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Q12851 (M4K2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 138. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | 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 kinase 2

EC=2.7.11.1
Alternative name(s):
B lymphocyte serine/threonine-protein kinase
Germinal center kinase
Short name=GC kinase
MAPK/ERK kinase kinase kinase 2
Short name=MEK kinase kinase 2
Short name=MEKKK 2
Rab8-interacting protein
Gene names
Name:MAP4K2
Synonyms:GCK, RAB8IP
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length820 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extend of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), lipid A, peptidoglycan (PGN), or bacterial flagellin. To a lesser degree, IL-1 and engagement of CD40 also stimulate MAP4K2-mediated JNKs activation. The requirement for MAP4K2/GCK is most pronounced for LPS signaling, and extends to LPS stimulation of c-Jun phosphorylation and induction of IL-8. Enhances MAP3K1 oligomerization, which may relieve N-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. Mediates also the SAP/JNK signaling pathway and the p38 MAPKs signaling pathway through activation of the MAP3Ks MAP3K10/MLK2 and MAP3K11/MLK3. May play a role in the regulation of vesicle targeting or fusion. regulation of vesicle targeting or fusion. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.4

Cofactor

Magnesium. Ref.4

Enzyme regulation

The tumor necrosis factor (TNF), as well as endotoxins and proinflammatory stimuli such as polyinosine-polycytidine (poly(IC)), lipopolysaccharides (LPS), peptidoglycan (PGN), flagellin, or lipid A activate MAP4K2 by promoting its autophosphorylation. Ref.5 Ref.8

Subunit structure

Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with RAB8A By similarity. Ref.6 Ref.7 Ref.8 Ref.9

Subcellular location

Cytoplasm By similarity. Basolateral cell membrane; Peripheral membrane protein By similarity. Golgi apparatus membrane; Peripheral membrane protein By similarity.

Tissue specificity

Highly expressed in germinal center but not mantle zone B-cells. Also expressed in lung, brain and placenta and at lower levels in other tissues examined. Ref.4

Domain

The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome. Ref.4

Post-translational modification

Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK.

Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or proinflammatory stimuli. Autophosphorylation leads to activation. Ref.6

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

Contains 1 CNH domain.

Contains 1 protein kinase domain.

Sequence caution

The sequence AAA20968.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

Ontologies

Keywords
   Biological processImmunity
Innate immunity
Stress response
   Cellular componentCell membrane
Cytoplasm
Golgi apparatus
Membrane
   Coding sequence diversityAlternative splicing
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processJNK cascade

Traceable author statement Ref.5. Source: ProtInc

activation of JUN kinase activity

Inferred from direct assay Ref.9. Source: UniProtKB

activation of MAPKKK activity

Inferred from Biological aspect of Ancestor. Source: GOC

immune response

Traceable author statement Ref.4. Source: ProtInc

innate immune response

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from direct assay Ref.7. Source: UniProtKB

positive regulation of JNK cascade

Inferred from direct assay Ref.9. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.7. Source: UniProtKB

vesicle targeting

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi membrane

Traceable author statement PubMed 8643544. Source: ProtInc

basolateral plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoplasm

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionATP binding

Inferred from direct assay Ref.7. Source: UniProtKB

MAP kinase kinase kinase kinase activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

mitogen-activated protein kinase kinase kinase binding

Inferred from physical interaction Ref.9. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.7. Source: IntAct

protein serine/threonine kinase activity

Inferred from direct assay Ref.7. Source: UniProtKB

small GTPase regulator activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

MAP3K1Q132332EBI-49783,EBI-49776

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q12851-1)

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: Q12851-2)

The sequence of this isoform differs from the canonical sequence as follows:
     426-433: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 820820Mitogen-activated protein kinase kinase kinase kinase 2
PRO_0000086275

Regions

Domain16 – 273258Protein kinase
Domain482 – 793312CNH
Nucleotide binding22 – 309ATP By similarity
Region294 – 31421PEST1
Region344 – 36017PEST2
Region405 – 44844PEST3

Sites

Active site1361Proton acceptor By similarity
Binding site451ATP By similarity

Amino acid modifications

Modified residue3941Phosphoserine Ref.12 Ref.13 Ref.14

Natural variations

Alternative sequence426 – 4338Missing in isoform 2.
VSP_054134

Experimental info

Sequence conflict1201A → R in AAA20968. Ref.4

Sequences

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

Last modified November 25, 2008. Version 2.
Checksum: A59C1E99BFFAEF41

FASTA82091,556
        10         20         30         40         50         60 
MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD PGDDISSLQQ 

        70         80         90        100        110        120 
EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE IYHATGPLEE RQIAYVCREA 

       130        140        150        160        170        180 
LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV KLADFGVSGE LTASVAKRRS FIGTPYWMAP 

       190        200        210        220        230        240 
EVAAVERKGG YNELCDVWAL GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT 

       250        260        270        280        290        300 
RWTQNFHHFL KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE 

       310        320        330        340        350        360 
DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE PWEEEWTLLG 

       370        380        390        400        410        420 
KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG TIKRAPFLGP LPTDPPAEEP 

       430        440        450        460        470        480 
LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ REDPERSSCH GLPPTPKVHM GACFSKVFNG 

       490        500        510        520        530        540 
CPLRIHAAVT WIHPVTRDQF LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL 

       550        560        570        580        590        600 
LSLSGKSTHI WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ 

       610        620        630        640        650        660 
CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM LEPLVLDGKE 

       670        680        690        700        710        720 
LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI PGSAQQVIQV DRDTILVSFE 

       730        740        750        760        770        780 
RCVRIVNMQG EPTATLAPEL TFDFPIETVV CLQDSVLAFW SHGMQGRSLD TNEVTQEITD 

       790        800        810        820 
ETRIFRVLGA HRDIILESIP TDNPEAHSNL YILTGHQSTY 

« Hide

Isoform 2 [UniParc].

