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Protein

Mitogen-activated protein kinase kinase kinase kinase 2

Gene

MAP4K2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.6 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+1 Publication

Enzyme regulationi

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.2 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei45 – 451ATPPROSITE-ProRule annotation
Active sitei136 – 1361Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi22 – 309ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • mitogen-activated protein kinase kinase kinase binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • activation of JUN kinase activity Source: UniProtKB
  • immune response Source: ProtInc
  • innate immune response Source: UniProtKB-KW
  • intracellular signal transduction Source: UniProtKB
  • JNK cascade Source: ProtInc
  • positive regulation of JNK cascade Source: UniProtKB
  • protein phosphorylation Source: UniProtKB
  • vesicle targeting Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Immunity, Innate immunity, Stress response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

SignaLinkiQ12851.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:MAP4K2
Synonyms:GCK, RAB8IP
OrganismiHomo sapiens (Human)Imported
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Unplaced

Organism-specific databases

HGNCiHGNC:6864. MAP4K2.

Subcellular locationi

GO - Cellular componenti

  • basolateral plasma membrane Source: UniProtKB-SubCell
  • Golgi membrane Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Golgi apparatus, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA30610.

Polymorphism and mutation databases

BioMutaiMAP4K2.
DMDMi215274019.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 820820Mitogen-activated protein kinase kinase kinase kinase 2PRO_0000086275Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei394 – 3941Phosphoserine3 Publications

Post-translational modificationi

Polyubiquitinated through 'Lys-48'-polyubiquitin chains, allowing proteasomal turnover. Ubiquitination requires the kinase activity of MAP4K2/GCK.1 Publication
Autophosphorylated in response to tumor necrosis factor (TNF), endotoxins or proinflammatory stimuli. Autophosphorylation leads to activation.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ12851.
PaxDbiQ12851.
PRIDEiQ12851.

PTM databases

PhosphoSiteiQ12851.

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiQ12851.
CleanExiHS_GCK.
HS_MAP4K2.
ExpressionAtlasiQ12851. baseline and differential.
GenevisibleiQ12851. HS.

Organism-specific databases

HPAiHPA007330.

Interactioni

Subunit structurei

Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with RAB8A (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
MAP3K1Q132332EBI-49783,EBI-49776

Protein-protein interaction databases

BioGridi111809. 16 interactions.
IntActiQ12851. 12 interactions.
MINTiMINT-8247528.
STRINGi9606.ENSP00000294066.

Structurei

3D structure databases

ProteinModelPortaliQ12851.
SMRiQ12851. Positions 11-389.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini16 – 273258Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini482 – 793312CNHPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni294 – 31421PEST1Add
BLAST
Regioni344 – 36017PEST2Add
BLAST
Regioni405 – 44844PEST3Add
BLAST

Domaini

The PEST domains are Pro-, Glu-, Ser-, and Thr-rich domains. Proteins with PEST domains are frequently targets of degradation by the ubiquitin proteasome.1 Publication

Sequence similaritiesi

Contains 1 CNH domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118848.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ12851.
KOiK04414.
OMAiAWATMKQ.
OrthoDBiEOG7WX07M.
PhylomeDBiQ12851.
TreeFamiTF105121.

Family and domain databases

InterProiIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038172. MAPKKKK. 1 hit.
SMARTiSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q12851-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD
60 70 80 90 100
PGDDISSLQQ EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE
110 120 130 140 150
IYHATGPLEE RQIAYVCREA LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV
160 170 180 190 200
KLADFGVSGE LTASVAKRRS FIGTPYWMAP EVAAVERKGG YNELCDVWAL
210 220 230 240 250
GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT RWTQNFHHFL
260 270 280 290 300
KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE
310 320 330 340 350
DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE
360 370 380 390 400
PWEEEWTLLG KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG
410 420 430 440 450
TIKRAPFLGP LPTDPPAEEP LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ
460 470 480 490 500
REDPERSSCH GLPPTPKVHM GACFSKVFNG CPLRIHAAVT WIHPVTRDQF
510 520 530 540 550
LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL LSLSGKSTHI
560 570 580 590 600
WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ
610 620 630 640 650
CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM
660 670 680 690 700
LEPLVLDGKE LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI
710 720 730 740 750
PGSAQQVIQV DRDTILVSFE RCVRIVNMQG EPTATLAPEL TFDFPIETVV
760 770 780 790 800
CLQDSVLAFW SHGMQGRSLD TNEVTQEITD ETRIFRVLGA HRDIILESIP
810 820
TDNPEAHSNL YILTGHQSTY
Length:820
Mass (Da):91,556
Last modified:November 25, 2008 - v2
Checksum:iA59C1E99BFFAEF41
GO
Isoform 2 (identifier: Q12851-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     426-433: Missing.

