MAP3K4 mitogen-activated protein kinase kinase kinase 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: MAP3K4provided by HGNC
Official Full Name: mitogen-activated protein kinase kinase kinase 4provided by HGNC
Primary source: HGNC:HGNC:6856
See related: Ensembl:ENSG00000085511 MIM:602425; AllianceGenome:HGNC:6856
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: MTK1; MEKK4; MEKK 4; MAPKKK4; PRO0412
Summary: The central core of each mitogen-activated protein kinase (MAPK) pathway is a conserved cascade of 3 protein kinases: an activated MAPK kinase kinase (MAPKKK) phosphorylates and activates a specific MAPK kinase (MAPKK), which then activates a specific MAPK. While the ERK MAPKs are activated by mitogenic stimulation, the CSBP2 and JNK MAPKs are activated by environmental stresses such as osmotic shock, UV irradiation, wound stress, and inflammatory factors. This gene encodes a MAPKKK, the MEKK4 protein, also called MTK1. This protein contains a protein kinase catalytic domain at the C terminus. The N-terminal nonkinase domain may contain a regulatory domain. Expression of MEKK4 in mammalian cells activated the CSBP2 and JNK MAPK pathways, but not the ERK pathway. In vitro kinase studies indicated that recombinant MEKK4 can specifically phosphorylate and activate PRKMK6 and SERK1, MAPKKs that activate CSBP2 and JNK, respectively but cannot phosphorylate PRKMK1, an MAPKK that activates ERKs. MEKK4 is a major mediator of environmental stresses that activate the CSBP2 MAPK pathway, and a minor mediator of the JNK pathway. Several alternatively spliced transcripts encoding distinct isoforms have been described. [provided by RefSeq, May 2014]
Expression: Ubiquitous expression in testis (RPKM 9.3), endometrium (RPKM 7.2) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 6q26

Exon count:: 29

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	6	NC_000006.12 (160991769..161117380)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	6	NC_060930.1 (162350255..162475786)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	6	NC_000006.11 (161412801..161538412)

Chromosome 6 - NC_000006.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract.
Title: CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract.
CircMAP3K4 protects human lens epithelial cells from H2O2-induced dysfunction by targeting miR-193a-3p/PLCD3 axis in age-related cataract.
Title: CircMAP3K4 protects human lens epithelial cells from H(2)O(2)-induced dysfunction by targeting miR-193a-3p/PLCD3 axis in age-related cataract.
Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease.
Title: Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease.
Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.
Title: Association between MAP3K4 gene polymorphisms and the risk of schizophrenia susceptibility in a Northeast Chinese Han population.
Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
Title: Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.
A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.
Title: A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.
These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.
Title: Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein.
MAP3K4 was up-regulated and its expression was inversely correlated with collagen expression in the osteoblasts from older donors.
Title: Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis.
IL-21 expression is promoted by MEKK4 in malignant T cells and is associated with progression risk in cutaneous T-cell lymphoma
Title: The Expression of IL-21 Is Promoted by MEKK4 in Malignant T Cells and Associated with Increased Progression Risk in Cutaneous T-Cell Lymphoma.
Mutations in genes such as AKT2, CCNA1, MAP3K4, and TGFBR1, were associated significantly with Epstein-Barr-positive gastric tumors, compared with EBV-negative tumors.
Title: Integrative identification of Epstein-Barr virus-associated mutations and epigenetic alterations in gastric cancer.

Submit: New GeneRIF Correction See all GeneRIFs (22)

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
Linkage and association of successful aging to the 6q25 region in large Amish kindreds. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SHGC-30412 (e-PCR)
- UniSTS:49215

