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Q92918

- M4K1_HUMAN

UniProt

Q92918 - M4K1_HUMAN

Protein

Mitogen-activated protein kinase kinase kinase kinase 1

Gene

MAP4K1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 139 (01 Oct 2014)
      Sequence version 1 (01 Feb 1997)
      Previous versions | rss
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    Functioni

    Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.2 Publications

    Catalytic activityi

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

    Cofactori

    Magnesium.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei46 – 461ATPPROSITE-ProRule annotation
    Active sitei137 – 1371Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi23 – 319ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB
    2. MAP kinase kinase kinase kinase activity Source: UniProtKB
    3. protein binding Source: UniProtKB
    4. protein kinase activity Source: ProtInc
    5. protein serine/threonine kinase activity Source: UniProtKB
    6. small GTPase regulator activity Source: InterPro

    GO - Biological processi

    1. activation of JUN kinase activity Source: ProtInc
    2. activation of MAPKKK activity Source: UniProtKB
    3. cell proliferation Source: UniProtKB
    4. intracellular signal transduction Source: UniProtKB
    5. peptidyl-serine phosphorylation Source: UniProtKB
    6. protein autophosphorylation Source: UniProtKB
    7. protein phosphorylation Source: UniProtKB
    8. response to stress Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    SignaLinkiQ92918.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase kinase kinase kinase 1 (EC:2.7.11.1)
    Alternative name(s):
    Hematopoietic progenitor kinase
    MAPK/ERK kinase kinase kinase 1
    Short name:
    MEK kinase kinase 1
    Short name:
    MEKKK 1
    Gene namesi
    Name:MAP4K1
    Synonyms:HPK1
    OrganismiHomo sapiens (Human)Imported
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 19

    Organism-specific databases

    HGNCiHGNC:6863. MAP4K1.

    Subcellular locationi

    GO - Cellular componenti

    1. membrane Source: UniProtKB

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi355 – 3551T → A: Retains kinase activity. Not degraded by the Cul7-RING ubiquitin-protein ligase complex containing FBXW8. 1 Publication

    Organism-specific databases

    PharmGKBiPA30609.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 833833Mitogen-activated protein kinase kinase kinase kinase 1PRO_0000086273Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei165 – 1651Phosphothreonine; by autocatalysis1 Publication
    Modified residuei171 – 1711Phosphoserine; by autocatalysis1 Publication
    Modified residuei175 – 1751Phosphothreonine; by autocatalysis1 Publication
    Modified residuei355 – 3551Phosphothreonine; by autocatalysis1 Publication
    Modified residuei405 – 4051Phosphoserine1 Publication
    Modified residuei407 – 4071Phosphoserine1 Publication
    Modified residuei413 – 4131Phosphoserine1 Publication
    Modified residuei421 – 4211Phosphoserine2 Publications
    Modified residuei586 – 5861Phosphoserine1 Publication

    Post-translational modificationi

    Autophosphorylates: phosphorylation promotes ubiquitination by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex, leading to its degradation by the proteasome.1 Publication
    Ubiquitinated by the Cul7-RING(FBXW8) ubiquitin-protein ligase complex following autophosphorylation, leading to its degradation by the proteasome.1 Publication

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ92918.
    PaxDbiQ92918.
    PRIDEiQ92918.

    PTM databases

    PhosphoSiteiQ92918.

    Miscellaneous databases

    PMAP-CutDBQ92918.

    Expressioni

    Tissue specificityi

    Expressed primarily in hematopoietic organs, including bone marrow, spleen and thymus. Also expressed at very low levels in lung, kidney, mammary glands and small intestine.1 Publication

    Gene expression databases

    ArrayExpressiQ92918.
    BgeeiQ92918.
    CleanExiHS_MAP4K1.
    GenevestigatoriQ92918.

    Organism-specific databases

    HPAiCAB007754.
    HPA007419.

    Interactioni

    Subunit structurei

    Interacts with MAP3K1. Interacts with FBXW8.2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ABL1P005193EBI-881,EBI-375543
    CRKP461083EBI-881,EBI-886
    CRKLP461095EBI-881,EBI-910
    FYNP062412EBI-881,EBI-515315
    GRB2P629938EBI-881,EBI-401755
    NCK1P163334EBI-881,EBI-389883
    PIK3R1P279862EBI-881,EBI-79464
    PLCG1P191746EBI-881,EBI-79387

    Protein-protein interaction databases

    BioGridi116354. 25 interactions.
    DIPiDIP-31019N.
    IntActiQ92918. 16 interactions.
    MINTiMINT-1176198.
    STRINGi9606.ENSP00000380066.

