MAP3K5 mitogen-activated protein kinase kinase kinase 5 [Homo sapiens (human)] - Gene

Summary

Official Symbol: MAP3K5provided by HGNC
Official Full Name: mitogen-activated protein kinase kinase kinase 5provided by HGNC
Primary source: HGNC:HGNC:6857
See related: Ensembl:ENSG00000197442 MIM:602448; AllianceGenome:HGNC:6857
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: ASK1; MEKK5; MAPKKK5
Summary: Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq, Jul 2008]
Expression: Broad expression in adrenal (RPKM 43.3), ovary (RPKM 21.3) and 23 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 6q23.3

Exon count:: 33

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	6	NC_000006.12 (136557046..136793091, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	6	NC_060930.1 (137745240..137981287, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	6	NC_000006.11 (136878184..137113615, complement)

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

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Apoptosis Signal-Regulated Kinase-1 Promotes Nucleus Pulposus Cell Senescence and Apoptosis to Regulate Intervertebral Disc Degeneration.
Title: Apoptosis Signal-Regulated Kinase-1 Promotes Nucleus Pulposus Cell Senescence and Apoptosis to Regulate Intervertebral Disc Degeneration.
Multiple Pathway-Dephosphorylated ASK-1 Confers Temozolomide-Resistance to Human Glioma Cells.
Title: Multiple Pathway-Dephosphorylated ASK-1 Confers Temozolomide-Resistance to Human Glioma Cells.
[Tumor antigen-loaded dendritic cells combined with cytokine-induced killer (CIK) enhance the killing activity of human esophageal cancer cells by promoting ASK1 activation].
Title: [Tumor antigen-loaded dendritic cells combined with cytokine-induced killer (CIK) enhance the killing activity of human esophageal cancer cells by promoting ASK1 activation].
Oxidative Stress Kinase Activation and Impaired Insulin Receptor Signaling Precede Overt Alzheimer's Disease Neuropathology.
Title: Oxidative Stress Kinase Activation and Impaired Insulin Receptor Signaling Precede Overt Alzheimer's Disease Neuropathology.
Apoptosis signal-regulating kinase-1 regulates thrombin-induced endothelial permeability.
Title: Apoptosis signal-regulating kinase-1 regulates thrombin-induced endothelial permeability.
Catalytic activity in vitro of the human protein kinase ASK1 mutants: Experimental and molecular simulation study.
Title: Catalytic activity in vitro of the human protein kinase ASK1 mutants: Experimental and molecular simulation study.
Phosphoproteomics identifies pathways underlying the role of receptor-interaction protein kinase 3 in alcohol-associated liver disease and uncovers apoptosis signal-regulating kinase 1 as a target.
Title: Phosphoproteomics identifies pathways underlying the role of receptor-interaction protein kinase 3 in alcohol-associated liver disease and uncovers apoptosis signal-regulating kinase 1 as a target.
Clinical investigation of lipopolysaccharide in the persistence of metabolic syndrome (MS) through the activation of GRP78-IRE1alpha-ASK1 signaling pathway.
Title: Clinical investigation of lipopolysaccharide in the persistence of metabolic syndrome (MS) through the activation of GRP78-IRE1α-ASK1 signaling pathway.
Activation of type 4 metabotropic glutamate receptor attenuates oxygen and glucose deprivation-induced apoptosis in human neural stem cells via inhibition of ASK1-p38 signaling pathway.
Title: Activation of type 4 metabotropic glutamate receptor attenuates oxygen and glucose deprivation-induced apoptosis in human neural stem cells via inhibition of ASK1-p38 signaling pathway.
Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions.
Title: Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions.

Submit: New GeneRIF Correction See all GeneRIFs (193)

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)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Binding of HIV-1 gp120 to DC-SIGN leads to excessive ASK-1 activation and promotes ASK-1-dependent apoptosis in human dendritic cells	PubMed
Nef	nef	HIV-1 Nef inhibits ASK1-induced phosphorylation of p54/p46 JNK in cells. Nef mutant (152DEVGEANN/AAAAAAAA159) abolishes its inhibitory activity	PubMed
	nef	Mutations within the motif (152DEVGEANN159) of HIV-1 Nef impair its ability to interact with ASK1 and restore ASK1 anti-apoptosis function	PubMed
	nef	Amino acids 152-159 in HIV-1 Nef and the N-terminal region (residues 1-318) and the C-terminal region (residues 905-1051) of ASK1 are involved in the binding between Nef and ASK1	PubMed
	nef	Inhibition of ASK1 by HIV-1 Nef leads to the inhibition of both Fas- and TNFalpha-mediated apoptosis, as well as the inhibition of the activation of the downstream c-Jun amino-terminal kinase	PubMed
	nef	HIV-1 Nef inhibits ASK1 catalytic activity by impairing stimulus-coupled release of its normal negative regulator, thioredoxin	PubMed
	nef	Nef inhibits ASK1/p38MAPK-dependent Mycobacterium tuberculosis-induced TNF-alpha production by inhibiting binding of ATF2 to the TNF-alpha promoter	PubMed
	nef	HIV-1 Nef binds to ASK1 as demonstrated by GST-pull down and coimmunoprecipitation experiments	PubMed
Vif	vif	ASK1 restricts the replication of HIV-1 by inhibiting Vif activity and promoting APOBEC3G incorporation into virions in CD4+ T-cells	PubMed
	vif	ASK1 inhibits the interaction of HIV-1 Vif with ELOB/C in a dose-dependent manner, whereas no significant change is observed in the binding of Vif with CUL5 or CBFbeta	PubMed
	vif	ASK1 markedly inhibits HIV-1 Vif-induced ubiquitination of APOBEC3G by a reduction in the Vif-ELOC interaction	PubMed
	vif	The BC box (amino-acid residues 144-149) of HIV-1 Vif binds the C-terminal domain (amino-acid residues 955-1374) of ASK1	PubMed
	vif	ASK1 directly binds HIV-1 Vif and inhibits the anti-APOBEC3G activity by Vif	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