Note: No experimental confirmation available.
Show »
Length:812
Mass (Da):90,809
Checksum:i8D2482212A9E1248
GO

Sequence cautioni

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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti120 – 1201A → R in AAA20968 (PubMed:7515885).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei426 – 4338Missing in isoform 2. 1 PublicationVSP_054134

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AP001462 Genomic DNA. No translation available.
CH471076 Genomic DNA. Translation: EAW74302.1.
BC047865 mRNA. Translation: AAH47865.1.
U07349 mRNA. Translation: AAA20968.1. Sequence problems.
CCDSiCCDS8082.1. [Q12851-1]
PIRiA53714.
RefSeqiNP_004570.2. NM_004579.4. [Q12851-1]
UniGeneiHs.534341.

Genome annotation databases

EnsembliENST00000294066; ENSP00000294066; ENSG00000168067. [Q12851-1]
ENST00000377350; ENSP00000366567; ENSG00000168067. [Q12851-2]
GeneIDi5871.
KEGGihsa:5871.
UCSCiuc001obh.3. human. [Q12851-1]
uc001obi.3. human.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AP001462 Genomic DNA. No translation available.
CH471076 Genomic DNA. Translation: EAW74302.1.
BC047865 mRNA. Translation: AAH47865.1.
U07349 mRNA. Translation: AAA20968.1. Sequence problems.
CCDSiCCDS8082.1. [Q12851-1]
PIRiA53714.
RefSeqiNP_004570.2. NM_004579.4. [Q12851-1]
UniGeneiHs.534341.

3D structure databases

ProteinModelPortaliQ12851.
SMRiQ12851. Positions 11-389.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111809. 16 interactions.
IntActiQ12851. 12 interactions.
MINTiMINT-8247528.
STRINGi9606.ENSP00000294066.

Chemistry

BindingDBiQ12851.
ChEMBLiCHEMBL5330.
GuidetoPHARMACOLOGYi2086.

PTM databases

PhosphoSiteiQ12851.

Polymorphism and mutation databases

BioMutaiMAP4K2.
DMDMi215274019.

Proteomic databases

MaxQBiQ12851.
PaxDbiQ12851.
PRIDEiQ12851.

Protocols and materials databases

DNASUi5871.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000294066; ENSP00000294066; ENSG00000168067. [Q12851-1]
ENST00000377350; ENSP00000366567; ENSG00000168067. [Q12851-2]
GeneIDi5871.
KEGGihsa:5871.
UCSCiuc001obh.3. human. [Q12851-1]
uc001obi.3. human.

Organism-specific databases

CTDi5871.
GeneCardsiGC11M064556.
H-InvDBHIX0026186.
HGNCiHGNC:6864. MAP4K2.
HPAiHPA007330.
MIMi603166. gene.
neXtProtiNX_Q12851.
PharmGKBiPA30610.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118848.
HOGENOMiHOG000230824.
HOVERGENiHBG036702.
InParanoidiQ12851.
KOiK04414.
OMAiAWATMKQ.
OrthoDBiEOG7WX07M.
PhylomeDBiQ12851.
TreeFamiTF105121.

Enzyme and pathway databases

SignaLinkiQ12851.

Miscellaneous databases

GeneWikiiMAP4K2.
GenomeRNAii5871.
NextBioi22804.
PROiQ12851.
SOURCEiSearch...

Gene expression databases

BgeeiQ12851.
CleanExiHS_GCK.
HS_MAP4K2.
ExpressionAtlasiQ12851. baseline and differential.
GenevisibleiQ12851. HS.

Family and domain databases

InterProiIPR001180. Citron.
IPR011009. Kinase-like_dom.
IPR021160. MAPKKKK.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF00780. CNH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
PIRSFiPIRSF038172. MAPKKKK. 1 hit.
SMARTiSM00036. CNH. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50219. CNH. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  2. 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. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-394, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Cervix carcinoma.
  13. 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.
  15. "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
    Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., Ye M., Zou H.
    J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.

Entry informationi

Entry nameiM4K2_HUMAN
AccessioniPrimary (citable) accession number: Q12851
Secondary accession number(s): Q86VU3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 25, 2008
Last modified: June 24, 2015
This is version 149 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.