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    MAP4K3 mitogen-activated protein kinase kinase kinase kinase 3 [ Homo sapiens (human) ]

    Gene ID: 8491, updated on 5-May-2024

    Summary

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    Official Symbol
    MAP4K3provided by HGNC
    Official Full Name
    mitogen-activated protein kinase kinase kinase kinase 3provided by HGNC
    Primary source
    HGNC:HGNC:6865
    See related
    Ensembl:ENSG00000011566 MIM:604921; AllianceGenome:HGNC:6865
    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
    GLK; MEKKK3; MEKKK 3; MAPKKKK3; RAB8IPL1
    Summary
    This gene encodes a member of the mitogen-activated protein kinase kinase kinase kinase family. The encoded protein activates key effectors in cell signalling, among them c-Jun. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]
    Expression
    Ubiquitous expression in thyroid (RPKM 14.7), testis (RPKM 13.3) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See MAP4K3 in Genome Data Viewer
    Location:
    2p22.1
    Exon count:
    35
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (39249266..39437285, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (39258084..39446168, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (39476407..39664426, complement)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene SOS Ras/Rac guanine nucleotide exchange factor 1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:39337207-39337706 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15612 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11384 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15613 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15614 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11385 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15615 Neighboring gene heat shock protein family E (Hsp10) member 1 pseudogene 13 Neighboring gene CRISPRi-validated cis-regulatory element chr2.1553 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:39376789-39377290 Neighboring gene CRISPRi-validated cis-regulatory element chr2.1554 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:39378016-39378184 Neighboring gene Sharpr-MPRA regulatory region 10874 Neighboring gene MPRA-validated peak3670 silencer Neighboring gene NANOG hESC enhancer GRCh37_chr2:39446895-39447396 Neighboring gene cyclin dependent kinase like 4 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr2:39547717-39548636 Neighboring gene MPRA-validated peak3671 silencer Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr2:39591272-39591838 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr2:39591839-39592405 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr2:39592406-39592972 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:39596426-39596599 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15616 Neighboring gene RNA, U6 small nuclear 1341, pseudogene Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15617 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11386 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11387 Neighboring gene MAP4K3 divergent transcript Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr2:39696648-39697148 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11388 Neighboring gene Sharpr-MPRA regulatory region 10578 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:39742467-39742687 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:39742776-39743368 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr2:39743369-39743960 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:39743961-39744553 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 15618 Neighboring gene transmembrane protein 178A Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:39948161-39948662 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:39948663-39949162

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus. Chuang HC, et al. Ann Rheum Dis, 2022 Feb. PMID 34610951, Free PMC Article
    2. Studying the Role and Molecular Mechanisms of MAP4K3 in Sorafenib Resistance of Hepatocellular Carcinoma. Shi Y, et al. Biomed Res Int, 2020. PMID 33204699, Free PMC Article
    3. Germinal-center kinase-like kinase co-crystal structure reveals a swapped activation loop and C-terminal extension. Marcotte D, et al. Protein Sci, 2017 Feb. PMID 27727493, Free PMC Article
    4. Prediction of early hepatocellular carcinoma recurrence using germinal center kinase-like kinase. Ho CH, et al. Oncotarget, 2016 Aug 2. PMID 27343552, Free PMC Article
    5. GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer. Hsu CP, et al. Oncotarget, 2016 Jul 5. PMID 27203390, Free PMC Article

    See all (50) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.
      Title: Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.
    2. MiR-338-3p inhibits growth of glioblastoma through targeting MAP4K3.
      Title: MiR-338-3p inhibits growth of glioblastoma through targeting MAP4K3.
    3. The GLK-induced AhR-ROR-gammat (and AhR-phosphorylated ROR-gammat) complex is a therapeutic target for the GLK(high)IL-17A(high) subpopulation of human patients with SLE.
      Title: AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLK(high)IL-17A(high) subpopulation of systemic lupus erythematosus.
    4. These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis
      Title: MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1.
    5. MiR-206 contributed to euthyrox resistance in PTC cells through blockage p38 and JNK signaling pathway by targeting MAP4K3.
      Title: Over-expression of miR-206 decreases the Euthyrox-resistance by targeting MAP4K3 in papillary thyroid carcinoma.
    6. MAP4K3 is identified as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy.
      Title: MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB.
    7. hepatocellular carcinoma recurrence may involve germinal center kinase-like kinase
      Title: Prediction of early hepatocellular carcinoma recurrence using germinal center kinase-like kinase.
    8. Data indicate that GLK/MAP4K3 is a prognostic biomarker for non-small cell lung cancer (NSCLC) recurrence.
      Title: GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer.
    9. Authors report that miR-199a-5p and let-7c cooperatively and efficiently inhibit HCC cell migration and invasion by targeting the metastasis promoter MAP4K3 and MAP4K3-mediated drug sensitization.
      Title: MiR-199a-5p and let-7c cooperatively inhibit migration and invasion by targeting MAP4K3 in hepatocellular carcinoma.
    10. This report details the first structure of GLK; comparison of its activation loop sequence and P-loop structure to that of Map4k4 suggests ideas for designing inhibitors that can distinguish between these family members to achieve selective pharmacological inhibitors.
      Title: Germinal-center kinase-like kinase co-crystal structure reveals a swapped activation loop and C-terminal extension.
    Submit: New GeneRIF Correction See all GeneRIFs (19)

