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    MAP4K4 mitogen-activated protein kinase kinase kinase kinase 4 [ Homo sapiens ]

    Gene ID: 9448, updated on 11-May-2012
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    Summary

    Official Symbol
    MAP4K4provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase kinase 4provided by HGNC
    Primary source
    HGNC:6866
    See related
    Ensembl:ENSG00000071054; HPRD:05235; MIM:604666; Vega:OTTHUMG00000155394
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    HGK; NIK; MEKKK4; FLH21957; FLJ10410; FLJ20373; FLJ90111; KIAA0687
    Summary
    The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase has been shown to specifically activate MAPK8/JNK. The activation of MAPK8 by this kinase is found to be inhibited by the dominant-negative mutants of MAP3K7/TAK1, MAP2K4/MKK4, and MAP2K7/MKK7, which suggests that this kinase may function through the MAP3K7-MAP2K4-MAP2K7 kinase cascade, and mediate the TNF-alpha signaling pathway. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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    Genomic context

    Location :
    2q11.2-q12
    Sequence :
    Chromosome: 2; NC_000002.11 (102314165..102511152)
    See MAP4K4 in Epigenomics, MapViewer

    Chromosome 2 - NC_000002.11Genomic Context describing neighboring genes Neighboring gene prolylcarboxypeptidase (angiotensinase C) pseudogene Neighboring gene ribosomal protein S6 pseudogene 3 Neighboring gene uncharacterized LOC100506328 Neighboring gene interleukin 1 receptor, type II

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    Genomic regions, transcripts, and products

    Go to nucleotideGraphics FASTA GenBank

    Go to reference sequence details
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    Bibliography

    Related articles in PubMed

    1. Protein phosphatase 1α interacting proteins in the human brain. Esteves SL, et al. OMICS, 2012 Jan-Feb. PMID 22321011.
    2. Systematic and quantitative assessment of the ubiquitin-modified proteome. Kim W, et al. Mol Cell, 2011 Oct 21. PMID 21906983.
    3. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Wagner SA, et al. Mol Cell Proteomics, 2011 Oct. PMID 21890473.
    4. ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth. Liu AW, et al. Clin Cancer Res, 2011 Feb 15. PMID 21196414.
    5. Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Danielsen JM, et al. Mol Cell Proteomics, 2011 Mar. PMID 21139048.

    See all (30) citations in PubMed

    See citations in PubMed for homologs of this gene provided by HomoloGene

    GeneRIFs: Gene References Into Functions What's a GeneRIF?

    1. MAP4K4 overexpression is an independent predictor of poor prognosis of Hepatocellular Carcinoma patients, and inhibition of its expression might be of therapeutic significance
      Title: ShRNA-targeted MAP4K4 inhibits hepatocellular carcinoma growth.
    2. Data show that down-regulation of hepatocyte progenitor kinase-like kinase (HGK) can obviously inhibit the migration and invasion of HepG2 cells in vitro, and suggest that HGK may be a new therapeutic target for treatment of hepatocellular carcinoma.
      Title: Lowered HGK expression inhibits cell invasion and adhesion in hepatocellular carcinoma cell line HepG2.
    3. Results identify MAP4K4 as a key upstream mediator of TNF-alpha action on the beta cell, preventing tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion.
      Title: Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion.
    4. MAP4K4 expression significantly correlated with overall and recurrence-free survival (P=0.025 and 0.004) independent of age, tumor size, differentiation, and stage.
      Title: Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma.
    5. MAP4K4 is a putative effector of Rap2, a Ras family small GTP-binding protein, mediating the activation of JNK by Rap2
      Title: Mitogen-activated protein kinase kinase kinase kinase 4 as a putative effector of Rap2 to activate the c-Jun N-terminal kinase.
    6. interaction with GBP3
      Title: A novel GTP-binding protein hGBP3 interacts with NIK/HGK.
    7. studies of the promigratory role of MAP4K4 showed that the knockdown of this transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility
      Title: A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase.
    8. MAP4K4 silencing prevents TNFa-induced insulin resistance in human skeletal muscle and restores appropriate signaling inputs to enhance glucose uptake
      Title: MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis factor-alpha-induced insulin resistance.
    9. The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion.
      Title: The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion.
    Submit: New GeneRIF Correction
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    Phenotypes

