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    MAP3K3 mitogen-activated protein kinase kinase kinase 3 [ Homo sapiens ]

    Gene ID: 4215, updated on 19-May-2012
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    Summary

    Official Symbol
    MAP3K3provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 3provided by HGNC
    Primary source
    HGNC:6855
    See related
    Ensembl:ENSG00000198909; HPRD:03965; MIM:602539
    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
    MEKK3; MAPKKK3
    Summary
    This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
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    Genomic context

    Location :
    17q23.3
    Sequence :
    Chromosome: 17; NC_000017.10 (61699801..61773670)
    See MAP3K3 in Epigenomics, MapViewer

    Chromosome 17 - NC_000017.10Genomic Context describing neighboring genes Neighboring gene translational activator of mitochondrially encoded cytochrome c oxidase I Neighboring gene family with sequence similarity 136, member A pseudogene Neighboring gene eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange protein) pseudogene Neighboring gene uncharacterized LOC729683 Neighboring gene LIM domain containing 2 Neighboring gene STE20-related kinase adaptor alpha

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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. A directed protein interaction network for investigating intracellular signal transduction. Vinayagam A, et al. Sci Signal, 2011 Sep 6. PMID 21900206.
    2. A human MAP kinase interactome. Bandyopadhyay S, et al. Nat Methods, 2010 Oct. PMID 20936779.
    3. Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study. Bailey SD, et al. Diabetes Care, 2010 Oct. PMID 20628086.
    4. The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. Kriegs M, et al. DNA Repair (Amst), 2010 Aug 5. PMID 20615764.
    5. Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas. Kuboki Y, et al. Mod Pathol, 2010 Aug. PMID 20495538.

    See all (53) 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. The regulation of NHEJ by EGFR was only blocked when ERK was affected by siRNA but not when AKT was knocked down. These data indicate that EGFR modulates DSB repair by regulating NHEJ via MAPK signalling.
      Title: The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining.
    2. EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms of the pancreas.
      Title: Association of epidermal growth factor receptor and mitogen-activated protein kinase with cystic neoplasms of the pancreas.
    3. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
      Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
    4. Observational study of gene-disease association. (HuGE Navigator)
      Title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
    5. PP2A plays an important role in the termination of LPA-mediated NF-kappaB activation through dephosphorylating and inactivating MEKK3
      Title: Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation.
    6. we report the identification of two regulatory phosphorylation sites at Thr-516 and Ser-520 within the kinase activation loop that is essential for MEKK3-mediated IkappaB kinase beta (IKKbeta)/NF-kappaB activation
      Title: Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation.
    7. The rear end acidic cluster of the p62 PB1 domain is used to organize cytosolic aggregates or speckles-associated TRAF6-p62-MEKK3 complex for control of NF-kappaB activation.
      Title: PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation.
    8. These results strongly suggested that Hsp90 could work as the molecular chaperone of MEKK3.
      Title: Heat shock protein 90 regulates the stability of MEKK3 in HEK293 cells.
    9. Specific ablation of MEKK3 in T cells of conditional knockout mice does not significantly alter thymic T cell development, but leads to a peripheral T cell homeostasis defect.
      Title: MEKK3 is essential for lymphopenia-induced T cell proliferation and survival.
    10. identifies a potentially important regulatory step in MEKK3 signaling via dephosphorylation of Thr(294), which reduces 14-3-3 binding correlating with MEKK3 pathway activation
      Title: Phosphorylation of MEKK3 at threonine 294 promotes 14-3-3 association to inhibit nuclear factor kappaB activation.
    Submit: New GeneRIF Correction See all (19)
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    Phenotypes

    Review eQTL and phenotype association data in this region using PheGenI

    Many sequence variants affecting diversity of adult human height.