    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

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    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 IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables MAP kinase kinase kinase kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein kinase activity TAS
    Traceable Author Statement
    more info
    		 PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in JNK cascade TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in intracellular signal transduction IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in intracellular signal transduction IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein phosphorylation IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in response to UV IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in response to tumor necrosis factor 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
    		  

    General protein information

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    Preferred Names
    mitogen-activated protein kinase kinase kinase kinase 3
    Names
    MAPK/ERK kinase kinase kinase 3
    MEK kinase kinase 3
    germinal center kinase-like kinase
    germinal center kinase-related protein kinase
    NP_001257354.1
    NP_001397682.1
    NP_003609.2
    XP_024308951.1
    XP_047302047.1
    XP_047302048.1
    XP_054200218.1
    XP_054200219.1
    XP_054200220.1

    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.

    Genomic

    1. NG_028007.1 RefSeqGene

      Range
      4794..192813
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001270425.2 → NP_001257354.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform 2

      See identical proteins and their annotated locations for NP_001257354.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an exon in the coding region, but maintains the reading frame, compared to variant 1. The encoded protein (isoform 2) is shorter than isoform 1.
      Source sequence(s)
      AC007684, AC079615, AK021553, AK314487, DA409370
      Consensus CDS
      CCDS58707.1
      UniProtKB/TrEMBL
      A8K602
      Related
      ENSP00000345434.5, ENST00000341681.9
      Conserved Domains (3) summary
      smart00036
      Location:540 → 853
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:16 → 273
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06613
      Location:15 → 273
      STKc_MAP4K3_like; Catalytic domain of Mitogen-activated protein kinase kinase kinase kinase (MAP4K) 3-like Serine/Threonine Kinases

    2. NM_001410753.1 → NP_001397682.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform 3

      Status: REVIEWED

      Source sequence(s)
      AC007684, AC079615
      Consensus CDS
      CCDS92741.1
      UniProtKB/TrEMBL
      F5H5A3
      Related
      ENSP00000416958.1, ENST00000437545.5

    3. NM_003618.4 → NP_003609.2  mitogen-activated protein kinase kinase kinase kinase 3 isoform 1

      See identical proteins and their annotated locations for NP_003609.2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer protein (isoform 1).
      Source sequence(s)
      AC007684, AC079615, AK021553, AK291467, DA409370
      Consensus CDS
      CCDS1803.1
      UniProtKB/Swiss-Prot
      Q6IQ39, Q8IVH7, Q8IVH8, Q9UDM5, Q9Y6R5
      UniProtKB/TrEMBL
      A8K602
      Related
      ENSP00000263881.3, ENST00000263881.8
      Conserved Domains (3) summary
      smart00036
      Location:561 → 874
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:16 → 273
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06613
      Location:15 → 273
      STKc_MAP4K3_like; Catalytic domain of Mitogen-activated protein kinase kinase kinase kinase (MAP4K) 3-like Serine/Threonine Kinases

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      39249266..39437285 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047446092.1 → XP_047302048.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X2

    2. XM_024453183.2 → XP_024308951.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X3

      UniProtKB/TrEMBL
      B4DSS3
      Conserved Domains (1) summary
      smart00036
      Location:114 → 427
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2

    3. XM_047446091.1 → XP_047302047.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X1

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      39258084..39446168 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054344244.1 → XP_054200219.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X2

    2. XM_054344245.1 → XP_054200220.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X3

      UniProtKB/TrEMBL
      B4DSS3

    3. XM_054344243.1 → XP_054200218.1  mitogen-activated protein kinase kinase kinase kinase 3 isoform X1

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q8IVH8.1 GenPept UniProtKB/Swiss-Prot:Q8IVH8

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