RH46702 (e-PCR)
- UniSTS:49216

STS-H27759 (e-PCR)
- UniSTS:71492

MAP3K4 (e-PCR)
- UniSTS:506451

WI-18238 (e-PCR)
- UniSTS:46165

RH46673 (e-PCR)
- UniSTS:11409

G59700 (e-PCR)
- UniSTS:136854

RH25424 (e-PCR)
- UniSTS:9932

SHGC-154618 (e-PCR)
- UniSTS:178141

RH46613 (e-PCR)
- UniSTS:79847

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables MAP kinase kinase kinase activity	IDA Inferred from Direct Assay 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 serine kinase activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in MAPK cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in chorionic trophoblast cell differentiation	IEA Inferred from Electronic Annotation more info
involved_in intracellular signal transduction	ISS Inferred from Sequence or Structural Similarity more info
involved_in male germ-line sex determination	IEA Inferred from Electronic Annotation more info
involved_in placenta development	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of JUN kinase activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of p38MAPK cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of telomerase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of telomere capping	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of telomere maintenance via telomerase	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of gene expression	IEA Inferred from Electronic Annotation more info
involved_in response to UV-C	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in perinuclear region of cytoplasm	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: mitogen-activated protein kinase kinase kinase 4

Names: MAP three kinase 1; MAP/ERK kinase kinase 4; MAPK/ERK kinase kinase 4; MEK kinase 4; SSK2/SSK22 MAP kinase kinase kinase, yeast, homolog of; dJ473J16.1 (mitogen-activated protein kinase kinase kinase 4); predicted protein of HQ0412

NP_001278887.1

EC 2.7.11.25

NP_001288001.2

EC 2.7.11.25

NP_001350511.2

EC 2.7.11.25

NP_005913.3

EC 2.7.11.25

NP_006715.3

EC 2.7.11.25

XP_047274739.1

EC 2.7.11.25

XP_054211427.1

EC 2.7.11.25

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)

NM_001291958.2 → NP_001278887.1 mitogen-activated protein kinase kinase kinase 4 isoform c

Status: REVIEWED

Description

Transcript Variant: This variant (3) contains an alternate exon compared to variant 1. The resulting isoform (c) has a shorter and distinct N-terminus compared to isoform a.

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

UniProtKB/Swiss-Prot

Q9Y6R4

Conserved Domains (2) summary

smart00220
Location:796 → 1054

S_TKc; Serine/Threonine protein kinases, catalytic domain

cd06626
Location:795 → 1054

STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
NM_001301072.2 → NP_001288001.2 mitogen-activated protein kinase kinase kinase 4 isoform d

Status: REVIEWED

Description

Transcript Variant: This variant (5) lacks an in-frame segment of a coding exon, compared to variant 1, resulting in a shorter protein (isoform d) compared to isoform a.

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

Consensus CDS

CCDS75544.1

UniProtKB/TrEMBL

F5H4R1, F5H538

Related

ENSP00000355887.2, ENST00000366920.6

Conserved Domains (1) summary

cd06626
Location:1338 → 1597

STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
NM_001363582.2 → NP_001350511.2 mitogen-activated protein kinase kinase kinase 4 isoform e

Status: REVIEWED

Description

Transcript Variant: This variant (6) uses an alternate in-frame splice junction and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (e) has the same N- and C-termini but is shorter compared to isoform a.

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

Consensus CDS

CCDS87464.1

UniProtKB/TrEMBL

F5H4R1, J3KNB8

Related

ENSP00000297332.10, ENST00000348824.11

Conserved Domains (1) summary

cd06626
Location:1288 → 1547

STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
NM_005922.4 → NP_005913.3 mitogen-activated protein kinase kinase kinase 4 isoform a

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (a).

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

Consensus CDS

CCDS34565.1

UniProtKB/Swiss-Prot

A6H8W0, B7ZLD3, B9EG75, Q5VTT8, Q5VTT9, Q92612, Q9H408, Q9Y6R4

UniProtKB/TrEMBL

F5H4R1

Related

ENSP00000375986.4, ENST00000392142.9

Conserved Domains (1) summary

cd06626
Location:1342 → 1601

STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4
NM_006724.4 → NP_006715.3 mitogen-activated protein kinase kinase kinase 4 isoform b

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an alternate in-frame exon compared to variant 1, resulting in a shorter protein (isoform b) compared to isoform a.

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

Consensus CDS

CCDS34566.1

UniProtKB/TrEMBL

F5H4R1

Related

ENSP00000355886.2, ENST00000366919.6

Conserved Domains (1) summary

cd06626
Location:1292 → 1551

STKc_MEKK4; Catalytic domain of the Protein Serine/Threonine Kinase, Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 4

RNA

NR_120425.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (4) contains an alternate exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AL109942, AL139393, AL591045, AL596452

Related

ENST00000544041.5