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    MAP3K3 mitogen-activated protein kinase kinase kinase 3 [ Homo sapiens (human) ]

    Gene ID: 4215, updated on 10-Dec-2024

    Summary

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    Official Symbol
    MAP3K3provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase 3provided by HGNC
    Primary source
    HGNC:HGNC:6855
    See related
    Ensembl:ENSG00000198909 MIM:602539; AllianceGenome:HGNC:6855
    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
    CCM5; 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]
    Expression
    Ubiquitous expression in spleen (RPKM 15.4), lung (RPKM 14.5) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP3K3 in Genome Data Viewer
    Location:
    17q23.3
    Exon count:
    19
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 17 NC_000017.11 (63622417..63696305)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 17 NC_060941.1 (64493028..64567209)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 17 NC_000017.10 (61699777..61773665)

    Chromosome 17 - NC_000017.11Genomic Context describing neighboring genes Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:61687966-61688466 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:61688467-61688967 Neighboring gene translational activator of cytochrome c oxidase I Neighboring gene family with sequence similarity 136 member A pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8821 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8822 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8823 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8824 Neighboring gene eukaryotic translation elongation factor 1 delta pseudogene 7 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12550 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12551 Neighboring gene VISTA enhancer hs1856 Neighboring gene uncharacterized LOC101927898 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12552 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12553 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12554 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:61771715-61772602 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12555 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12556 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12557 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 12558 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8826 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8827 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:61777898-61778483 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr17:61778484-61779068 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8829 Neighboring gene uncharacterized LOC729683 Neighboring gene LIM domain containing 2 Neighboring gene Sharpr-MPRA regulatory region 9817 Neighboring gene STE20 related adaptor alpha Neighboring gene H3K4me1 hESC enhancer GRCh37_chr17:61817285-61817784 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 8830

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

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    Related articles in PubMed

    1. MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3. Zhao L, et al. Mol Pharm, 2018 Apr 2. PMID 29528232
    2. Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. Ellinger-Ziegelbauer H, et al. J Biol Chem, 1997 Jan 31. PMID 9006902
    3. The expression and role of MEKK3 in renal clear cell carcinoma. Lu H, et al. Anat Rec (Hoboken), 2015 Apr. PMID 25388155
    4. Mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3) overexpression is an early event in esophageal tumorigenesis and is a predictor of poor disease prognosis. Hasan R, et al. BMC Cancer, 2014 Jan 2. PMID 24383423, Free PMC Article
    5. Insight into the binding properties of MEKK3 PB1 to MEK5 PB1 from its solution structure. Hu Q, et al. Biochemistry, 2007 Nov 27. PMID 17985933

    See all (114) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.
      Title: Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.
    2. Circ_0006988 promotes the proliferation, metastasis and angiogenesis of non-small cell lung cancer cells by modulating miR-491-5p/MAP3K3 axis.
      Title: Circ_0006988 promotes the proliferation, metastasis and angiogenesis of non-small cell lung cancer cells by modulating miR-491-5p/MAP3K3 axis.
    3. Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.
      Title: Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.
    4. MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling.
      Title: MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling.
    5. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation.
      Title: Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation.
    6. Overexpression of MAP3K3 promotes tumour growth through activation of the NF-kappaB signalling pathway in ovarian carcinoma.
      Title: Overexpression of MAP3K3 promotes tumour growth through activation of the NF-κB signalling pathway in ovarian carcinoma.
    7. This study suggests that expression of miR-194 is down-regulated in nasopharyngeal carcinoma, and that miR-194 can directly target MAP3K3 to regulate tumor progression. Given the pivotal involvement of MAP3K3 in nasopharyngeal carcinoma development, targeting miR-194 may be a novel strategy for the treatment of nasopharyngeal carcinoma.
      Title: MiR-194 regulates nasopharyngeal carcinoma progression by modulating MAP3K3 expression.
    8. MEKK3 overexpression prevented the inhibitory effects of miR9 on the viability, migration and invasion of PC cells.
      Title: MicroRNA‑9 suppresses human prostate cancer cell viability, invasion and migration via modulation of mitogen‑activated protein kinase kinase kinase 3 expression.
    9. the data revealed the novel role and target of miR505 in NSCLC cells, which may provide novel insights regarding its role in the carcinogenesis of NSCLC and its potential values for clinical applications.
      Title: miR‑505 inhibits cell growth and EMT by targeting MAP3K3 through the AKT‑NFκB pathway in NSCLC cells.
    10. Its downstream target MAP3K3 could be a potential therapeutic target for NSCLC.
      Title: MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3.
    Submit: New GeneRIF Correction See all GeneRIFs (45)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    EBI GWAS Catalog