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    Interactions

    Products Interactant Other Gene Complex Source Pubs Description
    NP_002392.2 NP_009225.1 BRCA1    BIND  PubMed BRCA1 interacts with MEKK3. 
    Q99759 P38398 BRCA1    HPRD  PubMed  
    Q99759 Q16543 CDC37    HPRD  PubMed  
    Q99759 Q13480 GAB1    HPRD  PubMed  
    Q99759 P07900 HSP90AA1    HPRD  PubMed  
    Q99759 P08238 HSP90AB1    HPRD  PubMed  
    Q99759 P54652 HSPA2    HPRD  PubMed  
    Q99759 O14920 IKBKB    HPRD  PubMed  
    Q99759 Q13163 MAP2K5    HPRD  PubMed  
    Q99759 Q99759 MAP3K3    HPRD  PubMed  
    Q99759 Q99683 MAP3K5    HPRD  PubMed  
    Q99759 O43318 MAP3K7    HPRD  PubMed  
    Q99759 Q7KZI7 MARK2    HPRD  PubMed  
    Q99759 P25963 NFKBIA    HPRD  PubMed  
    Q99759 Q9UHV9 PFDN2    HPRD  PubMed  
    Q99759 P17612 PRKACA    HPRD  PubMed  
    Q99759 P53805 RCAN1    HPRD  PubMed  
    Q99759 Q13546 RIPK1    HPRD  PubMed  
    Q99759 O60271 SPAG9    HPRD  PubMed  
    Q99759 Q9Y4K3 TRAF6    HPRD  PubMed  
    Q99759 Q6Q0C0 TRAF7    HPRD  PubMed  
    Q99759 Q9H4A3 WNK1    HPRD  PubMed  
    Q99759 P31946 YWHAB    HPRD  PubMed  
    Q99759 P62258 YWHAE    HPRD  PubMed  
    Q99759 P61981 YWHAG    HPRD  PubMed  
    Q99759 Q04917 YWHAH    HPRD  PubMed  
    Q99759 P27348 YWHAQ    HPRD  PubMed  
    Q99759 P63104 YWHAZ    HPRD  PubMed  
    Q99759 Q05516 ZBTB16    HPRD  PubMed  
    BioGRID:110379 BioGRID:107140 BRCA1    BioGRID  PubMed Affinity Capture-Western; Two-hybrid 
    BioGRID:110379 BioGRID:116312 CDC37    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:116183 COPS5    BioGRID  PubMed Two-hybrid 
    BioGRID:110379 BioGRID:108824 GAB1    BioGRID  PubMed Affinity Capture-Western; Reconstituted Complex 
    BioGRID:110379 BioGRID:109552 HSP90AA1    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:110379 BioGRID:109556 HSP90AA2    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:109540 HSPA4    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:111593 MAP2K5    BioGRID  PubMed Affinity Capture-MS; Affinity Capture-Western; Two-hybrid 
    BioGRID:110379 BioGRID:108326 MARK2    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:110811 NEDD4    BioGRID  PubMed Biochemical Activity; Reconstituted Complex 
    BioGRID:110379 BioGRID:116915 NEDD4L    BioGRID  PubMed Biochemical Activity 
    BioGRID:110379 BioGRID:247522 Nedd4    BioGRID  PubMed Biochemical Activity 
    BioGRID:110379 BioGRID:123533 PDRG1    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:111224 PFDN2    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:114505 SPAG9    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:110379 BioGRID:114397 SQSTM1    BioGRID  PubMed Affinity Capture-Western; Co-localization; Reconstituted Complex 
    BioGRID:110379 BioGRID:115352 TOM1L1    BioGRID  PubMed Two-hybrid 
    BioGRID:110379 BioGRID:113041 TRAF6    BioGRID  PubMed Affinity Capture-Western; Co-localization; Reconstituted Complex 
    NP_115647.2 TRAF7    BIND  PubMed TRAF7 interacts with an unspecified isoform of MAP3K3 (MEKK3). 
    BioGRID:110379 BioGRID:123964 TRAF7    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:113164 UBC    BioGRID  PubMed Affinity Capture-Western 
    BioGRID:110379 BioGRID:113289 VWF    BioGRID  PubMed Two-hybrid 
    BioGRID:110379 BioGRID:113363 YWHAE    BioGRID  PubMed Affinity Capture-Western; Reconstituted Complex; Two-hybrid 
    BioGRID:110379 BioGRID:113364 YWHAG    BioGRID  PubMed Affinity Capture-MS 
    BioGRID:110379 BioGRID:113498 ZBTB16    BioGRID  PubMed Two-hybrid 
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    General gene information