    Structurei

    3D structure databases

    ProteinModelPortaliQ92918.
    SMRiQ92918. Positions 17-274.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini17 – 274258Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini495 – 800306CNHPROSITE-ProRule annotationAdd
    BLAST

    Sequence similaritiesi

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

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000230824.
    HOVERGENiHBG036702.
    InParanoidiQ92918.
    KOiK04408.
    OMAiLQWYQPM.
    OrthoDBiEOG7WX07M.
    PhylomeDBiQ92918.
    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. 2 hits.
    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: Q92918-1) [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

    MDVVDPDIFN RDPRDHYDLL QRLGGGTYGE VFKARDKVSG DLVALKMVKM    50
    EPDDDVSTLQ KEILILKTCR HANIVAYHGS YLWLQKLWIC MEFCGAGSLQ 100
    DIYQVTGSLS ELQISYVCRE VLQGLAYLHS QKKIHRDIKG ANILINDAGE 150
    VRLADFGISA QIGATLARRL SFIGTPYWMA PEVAAVALKG GYNELCDIWS 200
    LGITAIELAE LQPPLFDVHP LRVLFLMTKS GYQPPRLKEK GKWSAAFHNF 250
    IKVTLTKSPK KRPSATKMLS HQLVSQPGLN RGLILDLLDK LKNPGKGPSI 300
    GDIEDEEPEL PPAIPRRIRS THRSSSLGIP DADCCRRHME FRKLRGMETR 350
    PPANTARLQP PRDLRSSSPR KQLSESSDDD YDDVDIPTPA EDTPPPLPPK 400
    PKFRSPSDEG PGSMGDDGQL SPGVLVRCAS GPPPNSPRPG PPPSTSSPHL 450
    TAHSEPSLWN PPSRELDKPP LLPPKKEKMK RKGCALLVKL FNGCPLRIHS 500
    TAAWTHPSTK DQHLLLGAEE GIFILNRNDQ EATLEMLFPS RTTWVYSINN 550
    VLMSLSGKTP HLYSHSILGL LERKETRAGN PIAHISPHRL LARKNMVSTK 600
    IQDTKGCRAC CVAEGASSGG PFLCGALETS VVLLQWYQPM NKFLLVRQVL 650
    FPLPTPLSVF ALLTGPGSEL PAVCIGVSPG RPGKSVLFHT VRFGALSCWL 700
    GEMSTEHRGP VQVTQVEEDM VMVLMDGSVK LVTPEGSPVR GLRTPEIPMT 750
    EAVEAVAMVG GQLQAFWKHG VQVWALGSDQ LLQELRDPTL TFRLLGSPRL 800
    ECSGTISPHC NLLLPGSSNS PASASRVAGI TGL 833
    Length:833
    Mass (Da):91,296
    Last modified:February 1, 1997 - v1
    Checksum:i3C98CF01BE42E151
    GO
    Isoform 2 (identifier: Q92918-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         800-833: LECSGTISPHCNLLLPGSSNSPASASRVAGITGL → PVVVETRPVDDPTAPSNLYIQE

    Show »
    Length:821
    Mass (Da):90,425
    Checksum:iA7CBFE3B39D1C66A
    GO

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti312 – 3121P → T.1 Publication
    Corresponds to variant rs55924696 [ dbSNP | Ensembl ].
    VAR_040739
    Natural varianti351 – 3511P → S.1 Publication
    Corresponds to variant rs34591617 [ dbSNP | Ensembl ].
    VAR_040740
    Natural varianti361 – 3611P → L.1 Publication
    Corresponds to variant rs56060067 [ dbSNP | Ensembl ].
    VAR_040741
    Natural varianti737 – 7371S → F in a metastatic melanoma sample; somatic mutation. 1 Publication
    VAR_040742
    Natural varianti811 – 8111N → S.
    Corresponds to variant rs12975825 [ dbSNP | Ensembl ].
    VAR_051643

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei800 – 83334LECSG…GITGL → PVVVETRPVDDPTAPSNLYI QE in isoform 2. CuratedVSP_040340Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U66464 mRNA. Translation: AAB97983.1.
    AC005933 Genomic DNA. No translation available.
    AC008649 Genomic DNA. No translation available.
    CCDSiCCDS42564.1. [Q92918-2]
    CCDS59385.1. [Q92918-1]
    RefSeqiNP_001036065.1. NM_001042600.2. [Q92918-2]
    NP_009112.1. NM_007181.5. [Q92918-1]
    UniGeneiHs.95424.

