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Q61161

- M4K2_MOUSE

UniProt

Q61161 - M4K2_MOUSE

Protein

Mitogen-activated protein kinase kinase kinase kinase 2

Gene

Map4k2

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 120 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      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.2 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.

    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. protein serine/threonine kinase activity Source: UniProtKB-KW
    3. small GTPase regulator activity Source: InterPro

    GO - Biological processi

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

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Immunity, Innate immunity, Stress response

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase kinase kinase kinase 2 (EC:2.7.11.1)
    Alternative name(s):
    Germinal center kinase
    Short name:
    GCK
    MAPK/ERK kinase kinase kinase 2
    Short name:
    MEK kinase kinase 2
    Short name:
    MEKKK 2
    Rab8-interacting protein
    Gene namesi
    Name:Map4k2
    Synonyms:Rab8ip
    OrganismiMus musculus (Mouse)Imported
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 19

    Organism-specific databases

    MGIiMGI:1346883. Map4k2.

    Subcellular locationi

    Cytoplasm 1 Publication. Basolateral cell membrane 1 Publication; Peripheral membrane protein 1 Publication. Golgi apparatus membrane 1 Publication; Peripheral membrane protein 1 Publication

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Golgi apparatus, Membrane

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 821821Mitogen-activated protein kinase kinase kinase kinase 2PRO_0000086276Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei394 – 3941PhosphoserineBy similarity

    Post-translational modificationi

    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.

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ61161.
    PaxDbiQ61161.
    PRIDEiQ61161.

    PTM databases

    PhosphoSiteiQ61161.

    Expressioni

    Gene expression databases

    ArrayExpressiQ61161.
    BgeeiQ61161.
    GenevestigatoriQ61161.

    Interactioni

    Subunit structurei

    Interacts with TRAF2, TRAF6, MAP3K1/MEKK1 and MAP3K11/MLK3 By similarity. Interacts with RAB8A.By similarity1 Publication

    Structurei

    3D structure databases

    ProteinModelPortaliQ61161.
    SMRiQ61161. Positions 10-362.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini16 – 273258Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini483 – 794312CNHPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni294 – 31421PEST1Add
    BLAST
    Regioni344 – 36017PEST2Add
    BLAST
    Regioni405 – 44945PEST3Add
    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.

    Sequence similaritiesi

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

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00690000101936.
    HOGENOMiHOG000230824.
    HOVERGENiHBG036702.
    InParanoidiQ61161.
    KOiK04414.
    OMAiIYHATGP.
    OrthoDBiEOG7WX07M.
    PhylomeDBiQ61161.
    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]

    Sequencei

    Sequence statusi: Complete.

    Q61161-1 [UniParc]FASTAAdd to Basket

    « 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 RPTAERLLQH PFTTQHLPPA LLTQLLDKAS DPHLGTLSPE 300
    DSELETHDMF PDTIHSRSHH GPAERTPSEI QFHQVKFGAP RRKETDPLNE 350
    PWEEEWTLLG KEELSGSLLQ SVQEALEERS LTIRPALELQ ELDSPDDAIG 400
    TIKRAPFLGL PHTESTSGDN AQSCSPGTLS APPAGPGSPA LLPTAWATLK 450
    QQEDRERSSC HGLPPTPKVH MGACFSKVFN GCPLQIHAAV TWVHPVTRDQ 500
    FLVVGAEEGI YTLNLHELHE DTMEKLISQR CSWLYCVNNV LLSLSGKSTH 550
    IWAHDLPGLF EQRRLQHQAP LSIPTNRITQ RIIPRRFALS TKIPDTKGCL 600
    QCRVVRNPYT GSTFLLAALP ASLLLLQWYE PLQKFLLLKN FSSPLPSPAG 650
    MLEPLVLDGK ELPQVCVGAE GPEGPGCRVL FHVLPLEAGL TPDILIPPEG 700
    IPGSAQQVIQ VDRDTVLVSF ERCVRIVNLQ GEPTAALAPE LTFDFTIETV 750
    VCLQDSVLAF WSHGMQGRSL DTNEVTQEIT DETRIFRVLG AHRDIILESI 800
    PTDNPGAHSN LYILTGHQSS Y 821
    Length:821
    Mass (Da):91,265
    Last modified:November 1, 1996 - v1
    Checksum:i2CCF750E45A53B05
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti223 – 2231L → M in BAC34507. (PubMed:16141072)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U50595 mRNA. Translation: AAC52571.1.
    AK051036 mRNA. Translation: BAC34507.1.
    CCDSiCCDS29503.1.
    RefSeqiNP_001278716.1. NM_001291787.1.
    NP_033032.1. NM_009006.3.
    UniGeneiMm.25860.

    Genome annotation databases

    EnsembliENSMUST00000025897; ENSMUSP00000025897; ENSMUSG00000024948.
    GeneIDi26412.
    KEGGimmu:26412.
    UCSCiuc008gie.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U50595 mRNA. Translation: AAC52571.1 .
    AK051036 mRNA. Translation: BAC34507.1 .
    CCDSi CCDS29503.1.
    RefSeqi NP_001278716.1. NM_001291787.1.
    NP_033032.1. NM_009006.3.
    UniGenei Mm.25860.

    3D structure databases

    ProteinModelPortali Q61161.
    SMRi Q61161. Positions 10-362.
    ModBasei Search...
    MobiDBi Search...

    PTM databases

    PhosphoSitei Q61161.

    Proteomic databases

    MaxQBi Q61161.
    PaxDbi Q61161.
    PRIDEi Q61161.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000025897 ; ENSMUSP00000025897 ; ENSMUSG00000024948 .
    GeneIDi 26412.
    KEGGi mmu:26412.
    UCSCi uc008gie.1. mouse.

    Organism-specific databases

    CTDi 5871.
    MGIi MGI:1346883. Map4k2.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00690000101936.
    HOGENOMi HOG000230824.
    HOVERGENi HBG036702.
    InParanoidi Q61161.
    KOi K04414.
    OMAi IYHATGP.
    OrthoDBi EOG7WX07M.
    PhylomeDBi Q61161.
    TreeFami TF105121.

    Miscellaneous databases

    NextBioi 304405.
    PROi Q61161.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q61161.
    Bgeei Q61161.
    Genevestigatori Q61161.

    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. "In its active form, the GTP-binding protein rab8 interacts with a stress-activated protein kinase."
      Ren M., Zeng J., De Lemos-Chiarandini C., Rosenfeld M., Adesnik M., Sabatini D.D.
      Proc. Natl. Acad. Sci. U.S.A. 93:5151-5155(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH RAB8, SUBCELLULAR LOCATION.
      Strain: BALB/c.
    2. "The transcriptional landscape of the mammalian genome."
      Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
      , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
      Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 42-821.
      Strain: C57BL/6J.
      Tissue: Embryo.
    3. "GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38."
      Zhong J., Gavrilescu L.C., Molnar A., Murray L., Garafalo S., Kehrl J.H., Simon A.R., Van Etten R.A., Kyriakis J.M.
      Proc. Natl. Acad. Sci. U.S.A. 106:4372-4377(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    4. "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.
    5. "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.

    Entry informationi

    Entry nameiM4K2_MOUSE
    AccessioniPrimary (citable) accession number: Q61161
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 28, 2003
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 120 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3