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

Gene ID: 8491, updated on 8-Apr-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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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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