STS-N39603 (e-PCR)
- UniSTS:52994

RH103229 (e-PCR)
- UniSTS:97561

D6S1974 (e-PCR)
- UniSTS:36387

RH102729 (e-PCR)
- UniSTS:97063

SHGC-83246 (e-PCR)
- UniSTS:96048

SHGC-78146 (e-PCR)
- UniSTS:96061

D6S2004 (e-PCR)
- UniSTS:24648

WI-13489 (e-PCR)
- UniSTS:2383

SHGC-58491 (e-PCR)
- UniSTS:94366

FCA844 (e-PCR)
- UniSTS:266179

RH102384 (e-PCR)
- UniSTS:96718

RH46739 (e-PCR)
- UniSTS:73183

MAP3K5_913 (e-PCR)
- UniSTS:277471

SHGC-100583 (e-PCR)
- UniSTS:170486

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IDA Inferred from Direct Assay more info	PubMed
enables JUN kinase kinase kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables MAP kinase kinase kinase activity	IBA Inferred from Biological aspect of Ancestor more info
enables MAP kinase kinase kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables identical protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables magnesium ion binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein domain specific binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IDA Inferred from Direct Assay more info	PubMed
enables protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables protein kinase binding	IEA Inferred from Electronic Annotation more info
enables protein phosphatase binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein serine kinase activity	IEA Inferred from Electronic Annotation more info
enables protein serine/threonine kinase activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
involved_in JNK cascade	IBA Inferred from Biological aspect of Ancestor more info
involved_in JNK cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in JNK cascade	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in MAPK cascade	IDA Inferred from Direct Assay more info	PubMed
involved_in apoptotic signaling pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to amino acid starvation	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to hydrogen peroxide	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular response to reactive nitrogen species	IEA Inferred from Electronic Annotation more info
involved_in cellular response to tumor necrosis factor	IEA Inferred from Electronic Annotation more info
involved_in cellular senescence	TAS Traceable Author Statement more info
involved_in endothelial cell apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in innate immune response	IEA Inferred from Electronic Annotation more info
involved_in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IBA Inferred from Biological aspect of Ancestor more info
involved_in intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in intrinsic apoptotic signaling pathway in response to oxidative stress	IBA Inferred from Biological aspect of Ancestor more info
involved_in intrinsic apoptotic signaling pathway in response to oxidative stress	IDA Inferred from Direct Assay more info	PubMed
involved_in neuron apoptotic process	IBA Inferred from Biological aspect of Ancestor more info
involved_in neuron apoptotic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in neuron intrinsic apoptotic signaling pathway in response to oxidative stress	IGI Inferred from Genetic Interaction more info	PubMed
involved_in p38MAPK cascade	IBA Inferred from Biological aspect of Ancestor more info
involved_in positive regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of JNK cascade	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of JUN kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in positive regulation of apoptotic process	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of cardiac muscle cell apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of myoblast differentiation	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of p38MAPK cascade	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of vascular associated smooth muscle cell proliferation	IEA Inferred from Electronic Annotation more info
involved_in programmed necrotic cell death	IEA Inferred from Electronic Annotation more info
involved_in protein phosphorylation	IDA Inferred from Direct Assay more info	PubMed
involved_in response to endoplasmic reticulum stress	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to ischemia	IEA Inferred from Electronic Annotation more info
involved_in stress-activated MAPK cascade	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
part_of IRE1-TRAF2-ASK1 complex	IDA Inferred from Direct Assay more info	PubMed
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in external side of plasma membrane	IEA Inferred from Electronic Annotation more info
part_of protein kinase complex	IDA Inferred from Direct Assay more info	PubMed
part_of protein-containing complex	IMP Inferred from Mutant Phenotype more info	PubMed

General protein information

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Preferred Names: mitogen-activated protein kinase kinase kinase 5

Names: ASK-1; MAP/ERK kinase kinase 5; MAPK/ERK kinase kinase 5; MEK kinase 5; MEKK 5; apoptosis signal-regulating kinase 1

