ASK1

MAP3K5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2CLQ, 3VW6, 4BF2, 4BHN, 4BIB, 4BIC, 4BID, 4BIE
Identifiers
Aliases	MAP3K5, ASK1, MAPKKK5, MEKK5, mitogen-activated protein kinase kinase kinase 5
External IDs	OMIM: 602448 MGI: 1346876 HomoloGene: 38114 GeneCards: MAP3K5
Gene location (Human) Chr. Chromosome 6 (human) Band 6q23.3 Start 136,557,046 bp End 136,792,477 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10|10 A3 Start 19,810,218 bp End 20,018,499 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell Brodmann area 23 pancreatic ductal cell adrenal cortex left adrenal gland right adrenal gland parietal pleura visceral pleura middle temporal gyrus tibia Top expressed in ciliary body cumulus cell pineal gland retinal pigment epithelium hair follicle iris ascending aorta blood conjunctival fornix median eminence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding protein homodimerization activity metal ion binding kinase activity protein binding protein phosphatase binding MAP kinase kinase kinase activity ATP binding protein kinase binding magnesium ion binding protein serine/threonine kinase activity protein domain specific binding identical protein binding Cellular component cytoplasm protein kinase complex endoplasmic reticulum IRE1-TRAF2-ASK1 complex cytosol external side of plasma membrane protein-containing complex Biological process intrinsic apoptotic signaling pathway in response to oxidative stress positive regulation of protein phosphorylation phosphorylation immune system process regulation of cell death positive regulation of neuron death positive regulation of JNK cascade response to endoplasmic reticulum stress cellular response to reactive nitrogen species MAPK cascade protein phosphorylation JNK cascade positive regulation of cysteine-type endopeptidase activity involved in apoptotic process intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress response to ischemia positive regulation of myoblast differentiation positive regulation of apoptotic process apoptotic signaling pathway p38MAPK cascade programmed necrotic cell death innate immune response viral process cellular response to hydrogen peroxide apoptotic process cellular response to tumor necrosis factor positive regulation of cardiac muscle cell apoptotic process positive regulation of p38MAPK cascade wound healing positive regulation of JUN kinase activity positive regulation of vascular associated smooth muscle cell proliferation endothelial cell apoptotic process cellular response to amino acid starvation positive regulation of transcription, DNA-templated stress-activated MAPK cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4217 26408 Ensembl ENSG00000197442 ENSMUSG00000071369 UniProt Q99683 O35099 RefSeq (mRNA) NM_005923 NM_008580 RefSeq (protein) NP_005914 NP_032606 Location (UCSC) Chr 6: 136.56 – 136.79 Mb Chr 10: 19.81 – 20.02 Mb PubMed search
Wikidata
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Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

MAP3K5 gene coding for the protein is located on chromosome 6 at locus 6q22.33. and the transcribed protein contains 1,374 amino acids with 11 kinase subdomains. Northern blot analysis shows that MAP3K5 transcript is abundant in human heart and pancreas.

Mechanism of activation

Under nonstress conditions ASK1 is oligomerized (a requirement for its activation) through its C-terminal coiled-coil domain (CCC), but remains in an inactive form by the suppressive effect of reduced thioredoxin (Trx) and calcium and integrin binding protein 1 (CIB1). Trx inhibits ASK1 kinase activity by direct binding to its N-terminal coiled-coil domain (NCC). Trx and CIB1 regulate ASK1 activation in a redox- or calcium- sensitive manner, respectively. Both appear to compete with TNF-α receptor-associated factor 2 (TRAF2), an ASK1 activator. TRAF2 and TRAF6 are then recruited to ASK1 to form a larger molecular mass complex. Subsequently, ASK1 forms homo-oligomeric interactions not only through the CCC, but also the NCC, which leads to full activation of ASK1 through autophosphorylation at threonine 845.

ASK1 gene transcription can be induced by inflammatory cytokines such as IL-1 and TNF-α through the activation of the NF-kb protein RelA. Interestingly, TNF-α is also able to stabilize the ASK1 protein through deubiquitination. Thus, unlike other members of the mitogen-activated protein kinase family, the regulation of ASK1 expression is transcriptional as well as post-transcriptional.

Interactions

ASK1 has been shown to interact with: