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Q12851

- M4K2_HUMAN

UniProt

Q12851 - M4K2_HUMAN

Protein

Mitogen-activated protein kinase kinase kinase kinase 2

Gene

MAP4K2

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 140 (01 Oct 2014)
      Sequence version 2 (25 Nov 2008)
      Previous versions | rss
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    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

    Magnesium.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

    1. ATP binding Source: UniProtKB
    2. mitogen-activated protein kinase kinase kinase binding Source: UniProtKB
    3. protein binding Source: IntAct
    4. protein serine/threonine kinase activity Source: UniProtKB
    5. small GTPase regulator activity Source: InterPro

    GO - Biological processi

    1. activation of JUN kinase activity Source: UniProtKB
    2. immune response Source: ProtInc
    3. innate immune response Source: UniProtKB-KW
    4. intracellular signal transduction Source: UniProtKB
    5. JNK cascade Source: ProtInc
    6. positive regulation of JNK cascade Source: UniProtKB
    7. protein phosphorylation Source: UniProtKB
    8. vesicle targeting Source: Ensembl

    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: Chromosome 11

    Organism-specific databases

    HGNCiHGNC:6864. MAP4K2.

    Subcellular locationi

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

    GO - Cellular componenti

    1. basolateral plasma membrane Source: UniProtKB-SubCell
    2. Golgi membrane Source: ProtInc

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Golgi apparatus, Membrane

    Pathology & Biotechi

    Organism-specific databases

    PharmGKBiPA30610.

    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.3 Publications

    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

    ArrayExpressiQ12851.
    BgeeiQ12851.
    CleanExiHS_GCK.
    HS_MAP4K2.
    GenevestigatoriQ12851.

    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 10-389.
    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.
    HOGENOMiHOG000230824.
    HOVERGENiHBG036702.
    InParanoidiQ12851.
    KOiK04414.
    OMAiIYHATGP.
    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_dom.
    [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. Align

    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

    MALLRDVSLQ DPRDRFELLQ RVGAGTYGDV YKARDTVTSE LAAVKIVKLD    50
    PGDDISSLQQ EITILRECRH PNVVAYIGSY LRNDRLWICM EFCGGGSLQE 100
    IYHATGPLEE RQIAYVCREA LKGLHHLHSQ GKIHRDIKGA NLLLTLQGDV 150
    KLADFGVSGE LTASVAKRRS FIGTPYWMAP EVAAVERKGG YNELCDVWAL 200
    GITAIELGEL QPPLFHLHPM RALMLMSKSS FQPPKLRDKT RWTQNFHHFL 250
    KLALTKNPKK RPTAEKLLQH PFTTQQLPRA LLTQLLDKAS DPHLGTPSPE 300
    DCELETYDMF PDTIHSRGQH GPAERTPSEI QFHQVKFGAP RRKETDPLNE 350
    PWEEEWTLLG KEELSGSLLQ SVQEALEERS LTIRSASEFQ ELDSPDDTMG 400
    TIKRAPFLGP LPTDPPAEEP LSSPPGTLPP PPSGPNSSPL LPTAWATMKQ 450
    REDPERSSCH GLPPTPKVHM GACFSKVFNG CPLRIHAAVT WIHPVTRDQF 500
    LVVGAEEGIY TLNLHELHED TLEKLISHRC SWLYCVNNVL LSLSGKSTHI 550
    WAHDLPGLFE QRRLQQQVPL SIPTNRLTQR IIPRRFALST KIPDTKGCLQ 600
    CRVVRNPYTG ATFLLAALPT SLLLLQWYEP LQKFLLLKNF SSPLPSPAGM 650
    LEPLVLDGKE LPQVCVGAEG PEGPGCRVLF HVLPLEAGLT PDILIPPEGI 700
    PGSAQQVIQV DRDTILVSFE RCVRIVNMQG EPTATLAPEL TFDFPIETVV 750
    CLQDSVLAFW SHGMQGRSLD TNEVTQEITD ETRIFRVLGA HRDIILESIP 800
    TDNPEAHSNL YILTGHQSTY 820
    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. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

    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:
    EMBL
    GenBank
    DDBJ
    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_004579.3. [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.

    Polymorphism databases

    DMDMi215274019.

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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.
    CCDSi CCDS8082.1. [Q12851-1 ]
    PIRi A53714.
    RefSeqi NP_004570.2. NM_004579.3. [Q12851-1 ]
    UniGenei Hs.534341.

    3D structure databases

    ProteinModelPortali Q12851.
    SMRi Q12851. Positions 10-389.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 111809. 16 interactions.
    IntActi Q12851. 12 interactions.
    MINTi MINT-8247528.
    STRINGi 9606.ENSP00000294066.

    Chemistry

    BindingDBi Q12851.
    ChEMBLi CHEMBL5330.
    GuidetoPHARMACOLOGYi 2086.

    PTM databases

    PhosphoSitei Q12851.

    Polymorphism databases

    DMDMi 215274019.

    Proteomic databases

    MaxQBi Q12851.
    PaxDbi Q12851.
    PRIDEi Q12851.

    Protocols and materials databases

    DNASUi 5871.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000294066 ; ENSP00000294066 ; ENSG00000168067 . [Q12851-1 ]
    ENST00000377350 ; ENSP00000366567 ; ENSG00000168067 . [Q12851-2 ]
    GeneIDi 5871.
    KEGGi hsa:5871.
    UCSCi uc001obh.3. human. [Q12851-1 ]
    uc001obi.3. human.

    Organism-specific databases

    CTDi 5871.
    GeneCardsi GC11M064556.
    H-InvDB HIX0026186.
    HGNCi HGNC:6864. MAP4K2.
    HPAi HPA007330.
    MIMi 603166. gene.
    neXtProti NX_Q12851.
    PharmGKBi PA30610.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000230824.
    HOVERGENi HBG036702.
    InParanoidi Q12851.
    KOi K04414.
    OMAi IYHATGP.
    PhylomeDBi Q12851.
    TreeFami TF105121.

    Enzyme and pathway databases

    SignaLinki Q12851.

    Miscellaneous databases

    GeneWikii MAP4K2.
    GenomeRNAii 5871.
    NextBioi 22804.
    PROi Q12851.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q12851.
    Bgeei Q12851.
    CleanExi HS_GCK.
    HS_MAP4K2.
    Genevestigatori Q12851.

    Family and domain databases

    InterProi IPR001180. 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 ]
    Pfami PF00780. CNH. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF038172. MAPKKKK. 1 hit.
    SMARTi SM00036. CNH. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS50219. CNH. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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.

    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: October 1, 2014
    This is version 140 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