Affinage

MAP3K5

Mitogen-activated protein kinase kinase kinase 5 · UniProt Q99683

Length
1374 aa
Mass
154.5 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K5/ASK1 is a redox- and stress-responsive serine/threonine MAP kinase kinase kinase that activates the SEK1/MKK4 and MKK3/MKK6 cascades to engage the JNK and p38 MAP kinases, thereby driving apoptosis, differentiation, and inflammation across diverse cell types (PMID:9875215, PMID:9926932). Its activation is gated by reduced thioredoxin (Trx), which binds and inhibits ASK1 and promotes its ubiquitination until oxidative stress (H2O2, TNF) releases Trx (PMID:12089063); activation requires homo-oligomerization, and structural analysis shows the catalytic domain forms a tight head-to-tail dimer with regulatory autophosphorylation sites (PMID:17937911). ASK1 propagates death and differentiation signals downstream of genotoxic stress, TNF/TRAF receptors, viral infection, calcium influx, and ferroptotic lipid peroxidation (PMID:9926932, PMID:10523862, PMID:12878192, PMID:14749717, PMID:28887319), with the p38 arm also directing neuronal and keratinocyte differentiation (PMID:10734135, PMID:11029458). A dense regulatory network controls ASK1: it is activated by scaffolds and recruiters including Daxx, DAB2IP, TRAF1, LRRK2, and DUSP22, and by CaMKII-mediated phosphorylation (PMID:12968034, PMID:19903888, PMID:31650881, PMID:28888991, PMID:27711255, PMID:14749717), and is restrained by inhibitory phosphorylation at Ser967 (PDK1) and Ser83 (Akt/Hsp90, PIM1), by calcineurin-mediated Ser967 dephosphorylation that toggles 14-3-3 binding, by JAK2/SOCS1-driven Tyr718 phosphorylation and degradation reversed by SHP2, by binding partners that block N-terminal dimerization (GSTM2, MVP), and by deubiquitination via TNFAIP3 (PMID:19920149, PMID:15782121, PMID:19749799, PMID:16648474, PMID:19287004, PMID:34656650, PMID:35387478, PMID:29227477). Beyond stress apoptosis, ASK1 phosphorylates non-canonical substrates: cardiac troponin T to impair contractility (PMID:12819028), EB1 to control mitotic spindle orientation (PMID:27721984), HDAC6 to regulate cilia disassembly (PMID:32275885), and IRF3 to suppress UCP1 and thermogenesis in adipocytes (PMID:32242025). Inactivating somatic MAP3K5 mutations occur in melanoma, where one mutant attenuates signaling by increasing Trx binding, consistent with a tumor-suppressive ASK1-JNK axis (PMID:22197930, PMID:24008424).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 Medium

    Established ASK1 as a MAP3K that couples to both JNK and p38 cascades and physically engages a downstream kinase, defining its position in the stress-activated MAPK module.

    Evidence Yeast two-hybrid and co-IP in 293 cells identifying MAPKKK6 interaction

    PMID:9875215

    Open questions at the time
    • Did not define the activating stimulus
    • No structural or oligomerization mechanism
  2. 1999 Medium

    Defined the apoptotic output of ASK1 and its receptor inputs, showing it acts upstream of caspases via MKK4/MKK3-MKK6 and mediates TRAF-dependent TNF receptor signaling.

    Evidence Dominant-negative ASK1 (K709R), kinase/caspase assays, and TRAF2/5/6 co-IP with JNK activation

    PMID:10523862 PMID:9926932

    Open questions at the time
    • Mechanism of TRAF-induced ASK1 activation not resolved
    • Endogenous requirement not yet shown by knockout
  3. 2002 High

    Identified the redox switch governing ASK1: reduced thioredoxin holds ASK1 inactive and its oxidative release activates signaling, explaining how ROS triggers ASK1.

    Evidence Co-IP with Trx mutants, ubiquitination, JNK and caspase-3 assays; in vivo ischemia/reperfusion with antioxidant

    PMID:12089063 PMID:12165419

    Open questions at the time
    • Structural basis of Trx-ASK1 interface not defined
    • Link between Trx release and oligomerization incomplete
  4. 2003 High

    Showed ASK1 oligomerization is a controllable activation step engaged by Daxx and antagonized by CIIA, and uncovered the first non-canonical substrate (cardiac troponin T) linking ASK1 to contractile dysfunction.