    Markers

    Genotypes

    Homology

    Pathways from BioSystems

    • Cytokine Signaling in Immune system, organism-specific biosystem (from REACTOME)
      Cytokine Signaling in Immune system, organism-specific biosystemCytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted in response to immune stimuli, and usually act briefly, locally, at very low concen...
    • EGFR1 Signaling Pathway, organism-specific biosystem (from WikiPathways)
      EGFR1 Signaling Pathway, organism-specific biosystemThe androgen receptor is a member of the nuclear receptor family of ligand activated transcription factors. These receptors bind to steroid hormones, thyroid hormone, retinoids and vitamin D among ot...
    • GnRH signaling pathway, organism-specific biosystem (from KEGG)
      GnRH signaling pathway, organism-specific biosystemGonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnR...
    • GnRH signaling pathway, conserved biosystem (from KEGG)
      GnRH signaling pathway, conserved biosystemGonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnR...
    • HTLV-I infection, organism-specific biosystem (from KEGG)
      HTLV-I infection, organism-specific biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...
    • HTLV-I infection, conserved biosystem (from KEGG)
      HTLV-I infection, conserved biosystemHuman T-lymphotropic virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammato...
    • IL1-mediated signaling events, organism-specific biosystem (from Pathway Interaction Database)
      IL1-mediated signaling events, organism-specific biosystem
      IL1-mediated signaling events
    • Immune System, organism-specific biosystem (from REACTOME)
      Immune System, organism-specific biosystemHumans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first crit...
    • Insulin Signaling, organism-specific biosystem (from WikiPathways)
      Insulin Signaling, organism-specific biosystem
      Insulin Signaling
    • Interleukin-1 signaling, organism-specific biosystem (from REACTOME)
      Interleukin-1 signaling, organism-specific biosystemInterleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand bindi...
    • MAPK Cascade, organism-specific biosystem (from WikiPathways)
      MAPK Cascade, organism-specific biosystem
      MAPK Cascade
    • MAPK signaling pathway, organism-specific biosystem (from KEGG)
      MAPK signaling pathway, organism-specific biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...
    • MAPK signaling pathway, conserved biosystem (from KEGG)
      MAPK signaling pathway, conserved biosystemThe mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals e...
    • Neurotrophin signaling pathway, organism-specific biosystem (from KEGG)
      Neurotrophin signaling pathway, organism-specific biosystemNeurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic facto...
    • Neurotrophin signaling pathway, conserved biosystem (from KEGG)
      Neurotrophin signaling pathway, conserved biosystemNeurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic facto...
    • Regulation of p38-alpha and p38-beta, organism-specific biosystem (from Pathway Interaction Database)
      Regulation of p38-alpha and p38-beta, organism-specific biosystem
      Regulation of p38-alpha and p38-beta
    • Signaling by Interleukins, organism-specific biosystem (from REACTOME)
      Signaling by Interleukins, organism-specific biosystemInterleukins are low molecular weight proteins that bind to cell surface receptors and act in an autocrine and/or paracrine fashion. They were first identified as factors produced by leukocytes but a...
    • TNF receptor signaling pathway, organism-specific biosystem (from Pathway Interaction Database)
      TNF receptor signaling pathway, organism-specific biosystem
      TNF receptor signaling pathway
    • TNF-alpha/NF-kB Signaling Pathway, organism-specific biosystem (from WikiPathways)
      TNF-alpha/NF-kB Signaling Pathway, organism-specific biosystem"The Tumor Necrosis Factor alpha is a proinflammatory cytokine belonging to the TNF superfamily. It signals through 2 separate receptors - TNFRSF1A and TNFRSF1B, both members of the TNF receptor supe...
    • p38 MAPK signaling pathway, organism-specific biosystem (from Pathway Interaction Database)
      p38 MAPK signaling pathway, organism-specific biosystem
      p38 MAPK signaling pathway

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    MAP kinase kinase kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    nucleotide binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    protein kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    protein serine/threonine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    MAPK cascade TAS
    Traceable Author Statement
    more info
    		 PubMed 
    activation of MAPKK activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    intracellular protein kinase cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    positive regulation of I-kappaB kinase/NF-kappaB cascade IEP
    Inferred from Expression Pattern
    more info
    		 PubMed 
    protein autophosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    cytosol TAS
    Traceable Author Statement
    more info
    		  
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    General protein information