Checksum: 8D2482212A9E1248
Show »

FASTA81290,809

References

« Hide 'large scale' references
[1]"Human chromosome 11 DNA sequence and analysis including novel gene identification."
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. expand/collapse author list , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y.
Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[2]Mural R.J., Istrail S., Sutton 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases
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).
Tissue: Uterus.
[4]"Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center."
Katz P., Whalen G., Kehrl J.H.
J. Biol. Chem. 269:16802-16809(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 2-820 (ISOFORM 1), FUNCTION, DOMAIN, TISSUE SPECIFICITY.
Tissue: Tonsil.
[5]"Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase."
Pombo C.M., Kehrl J.H., Sanchez I., Katz P., Avruch J., Zon L.I., Woodgett J.R., Force T., Kyriakis J.M.
Nature 377:750-754(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION.
[6]"Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38."
Yuasa T., Ohno S., Kehrl J.H., Kyriakis J.M.
J. Biol. Chem. 273:22681-22692(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, AUTOPHOSPHORYLATION, INTERACTION WITH MAP3K1/MEKK1 AND TRAF2.
[7]"Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2."
Chadee D.N., Yuasa T., Kyriakis J.M.
Mol. Cell. Biol. 22:737-749(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRAF2 AND MAP3K1.
[8]"Germinal center kinase is required for optimal Jun N-terminal kinase activation by Toll-like receptor agonists and is regulated by the ubiquitin proteasome system and agonist-induced, TRAF6-dependent stabilization."
Zhong J., Kyriakis J.M.
Mol. Cell. Biol. 24:9165-9175(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, FUNCTION, UBIQUITINATION, INTERACTION WITH TRAF6.
[9]"Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release."
Zhong J., Kyriakis J.M.
J. Biol. Chem. 282:24246-24254(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MAP3K11/MLK3.
[10]"Signaling by the germinal center kinase family of protein kinases."
Kyriakis J.M.
J. Biol. Chem. 274:5259-5262(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[11]"The Ste20 group kinases as regulators of MAP kinase cascades."
Dan I., Watanabe N.M., Kusumi A.
Trends Cell Biol. 11:220-230(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
[12]"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-394, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[13]"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-394, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]"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-394, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AP001462 Genomic DNA. No translation available.
CH471076 Genomic DNA. Translation: EAW74302.1.
BC047865 mRNA. Translation: AAH47865.1.
U07349 mRNA. Translation: AAA20968.1. Sequence problems.
CCDSCCDS8082.1.
PIRA53714.
RefSeqNP_004570.2. NM_004579.3. [Q12851-1]
UniGeneHs.534341.

3D structure databases

ProteinModelPortalQ12851.
SMRQ12851. Positions 10-389.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid111809. 16 interactions.
IntActQ12851. 11 interactions.
MINTMINT-8247528.
STRING9606.ENSP00000294066.

Chemistry

BindingDBQ12851.
ChEMBLCHEMBL5330.
GuidetoPHARMACOLOGY2086.

PTM databases

PhosphoSiteQ12851.

Polymorphism databases

DMDM215274019.

Proteomic databases

MaxQBQ12851.
PaxDbQ12851.
PRIDEQ12851.

Protocols and materials databases

DNASU5871.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000294066; ENSP00000294066; ENSG00000168067.
ENST00000377350; ENSP00000366567; ENSG00000168067.
GeneID5871.
KEGGhsa:5871.
UCSCuc001obh.3. human. [Q12851-1]

Organism-specific databases

CTD5871.
GeneCardsGC11M064556.
H-InvDBHIX0026186.
HGNCHGNC:6864. MAP4K2.
HPAHPA007330.
MIM603166. gene.
neXtProtNX_Q12851.
PharmGKBPA30610.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000230824.
HOVERGENHBG036702.
InParanoidQ12851.
KOK04414.
OMAIYHATGP.
PhylomeDBQ12851.
TreeFamTF105121.

Enzyme and pathway databases

SignaLinkQ12851.

Gene expression databases

ArrayExpressQ12851.
BgeeQ12851.
CleanExHS_GCK.
HS_MAP4K2.
GenevestigatorQ12851.

Family and domain databases

InterProIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
[Graphical view]
PfamPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFPIRSF038172. MAPKKKK. 1 hit.
SMARTSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiMAP4K2.
GenomeRNAi5871.
NextBio22804.
PROQ12851.
SOURCESearch...

Entry information

Entry nameM4K2_HUMAN
AccessionPrimary (citable) accession number: Q12851
Secondary accession number(s): Q86VU3
Entry history
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 25, 2008
Last modified: July 9, 2014
This is version 138 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

MIM cross-references

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

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM