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Protein

Mitogen-activated protein kinase kinase kinase kinase 2

Gene

MAP4K2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 extent 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

Activity 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)DescriptionActionsGraphical viewLength
Binding sitei45ATPPROSITE-ProRule annotation1
Active sitei136Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi22 – 30ATPPROSITE-ProRule annotation9

GO - Molecular functioni

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

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processImmunity, Innate immunity, Stress response
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

SignaLinkiQ12851
SIGNORiQ12851

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
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000168067.11
HGNCiHGNC:6864 MAP4K2
MIMi603166 gene
neXtProtiNX_Q12851

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Golgi apparatus, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi5871
OpenTargetsiENSG00000168067
PharmGKBiPA30610

Chemistry databases

ChEMBLiCHEMBL5330
GuidetoPHARMACOLOGYi2086

Polymorphism and mutation databases

BioMutaiMAP4K2
DMDMi215274019

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862751 – 820Mitogen-activated protein kinase kinase kinase kinase 2Add BLAST820

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei328PhosphoserineCombined sources1
Modified residuei394PhosphoserineCombined sources1

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

EPDiQ12851
MaxQBiQ12851
PaxDbiQ12851
PeptideAtlasiQ12851
PRIDEiQ12851
ProteomicsDBi58984

PTM databases

iPTMnetiQ12851
PhosphoSitePlusiQ12851

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

BgeeiENSG00000168067 Expressed in 157 organ(s), highest expression level in blood
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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi111809, 17 interactors
IntActiQ12851, 14 interactors
MINTiQ12851
STRINGi9606.ENSP00000294066

Chemistry databases

BindingDBiQ12851

Structurei

3D structure databases

ProteinModelPortaliQ12851
SMRiQ12851
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini16 – 273Protein kinasePROSITE-ProRule annotationAdd BLAST258
Domaini482 – 793CNHPROSITE-ProRule annotationAdd BLAST312

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni294 – 314PEST1Add BLAST21
Regioni344 – 360PEST2Add BLAST17
Regioni405 – 448PEST3Add BLAST44

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

Phylogenomic databases

eggNOGiKOG0576 Eukaryota
ENOG410XP9G LUCA
GeneTreeiENSGT00920000148966
HOGENOMiHOG000230824
HOVERGENiHBG036702
InParanoidiQ12851
KOiK04414
OMAiAWATMKQ
OrthoDBiEOG091G022R
PhylomeDBiQ12851
TreeFamiTF105121

Family and domain databases

InterProiView protein in InterPro
IPR001180 CNH_dom
IPR011009 Kinase-like_dom_sf
IPR021160 MAPKKKK
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
PfamiView protein in Pfam
PF00780 CNH, 1 hit
PF00069 Pkinase, 1 hit
PIRSFiPIRSF038172 MAPKKKK, 1 hit
SMARTiView protein in SMART
SM00036 CNH, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50219 CNH, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H7C208H7C208_HUMAN
Mitogen-activated protein kinase ki...
MAP4K2
144Annotation score:
C9JCU6C9JCU6_HUMAN
Mitogen-activated protein kinase ki...
MAP4K2
307Annotation score:
F8WCP4F8WCP4_HUMAN
Mitogen-activated protein kinase ki...
MAP4K2
58Annotation score:
F2Z2B3F2Z2B3_HUMAN
Mitogen-activated protein kinase ki...
MAP4K2
57Annotation score:

Sequence cautioni

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

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti120A → R in AAA20968 (PubMed:7515885).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_054134426 – 433Missing in isoform 2. 1 Publication8

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]
CCDS81582.1 [Q12851-2]
PIRiA53714
RefSeqiNP_001294919.1, NM_001307990.1 [Q12851-2]
NP_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.4 human [Q12851-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

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]
CCDS81582.1 [Q12851-2]
PIRiA53714
RefSeqiNP_001294919.1, NM_001307990.1 [Q12851-2]
NP_004570.2, NM_004579.4 [Q12851-1]
UniGeneiHs.534341

3D structure databases

ProteinModelPortaliQ12851
SMRiQ12851
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111809, 17 interactors
IntActiQ12851, 14 interactors
MINTiQ12851
STRINGi9606.ENSP00000294066

Chemistry databases

BindingDBiQ12851
ChEMBLiCHEMBL5330
GuidetoPHARMACOLOGYi2086

PTM databases

iPTMnetiQ12851
PhosphoSitePlusiQ12851

Polymorphism and mutation databases

BioMutaiMAP4K2
DMDMi215274019

Proteomic databases

EPDiQ12851
MaxQBiQ12851
PaxDbiQ12851
PeptideAtlasiQ12851
PRIDEiQ12851
ProteomicsDBi58984

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.4 human [Q12851-1]

Organism-specific databases

CTDi5871
DisGeNETi5871
EuPathDBiHostDB:ENSG00000168067.11
GeneCardsiMAP4K2
H-InvDBiHIX0026186
HGNCiHGNC:6864 MAP4K2
HPAiHPA007330
MIMi603166 gene
neXtProtiNX_Q12851
OpenTargetsiENSG00000168067
PharmGKBiPA30610
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0576 Eukaryota
ENOG410XP9G LUCA
GeneTreeiENSGT00920000148966
HOGENOMiHOG000230824
HOVERGENiHBG036702
InParanoidiQ12851
KOiK04414
OMAiAWATMKQ
OrthoDBiEOG091G022R
PhylomeDBiQ12851
TreeFamiTF105121

Enzyme and pathway databases

SignaLinkiQ12851
SIGNORiQ12851

Miscellaneous databases

GeneWikiiMAP4K2
GenomeRNAii5871
PROiPR:Q12851
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168067 Expressed in 157 organ(s), highest expression level in blood
CleanExiHS_GCK
HS_MAP4K2
ExpressionAtlasiQ12851 baseline and differential
GenevisibleiQ12851 HS

Family and domain databases

InterProiView protein in InterPro
IPR001180 CNH_dom
IPR011009 Kinase-like_dom_sf
IPR021160 MAPKKKK
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
PfamiView protein in Pfam
PF00780 CNH, 1 hit
PF00069 Pkinase, 1 hit
PIRSFiPIRSF038172 MAPKKKK, 1 hit
SMARTiView protein in SMART
SM00036 CNH, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50219 CNH, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiM4K2_HUMAN
AccessioniPrimary (citable) accession number: Q12851
Secondary accession number(s): Q86VU3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 25, 2008
Last modified: September 12, 2018
This is version 175 of the entry and version 2 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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Main funding by: National Institutes of Health

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