    Review eQTL and phenotype association data in this region using PheGenI

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    Interactions

    Products Interactant Other Gene Complex Source Pubs Description
    O95819 Q99704 DOK1    HPRD  PubMed  
    O95819 Q9H0R5 GBP3    HPRD  PubMed  
    O95819 P05556 ITGB1    HPRD  PubMed  
    O95819 O43318 MAP3K7    HPRD  PubMed  
    O95819 P16333 NCK1    HPRD  PubMed  
    O95819 P10114 RAP2A    HPRD  PubMed  
    O95819 P20936 RASA1    HPRD  PubMed  
    O95819 P19634 SLC9A1    HPRD  PubMed  
    NP_056999.2 ATL1    BIND  PubMed hGBP3 interacts with HGK. 
    BioGRID:114838 BioGRID:107140 BRCA1    BioGRID  PubMed Protein-peptide 
    BioGRID:114838 BioGRID:108905 GBP3    BioGRID  PubMed Affinity Capture-Western; Reconstituted Complex; Two-hybrid 
    BioGRID:114838 BioGRID:113945 HIST2H2BE    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:109894 ITGB1    BioGRID  PubMed Affinity Capture-Western; Reconstituted Complex; Two-hybrid 
    BioGRID:114838 BioGRID:120398 KIF26B    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:109999 KIF5A    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:110378 MAP3K1    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:114838 BioGRID:112748 MAP3K7    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:114838 BioGRID:110770 NCK1    BioGRID  PubMed Affinity Capture-Western; Reconstituted Complex 
    BioGRID:114838 BioGRID:111493 PPP1CA    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:111567 PRKCE    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:111856 RASA1    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:114838 BioGRID:112438 SLC9A1    BioGRID  PubMed Two-hybrid 
    BioGRID:114838 BioGRID:113164 UBC    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:114838 BioGRID:120139 ZRANB1    BioGRID  PubMed Affinity Capture-MS 
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    General gene information

    Markers

    Genotypes

    Homology

    Pathways from BioSystems

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    ATP binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    nucleotide binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    small GTPase regulator activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    intracellular protein kinase cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    regulation of JNK cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    response to stress IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
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    General protein information

    Preferred Names
    mitogen-activated protein kinase kinase kinase kinase 4
    Names
    mitogen-activated protein kinase kinase kinase kinase 4
    MEK kinase kinase 4
    nck-interacting kinase
    HPK/GCK-like kinase HGK
    Ste20 group protein kinase HGK
    MAPK/ERK kinase kinase kinase 4
    hepatocyte progenitor kinase-like/germinal center kinase-like kinase
    NP_001229488.1
    NP_001229489.1
    NP_004825.3
    NP_663719.2
    NP_663720.1
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    NCBI Reference Sequences (RefSeq)

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    mRNA and Protein(s)

    1. NM_001242559.1 → NP_001229488.1  mitogen-activated protein kinase kinase kinase kinase 4 isoform 4

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) uses two alternate in-frame splice sites and lacks an alternate in-frame exon in the central coding region, compared to variant 2. The encoded isoform (4) is shorter than isoform 2. The 5' UTR of this variant is incomplete due to a lack of 5'-complete transcripts representing this variant, and the presence of splicing ambiguity in the 5' UTR.
      Source sequence(s)
      AC005035, AY212247, BU625485, DB086475
      Consensus CDS
      CCDS56130.1
      UniProtKB/Swiss-Prot
      O95819
      Related
      ENSP00000314363, OTTHUMP00000207903, ENST00000347699, OTTHUMT00000339839
      Conserved Domains (3) summary
      cd06636
      Location:8 – 289
      Blast Score: 1359
      STKc_MAP4K4_6; Catalytic domain of the Protein Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 and 6
      smart00220
      Location:25 – 289
      Blast Score: 632
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl02434
      Location:921 – 1219
      Blast Score: 822
      CNH; CNH domain

    2. NM_001242560.1 → NP_001229489.1  mitogen-activated protein kinase kinase kinase kinase 4 isoform 5

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks two alternate in-frame exons but includes two different alternate in-frame exons in the central coding region, compared to variant 2. The encoded isoform (5) is shorter than isoform 2.
      Source sequence(s)
      AC005035, AC007005, AK296396, BU625485, DR002278
      UniProtKB/TrEMBL
      B7Z3V5
      Related
      ENSP00000343658, ENST00000350878
      Conserved Domains (3) summary
      smart00220
      Location:25 – 289
      Blast Score: 633
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl02434
      Location:917 – 1215
      Blast Score: 820
      CNH; CNH domain
      cl09925
      Location:8 – 289
      Blast Score: 1358
      PKc_like; Protein Kinases, catalytic domain

