; ENSP00000461988; ENSG00000198909. [Q99759-2]
GeneID4215.
KEGGhsa:4215.
UCSCuc002jbe.3. human. [Q99759-2]
uc002jbg.3. human. [Q99759-1]

Organism-specific databases

CTD4215.
GeneCardsGC17P061699.
HGNCHGNC:6855. MAP3K3.
HPACAB007764.
HPA035410.
HPA035411.
MIM602539. gene.
neXtProtNX_Q99759.
PharmGKBPA30599.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000049130.
HOVERGENHBG006303.
KOK04421.
OMAQALHSIM.
OrthoDBEOG747PHJ.
PhylomeDBQ99759.
TreeFamTF105113.

Enzyme and pathway databases

BRENDA2.7.12.2. 2681.
ReactomeREACT_6900. Immune System.
SignaLinkQ99759.

Gene expression databases

ArrayExpressQ99759.
BgeeQ99759.
CleanExHS_MAP3K3.
GenevestigatorQ99759.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000270. OPR_PB1.
IPR000719. Prot_kinase_dom.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
[Graphical view]
PfamPF00564. PB1. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00666. PB1. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAP3K3. human.
EvolutionaryTraceQ99759.
GeneWikiMAP3K3.
GenomeRNAi4215.
NextBio16621.
PROQ99759.
SOURCESearch...

Entry information

Entry nameM3K3_HUMAN
AccessionPrimary (citable) accession number: Q99759
Secondary accession number(s): B2RCW2 expand/collapse secondary AC list , D3DU15, Q5BKZ6, Q8N3I9
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 13, 2007
Last modified: April 16, 2014
This is version 151 of the entry and version 2 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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

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 17

Human chromosome 17: entries, gene names and cross-references to MIM