    Genome annotation databases

    EnsembliENST00000396857; ENSP00000380066; ENSG00000104814. [Q92918-2]
    ENST00000591517; ENSP00000465039; ENSG00000104814. [Q92918-1]
    GeneIDi11184.
    KEGGihsa:11184.
    UCSCiuc002oix.1. human. [Q92918-1]
    uc002oiy.1. human. [Q92918-2]

    Polymorphism databases

    DMDMi29427916.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U66464 mRNA. Translation: AAB97983.1 .
    AC005933 Genomic DNA. No translation available.
    AC008649 Genomic DNA. No translation available.
    CCDSi CCDS42564.1. [Q92918-2 ]
    CCDS59385.1. [Q92918-1 ]
    RefSeqi NP_001036065.1. NM_001042600.2. [Q92918-2 ]
    NP_009112.1. NM_007181.5. [Q92918-1 ]
    UniGenei Hs.95424.

    3D structure databases

    ProteinModelPortali Q92918.
    SMRi Q92918. Positions 17-274.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 116354. 25 interactions.
    DIPi DIP-31019N.
    IntActi Q92918. 16 interactions.
    MINTi MINT-1176198.
    STRINGi 9606.ENSP00000380066.

    Chemistry

    BindingDBi Q92918.
    ChEMBLi CHEMBL5749.
    GuidetoPHARMACOLOGYi 2085.

    PTM databases

    PhosphoSitei Q92918.

    Polymorphism databases

    DMDMi 29427916.

    Proteomic databases

    MaxQBi Q92918.
    PaxDbi Q92918.
    PRIDEi Q92918.

    Protocols and materials databases

    DNASUi 11184.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000396857 ; ENSP00000380066 ; ENSG00000104814 . [Q92918-2 ]
    ENST00000591517 ; ENSP00000465039 ; ENSG00000104814 . [Q92918-1 ]
    GeneIDi 11184.
    KEGGi hsa:11184.
    UCSCi uc002oix.1. human. [Q92918-1 ]
    uc002oiy.1. human. [Q92918-2 ]

    Organism-specific databases

    CTDi 11184.
    GeneCardsi GC19M039078.
    HGNCi HGNC:6863. MAP4K1.
    HPAi CAB007754.
    HPA007419.
    MIMi 601983. gene.
    neXtProti NX_Q92918.
    PharmGKBi PA30609.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000230824.
    HOVERGENi HBG036702.
    InParanoidi Q92918.
    KOi K04408.
    OMAi LQWYQPM.
    OrthoDBi EOG7WX07M.
    PhylomeDBi Q92918.
    TreeFami TF105121.

    Enzyme and pathway databases

    SignaLinki Q92918.

    Miscellaneous databases

    GeneWikii MAP4K1.
    GenomeRNAii 11184.
    NextBioi 42561.
    PMAP-CutDB Q92918.
    PROi Q92918.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q92918.
    Bgeei Q92918.
    CleanExi HS_MAP4K1.
    Genevestigatori Q92918.

    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. 2 hits.
    PROSITEi PS50219. CNH. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade."
      Hu M.C.-T., Qiu W.R., Wang X., Meyer C.F., Tan T.-H.
      Genes Dev. 10:2251-2264(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH MAP3K1.
      Tissue: Fetal liver.
    2. "The DNA sequence and biology of human chromosome 19."
      Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V.
      , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
      Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    3. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-421 AND SER-586, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    4. "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-405; SER-407; SER-413 AND SER-421, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    5. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    6. "Patterns of somatic mutation in human cancer genomes."
      Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
      , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
      Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-312; SER-351; LEU-361 AND PHE-737.
    7. "The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1."
      Wang H., Chen Y., Lin P., Li L., Zhou G., Liu G., Logsdon C., Jin J., Abbruzzese J.L., Tan T.H., Wang H.
      J. Biol. Chem. 289:4009-4017(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT THR-165; SER-171; THR-175 AND THR-355, UBIQUITINATION, MUTAGENESIS OF THR-355, INTERACTION WITH FBXW8.

    Entry informationi

    Entry nameiM4K1_HUMAN
    AccessioniPrimary (citable) accession number: Q92918
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: March 28, 2003
    Last sequence update: February 1, 1997
    Last modified: October 1, 2014
    This is version 139 of the entry and version 1 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 19
      Human chromosome 19: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3