    3. NM_004834.4 → NP_004825.3  mitogen-activated protein kinase kinase kinase kinase 4 isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) lacks two alternate in-frame exons but includes a different in-frame exon in the central coding region, and uses an alternate in-frame splice site in both the central and 3' coding regions, compared to variant 2. The encoded isoform (1) is shorter than isoform 2.
      Source sequence(s)
      AC005035, AC007005, AF096300, BU625485, DR002278
      UniProtKB/Swiss-Prot
      O95819
      Related
      ENSP00000389752, OTTHUMP00000207971, ENST00000413150, OTTHUMT00000339992
      Conserved Domains (3) summary
      cd06636
      Location:8 – 289
      Blast Score: 1360
      STKc_MAP4K4_6; Catalytic domain of the Protein Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 and 6
      smart00220
      Location:25 – 289
      Blast Score: 628
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl02434
      Location:839 – 1145
      Blast Score: 810
      CNH; CNH domain

    4. NM_145686.3 → NP_663719.2  mitogen-activated protein kinase kinase kinase kinase 4 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) represents the longest transcript and encodes the longest isoform (2).
      Source sequence(s)
      AC005035, AC007005, BC064691, BU625485, DR002278
      Related
      ENSP00000392830, OTTHUMP00000207902, ENST00000425019, OTTHUMT00000339838
      Conserved Domains (3) summary
      cd06636
      Location:8 – 289
      Blast Score: 1359
      STKc_MAP4K4_6; Catalytic domain of the Protein Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 and 6
      smart00220
      Location:25 – 289
      Blast Score: 632
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl02434
      Location:955 – 1253
      Blast Score: 822
      CNH; CNH domain

    5. NM_145687.3 → NP_663720.1  mitogen-activated protein kinase kinase kinase kinase 4 isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an alternate in-frame exon but includes a different in-frame exon in the central coding region, compared to variant 2. The encoded isoform (3) is shorter than isoform 2. The 5' UTR of this variant is incomplete due to a lack of 5'-complete transcripts representing this variant, and the presence of splicing ambiguity in the 5' UTR.
      Source sequence(s)
      AB014587, AC005035, BU625485, DB086475
      UniProtKB/Swiss-Prot
      O95819
      Conserved Domains (3) summary
      cd06636
      Location:8 – 289
      Blast Score: 1360
      STKc_MAP4K4_6; Catalytic domain of the Protein Serine/Threonine Kinases, Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 and 6
      smart00220
      Location:25 – 289
      Blast Score: 632
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cl02434
      Location:894 – 1192
      Blast Score: 822
      CNH; CNH domain

    RefSeqs of Annotated Genomes: Build 37.3

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh37.p5 Primary Assembly

    Genomic

    1. NC_000002.11 Reference GRCh37.p5 Primary Assembly

      Range
      102314165..102511152
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate HuRef

    Genomic

    1. AC_000134.1 Alternate HuRef

      Range
      96077883..96275019
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
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    Related Sequences

    Nucleotide Protein
    Heading Accession and Version
    genomic AC005035.2 AAY14969.1
      AAY14970.1
    genomic AC007005.3 AAY24319.1
    genomic CH471127.2 EAX01805.1
      EAX01806.1
      EAX01807.1
      EAX01808.1
      EAX01809.1
      EAX01810.1
    mRNA AB013385.1 BAA33714.1
    mRNA AB014587.1 BAA31662.1
    mRNA AF096300.1 AAD16137.1
    mRNA AK000380.1 BAA91127.1
    mRNA AK001272.1 None
    mRNA AK025610.1 None
    mRNA AK074592.1 None
    mRNA AK074900.1 None
    mRNA AK130085.1 None
    mRNA AK295610.1 BAH12124.1
    mRNA AK296396.1 BAH12341.1
    mRNA AK307879.1 None
    mRNA AL137755.1 CAB70907.2
    mRNA AY212247.1 AAO32626.1
    mRNA AY834276.1 AAV97884.1
    mRNA BC010909.1 None
    mRNA BC040077.1 None
    mRNA BC045694.1 None
    mRNA BC051791.1 None
    mRNA BC054038.1 None
    mRNA BC064691.1 None
    mRNA BC065036.1 None
    mRNA BU595561.1 None
    mRNA BU625485.1 None
    mRNA DB086475.1 None
    mRNA DR002278.1 None
    other-genetic BC156089.1 AAI56090.1
    other-genetic BC156887.1 AAI56888.1
    Protein Accession Links
    GenPept Link UniProtKB Link
    O95819.2 GenPept UniProtKB/Swiss-Prot:O95819
    Q53TW0 GenPept UniProtKB/TrEMBL:Q53TW0
    Q53TX7 GenPept UniProtKB/TrEMBL:Q53TX7
    Q53TX8 GenPept UniProtKB/TrEMBL:Q53TX8
    Q5MD60 GenPept UniProtKB/TrEMBL:Q5MD60
    Q9NX89 GenPept UniProtKB/TrEMBL:Q9NX89
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    Additional Links

    Additional Links

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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