    Preferred Names
    mitogen-activated protein kinase kinase kinase 3
    Names
    mitogen-activated protein kinase kinase kinase 3
    MEKK 3
    MEK kinase 3
    MAP/ERK kinase kinase 3
    MAPK/ERK kinase kinase 3
    NP_002392.2
    NP_976226.1
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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_002401.3 → NP_002392.2  mitogen-activated protein kinase kinase kinase 3 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an in-frame coding exon compared to variant 1. The resulting isoform (2) lacks an internal region, as compared to isoform 1.
      Source sequence(s)
      AL834303, BM728104, BM800091, BQ643432, BU633068
      Consensus CDS
      CCDS32702.1
      UniProtKB/Swiss-Prot
      Q99759
      Related
      ENSP00000354485, ENST00000361733
      Conserved Domains (3) summary
      cd06405
      Location:45 – 123
      Blast Score: 362
      PB1_Mekk2_3; The PB1 domain is present in the two mitogen-activated protein kinase kinases MEKK2 and MEKK3 which are two members of the signaling kinase cascade involved in angiogenesis and early cardiovascular development. The PB1 domain of MEKK2 (and/or MEKK3) ...
      cd06651
      Location:359 – 624
      Blast Score: 1430
      STKc_MEKK3; Catalytic domain of the Protein Serine/Threonine Kinase, MAP/ERK kinase kinase 3
      smart00220
      Location:362 – 621
      Blast Score: 781
      S_TKc; Serine/Threonine protein kinases, catalytic domain

    2. NM_203351.1 → NP_976226.1  mitogen-activated protein kinase kinase kinase 3 isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AL834303, BM479726, BM728104, BM800091, BU633068
      Consensus CDS
      CCDS32701.1
      UniProtKB/Swiss-Prot
      Q99759
      Related
      ENSP00000354927, ENST00000361357
      Conserved Domains (3) summary
      cd06405
      Location:76 – 154
      Blast Score: 363
      PB1_Mekk2_3; The PB1 domain is present in the two mitogen-activated protein kinase kinases MEKK2 and MEKK3 which are two members of the signaling kinase cascade involved in angiogenesis and early cardiovascular development. The PB1 domain of MEKK2 (and/or MEKK3) ...
      cd06651
      Location:390 – 655
      Blast Score: 1431
      STKc_MEKK3; Catalytic domain of the Protein Serine/Threonine Kinase, MAP/ERK kinase kinase 3
      smart00220
      Location:393 – 652
      Blast Score: 784
      S_TKc; Serine/Threonine protein kinases, catalytic 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_000017.10 Reference GRCh37.p5 Primary Assembly

      Range
      61699801..61773670
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate HuRef

    Genomic

    1. AC_000149.1 Alternate HuRef

      Range
      57077975..57141816
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
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    Related Sequences

    Nucleotide Protein
    Heading Accession and Version
    genomic AC046185.14 (33313..107182) None
    genomic CH471109.2 EAW94297.1
      EAW94298.1
      EAW94299.1
    genomic CQ760470.1 CAF32906.1
    mRNA AF172823.1 AAQ13617.1
    mRNA AK022333.1 None
    mRNA AK225784.1 None
    mRNA AK308152.1 None
    mRNA AK315305.1 BAG37709.1
    mRNA AL834303.1 CAD38973.1
    mRNA AX775739.1 CAE11569.1
    mRNA AX775741.1 CAE11570.1
    mRNA BC008336.1 AAH08336.1
    mRNA BC010464.1 None
    mRNA BC018021.1 None
    mRNA BC090859.1 AAH90859.1
    mRNA BC093672.1 AAH93672.1
    mRNA BC093674.1 AAH93674.1
    mRNA BC143224.1 None
    mRNA BC143235.1 None
    mRNA BM479726.1 None
    mRNA BM728104.1 None
    mRNA BM800091.1 None
    mRNA BQ643432.1 None
    mRNA BU633068.1 None
    mRNA DQ454151.1 ABE11554.1
    mRNA U78876.1 AAB41729.1
    other-genetic AM392833.1 CAL37711.1
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q1PBM3 GenPept UniProtKB/TrEMBL:Q1PBM3
    Q7Z4E6 GenPept UniProtKB/TrEMBL:Q7Z4E6
    Q96HN9 GenPept UniProtKB/TrEMBL:Q96HN9
    Q99759.2 GenPept UniProtKB/Swiss-Prot:Q99759
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    Additional Links

    Gene LinkOut

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

    Chemical Information
    Medical
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