Mitogen-activated protein kinase kinase kinase 5
Also known as: ASK1, MAP3K5, MAPKKK5, MEKK5
Function
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).
Classification
- Family (Pfam)
- PF19039 ASK_PH, PF20309 DRHyd-ASK, PF20302 HisK-N-like, PF13281 MAP3K_TRAF_bd, PF00069 Pkinase
- InterPro
- DRHyd-ASK, HisK-N-like, Kinase-like_dom_sf, MAP3K_PH, MAP3K_TRAF-bd, Prot_kinase_dom, Protein_kinase_ATP_BS, SAM/pointed_sf, Ser/Thr_kinase_AS
- Functional cluster
- S-Adenosylmethionine Synthases & related
Experimental structures · PDB · 27
- 2CLQ X-ray 2.30A
- 3VW6 X-ray 2.40A
- 4BF2 X-ray 2.11A
- 4BHN X-ray 2.30A
- 4BIB X-ray 2.43A
- 4BIC X-ray 2.62A
- 4BID X-ray 2.80A
- 4BIE X-ray 2.36A
- 5ULM X-ray 2.10A
- 5UOR X-ray 2.75A
- 5UOX X-ray 2.50A
- 5UP3 X-ray 2.95A
- … and 15 more
A predicted model is available from AlphaFold.
Gene Ontology · 35
- GO:0005737 cytoplasm
- GO:0005829 cytosol
- GO:1990604 IRE1-TRAF2-ASK1 complex
- GO:1902911 protein kinase complex
- GO:0032991 protein-containing complex
- GO:0005524 ATP binding
- GO:0042802 identical protein binding
- GO:0004706 JUN kinase kinase kinase activity
- GO:0000287 magnesium ion binding
- GO:0004709 MAP kinase kinase kinase activity
- GO:0019904 protein domain specific binding
- GO:0042803 protein homodimerization activity
- GO:0004672 protein kinase activity
- GO:0019901 protein kinase binding
- GO:0019903 protein phosphatase binding
- GO:0106310 protein serine kinase activity
- GO:0004674 protein serine/threonine kinase activity
- GO:0097190 apoptotic signaling pathway
- GO:0034198 cellular response to amino acid starvation
- GO:0070301 cellular response to hydrogen peroxide
- GO:0090398 cellular senescence
- GO:0045087 innate immune response
- GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
- GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress
- GO:0007254 JNK cascade
- GO:0000165 MAPK cascade
- GO:0051402 neuron apoptotic process
- GO:0036480 neuron intrinsic apoptotic signaling pathway in response to oxidative stress
- GO:0038066 p38MAPK cascade
- GO:0043065 positive regulation of apoptotic process
- GO:0045893 positive regulation of DNA-templated transcription
- GO:0046330 positive regulation of JNK cascade
- GO:0045663 positive regulation of myoblast differentiation
- GO:0034976 response to endoplasmic reticulum stress
- GO:0051403 stress-activated MAPK cascade
Drugs targeting this protein · 1
- SELONSERTIB inhibitor
Related proteins · sequence + function similarity
- Mitogen-activated protein kinase kinase kinase 5 0.99
- Mitogen-activated protein kinase kinase kinase 15 0.86
- Mitogen-activated protein kinase kinase kinase 15 0.82
- Mitogen-activated protein kinase kinase kinase nsy-1 0.75
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 0.54
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 0.54
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 0.54
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 0.54
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3 0.54
- WD repeat-containing protein 19 0.54
- Mitogen-activated protein kinase kinase kinase kinase 5 0.54
- Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 0.54
Co-cited proteins · studied together in the literature
- Mitogen-activated protein kinase kinase kinase 5 6 shared papers
- Dual specificity protein phosphatase 13A 1 shared papers
- Disabled homolog 2-interacting protein 4 shared papers
- Maternal embryonic leucine zipper kinase 1 shared papers
- Serine/threonine-protein phosphatase Pgam5, mitochondrial 1 shared papers
- Mitogen-activated protein kinase kinase kinase 6 1 shared papers
- Mitogen-activated protein kinase kinase kinase 6 1 shared papers
- Mitogen-activated protein kinase 10 2 shared papers
- Protein phosphatase 1L 1 shared papers
- Protein Nef 1 shared papers
- Serine/threonine-protein kinase pim-1 1 shared papers
- E3 ubiquitin-protein ligase TRIM48 1 shared papers
Literature · 55 cited papers
- TRIM48 Promotes ASK1 Activation and Cell Death through Ubiquitination-Dependent Degradation of the ASK1-Negative Regulator PRMT1. Cell Rep. · 2017
- PMID 27825085 J. Biol. Chem. · 2016
- Cyclophilin A regulates JNK/p38-MAPK signaling through its physical interaction with ASK1. Biochem. Biophys. Res. Commun. · 2015
- Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. Sci. Signal. · 2014
- An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5. Mol. Cell · 2012
- Arginine methylation-dependent regulation of ASK1 signaling by PRMT1. Cell Death Differ. · 2012
- Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A. Cell. Mol. Life Sci. · 2010
- PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene · 2009
- Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1. Proc. Natl. Acad. Sci. U.S.A. · 2009
- The roles of ASK family proteins in stress responses and diseases. Cell Commun. Signal. · 2009
- … and 43 more in the literature graph
A document in the lmmol reference corpus — open public data (UniProt, GO, PDB, the literature graph) rendered as a single cross-linked page. Hover any link to preview its target.