NP_005914.1

EC 2.7.11.25

XP_011534141.2

EC 2.7.11.25

XP_016866361.1

EC 2.7.11.25

XP_016866362.1

EC 2.7.11.25

XP_016866364.1

EC 2.7.11.25

XP_016866366.1

EC 2.7.11.25

XP_047274740.1

EC 2.7.11.25

XP_047274741.1

EC 2.7.11.25

XP_047274742.1

EC 2.7.11.25

XP_047274743.1

EC 2.7.11.25

XP_054211428.1

EC 2.7.11.25

XP_054211429.1

EC 2.7.11.25

XP_054211430.1

EC 2.7.11.25

XP_054211431.1

EC 2.7.11.25

XP_054211432.1

EC 2.7.11.25

XP_054211433.1

EC 2.7.11.25

XP_054211434.1

EC 2.7.11.25

XP_054211435.1

EC 2.7.11.25

XP_054211436.1

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.

Genomic

NG_011965.1 RefSeqGene

Range

5042..240473

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_005923.4 → NP_005914.1 mitogen-activated protein kinase kinase kinase 5

See identical proteins and their annotated locations for NP_005914.1

Status: REVIEWED

Source sequence(s)

AL024508, AL121933

Consensus CDS

CCDS5179.1

UniProtKB/Swiss-Prot

A6NIA0, B4DGB2, Q5THN3, Q99461, Q99683

UniProtKB/TrEMBL

Q59GL6

Related

ENSP00000351908.4, ENST00000359015.5

Conserved Domains (3) summary

smart00220
Location:685 → 938

S_TKc; Serine/Threonine protein kinases, catalytic domain

cd06624
Location:671 → 938

STKc_ASK; Catalytic domain of the Serine/Threonine Kinase, Apoptosis signal-regulating kinase

pfam13281
Location:165 → 544

DUF4071; Domain of unknown function (DUF4071)

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

NC_000006.12 Reference GRCh38.p14 Primary Assembly

Range

136557046..136793091 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017010875.2 → XP_016866364.1 mitogen-activated protein kinase kinase kinase 5 isoform X4

UniProtKB/TrEMBL

Q59GL6
XM_047418784.1 → XP_047274740.1 mitogen-activated protein kinase kinase kinase 5 isoform X3

UniProtKB/TrEMBL

Q59GL6
XM_017010873.2 → XP_016866362.1 mitogen-activated protein kinase kinase kinase 5 isoform X2

UniProtKB/TrEMBL

A0A8V8TMH5, Q59GL6

Related

ENSP00000514039.1, ENST00000698928.1
XM_017010872.2 → XP_016866361.1 mitogen-activated protein kinase kinase kinase 5 isoform X1

UniProtKB/TrEMBL

Q59GL6
XM_047418785.1 → XP_047274741.1 mitogen-activated protein kinase kinase kinase 5 isoform X7

UniProtKB/TrEMBL

B4DF67
XM_017010877.2 → XP_016866366.1 mitogen-activated protein kinase kinase kinase 5 isoform X6

UniProtKB/TrEMBL

B4DF67
XM_011535839.4 → XP_011534141.2 mitogen-activated protein kinase kinase kinase 5 isoform X5

UniProtKB/TrEMBL

Q59GL6
XM_047418786.1 → XP_047274742.1 mitogen-activated protein kinase kinase kinase 5 isoform X8
XM_047418787.1 → XP_047274743.1 mitogen-activated protein kinase kinase kinase 5 isoform X9

Alternate T2T-CHM13v2.0

Genomic

NC_060930.1 Alternate T2T-CHM13v2.0

Range

137745240..137981287 complement

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_054355455.1 → XP_054211430.1 mitogen-activated protein kinase kinase kinase 5 isoform X3

UniProtKB/TrEMBL

Q59GL6
XM_054355456.1 → XP_054211431.1 mitogen-activated protein kinase kinase kinase 5 isoform X4

UniProtKB/TrEMBL

Q59GL6
XM_054355454.1 → XP_054211429.1 mitogen-activated protein kinase kinase kinase 5 isoform X2

UniProtKB/TrEMBL

A0A8V8TMH5, Q59GL6
XM_054355453.1 → XP_054211428.1 mitogen-activated protein kinase kinase kinase 5 isoform X1

UniProtKB/TrEMBL

Q59GL6
XM_054355459.1 → XP_054211434.1 mitogen-activated protein kinase kinase kinase 5 isoform X7

UniProtKB/TrEMBL

B4DF67
XM_054355458.1 → XP_054211433.1 mitogen-activated protein kinase kinase kinase 5 isoform X6

UniProtKB/TrEMBL

B4DF67
XM_054355457.1 → XP_054211432.1 mitogen-activated protein kinase kinase kinase 5 isoform X5

UniProtKB/TrEMBL

Q59GL6
XM_054355460.1 → XP_054211435.1 mitogen-activated protein kinase kinase kinase 5 isoform X8
XM_054355461.1 → XP_054211436.1 mitogen-activated protein kinase kinase kinase 5 isoform X9