    Description
    Genome-wide association study of body height in African Americans: the Women's Health Initiative SNP Health Association Resource (SHARe).
    EBI GWAS Catalog
    Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry.
    EBI GWAS Catalog
    Many sequence variants affecting diversity of adult human height.
    EBI GWAS Catalog
    Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables JUN kinase kinase kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables MAP kinase kinase kinase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein serine/threonine kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    Process Evidence Code Pubs
    involved_in MAPK cascade TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in blood vessel development IEA
    Inferred from Electronic Annotation
    more info
    		  
    acts_upstream_of_or_within intracellular signal transduction IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of canonical NF-kappaB signal transduction IEP
    Inferred from Expression Pattern
    more info
    		 PubMed 
    involved_in positive regulation of p38MAPK cascade IEA
    Inferred from Electronic Annotation
    more info
    		  
    acts_upstream_of_or_within protein autophosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase 3
    Names
    MAP/ERK kinase kinase 3
    MAPK/ERK kinase kinase 3
    MEK kinase 3
    MEKK 3
    NP_001317360.1
    NP_001350697.1
    NP_002392.2
    NP_976226.1
    XP_005257435.1
    XP_047292040.1
    XP_047292041.1
    XP_047292042.1
    XP_047292043.1
    XP_047292044.1
    XP_054172127.1
    XP_054172128.1
    XP_054172129.1
    XP_054172130.1
    XP_054172131.1
    XP_054172132.1

    NCBI Reference Sequences (RefSeq)

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    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_001330431.2 → NP_001317360.1  mitogen-activated protein kinase kinase kinase 3 isoform 3

      Status: REVIEWED

      Source sequence(s)
      AC046185, AK225784, BC008336, BC143224, BE396317, BU633068, CN281110
      Consensus CDS
      CCDS82186.1
      UniProtKB/TrEMBL
      J3KRN4, Q1PBM3
      Related
      ENSP00000462086.1, ENST00000577395.5
      Conserved Domains (2) summary
      cd06405
      Location:45 → 123
      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) ...
      cd06625
      Location:357 → 617
      STKc_MEKK3_like; Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases

    2. NM_001363768.2 → NP_001350697.1  mitogen-activated protein kinase kinase kinase 3 isoform 4

      Status: REVIEWED

      Source sequence(s)
      AC046185, AK225784
      Consensus CDS
      CCDS86624.1
      UniProtKB/TrEMBL
      J3QRB6, Q1PBM3
      Related
      ENSP00000464130.1, ENST00000584573.5
      Conserved Domains (2) summary
      cd06405
      Location:76 → 154
      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) ...
      cd06625
      Location:388 → 648
      STKc_MEKK3_like; Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases

    3. NM_002401.5 → NP_002392.2  mitogen-activated protein kinase kinase kinase 3 isoform 2

      See identical proteins and their annotated locations for NP_002392.2

      Status: REVIEWED

      Source sequence(s)
      AC046185, AL834303, BM728104, BM800091, BQ643432, BU633068
      Consensus CDS
      CCDS32702.1
      UniProtKB/Swiss-Prot
      B2RCW2, D3DU15, Q5BKZ6, Q8N3I9, Q99759
      UniProtKB/TrEMBL
      Q1PBM3
      Related
      ENSP00000354485.4, ENST00000361733.8
      Conserved Domains (2) summary
      cd06405
      Location:45 → 123
      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) ...
      cd06625
      Location:361 → 621
      STKc_MEKK3_like; Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases

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

      See identical proteins and their annotated locations for NP_976226.1

      Status: REVIEWED

      Source sequence(s)
      AC046185, AL834303
      Consensus CDS
      CCDS32701.1
      UniProtKB/TrEMBL
      Q1PBM3
      Related
      ENSP00000354927.3, ENST00000361357.7
      Conserved Domains (2) summary
      cd06405
      Location:76 → 154
      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) ...
      cd06625
      Location:392 → 652
      STKc_MEKK3_like; Catalytic domain of Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 3-like Serine/Threonine Kinases

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000017.11 Reference GRCh38.p14 Primary Assembly

      Range
      63622417..63696305
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_005257378.3 → XP_005257435.1  mitogen-activated protein kinase kinase kinase 3 isoform X1

      Conserved Domains (2) summary
      cd06405
      Location:76 → 154
      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) ...
      cl21453
      Location:392 → 524
      PKc_like; Protein Kinases, catalytic domain

    2. XM_047436084.1 → XP_047292040.1  mitogen-activated protein kinase kinase kinase 3 isoform X2

    3. XM_047436085.1 → XP_047292041.1  mitogen-activated protein kinase kinase kinase 3 isoform X3

    4. XM_047436086.1 → XP_047292042.1  mitogen-activated protein kinase kinase kinase 3 isoform X4

    5. XM_047436087.1 → XP_047292043.1  mitogen-activated protein kinase kinase kinase 3 isoform X5

    6. XM_047436088.1 → XP_047292044.1  mitogen-activated protein kinase kinase kinase 3 isoform X6

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060941.1 Alternate T2T-CHM13v2.0

      Range
      64493028..64567209
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054316152.1 → XP_054172127.1  mitogen-activated protein kinase kinase kinase 3 isoform X1

    2. XM_054316153.1 → XP_054172128.1  mitogen-activated protein kinase kinase kinase 3 isoform X2

    3. XM_054316154.1 → XP_054172129.1  mitogen-activated protein kinase kinase kinase 3 isoform X3

    4. XM_054316155.1 → XP_054172130.1  mitogen-activated protein kinase kinase kinase 3 isoform X4

    5. XM_054316156.1 → XP_054172131.1  mitogen-activated protein kinase kinase kinase 3 isoform X5

    6. XM_054316157.1 → XP_054172132.1  mitogen-activated protein kinase kinase kinase 3 isoform X6

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q99759.2 GenPept UniProtKB/Swiss-Prot:Q99759

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