    Evidence Kinase-cascade epistasis with Daxx relocalization, CIIA antisense oligomerization assays, and cTnT phosphorylation with cardiomyocyte contractility readout

    PMID:12819028 PMID:12968034 PMID:14557248

    Open questions at the time
    • Oligomerization stoichiometry not defined
    • Substrate scope beyond cTnT unknown at this stage
  5. 2004 High

    Established ASK1 as an essential mediator of calcium-to-p38 signaling, placing CaMKII upstream as a direct activating kinase.

    Evidence ASK1-knockout neurons, constitutively active CaMKII, and in vitro phosphorylation

    PMID:14749717

    Open questions at the time
    • CaMKII phosphosite on ASK1 not pinpointed here
    • Relation to redox activation not integrated
  6. 2006 High

    Resolved the Ser967/14-3-3 inhibitory checkpoint by showing calcineurin dephosphorylates Ser967 to release 14-3-3 and activate ASK1, with reciprocal ASK1 control of NFAT.

    Evidence In vitro phosphatase assay with purified proteins, endogenous co-IP, and ASK1-deficient MEFs

    PMID:16648474

    Open questions at the time
    • Integration with kinase-mediated Ser967 phosphorylation not addressed
    • Tissue specificity of the calcineurin-ASK1 axis unclear
  7. 2005 High

    Defined an Akt/Hsp90-based inhibitory arm acting through Ser83 phosphorylation, showing kinase inputs that suppress ASK1-p38 signaling.

    Evidence Reciprocal co-IP, domain mapping, Akt-knockout cells, in vitro kinase assay

    PMID:15782121

    Open questions at the time
    • How Ser83 phosphorylation mechanistically blocks activation not fully resolved
  8. 2007 High

    Provided the structural basis for ASK1 activation, showing the catalytic domain dimerizes head-to-tail and mapping regulatory autophosphorylation sites.

    Evidence X-ray crystallography, analytical ultracentrifugation, mass spectrometry, mutagenesis, reporter assays

    PMID:17937911

    Open questions at the time
    • Full-length signalosome architecture not solved
    • Mechanism by which autophosphorylation regulates output independent of catalytic activity unclear
  9. 2009 High

    Expanded the regulatory kinase/phosphatase network controlling ASK1, defining PIM1 and PDK1 as Ser83/Ser967 inhibitory kinases and the JAK2/SOCS1/SHP2 axis controlling Tyr718-dependent degradation, plus DAB2IP as a scaffold enhancing activation.

    Evidence In vitro kinase assays, co-IP, siRNA/substrate-trapping mutants, SHP2-KO cells, and xenograft models

    PMID:19287004 PMID:19749799 PMID:19903888 PMID:19920149

    Open questions at the time
    • Hierarchy/competition among Ser83 and Ser967 inputs not resolved
    • In vivo balance of these regulators uncertain
  10. 2011 Medium

    Linked ASK1 to cancer by identifying inactivating somatic MAP3K5 mutations in melanoma, supporting a tumor-suppressive signaling role.

    Evidence Exome sequencing, in vitro kinase assay, overexpression with downstream phosphorylation readout; later mechanism via increased Trx binding

    PMID:22197930 PMID:24008424

    Open questions at the time
    • Causal contribution to melanomagenesis in vivo not established
    • Penetrance/frequency of inactivating mutations unclear
  11. 2016 High

    Revealed non-apoptotic ASK1 functions through new substrates, phosphorylating EB1 to control mitotic spindle orientation and acting via PKA-ASK1-p38 in adipocyte thermogenesis.

    Evidence In vitro kinase assays with phosphosite mutagenesis, live-cell imaging, and global/fat-specific ASK1-knockout mice

    PMID:27045525 PMID:27721984

    Open questions at the time
    • How redox/stress regulation intersects with mitotic substrate phosphorylation unclear
    • Tissue context selecting canonical vs non-canonical substrates undefined
  12. 2017 High

    Mapped a ubiquitin- and scaffold-based regulatory layer (TNFAIP3 deubiquitination, TRIM48-PRMT1, LRRK2 scaffolding/Thr832 phosphorylation, DUSP22) and connected ASK1 to ferroptotic and disease contexts including NASH and neurodegeneration.

    Evidence Deubiquitination/ubiquitination assays, in vitro kinase assays, conditional knockout mice, and pharmacological ferroptosis epistasis

    PMID:27711255 PMID:28887319 PMID:28888991 PMID:29186683 PMID:29227477

    Open questions at the time
    • Relative contribution of competing ubiquitin regulators in vivo unclear
    • Integration of LRRK2 scaffolding with redox activation incomplete
  13. 2020 High

    Extended ASK1 substrate repertoire to HDAC6 (controlling cilia disassembly) and IRF3 (suppressing UCP1), establishing roles in ciliary biology and energy expenditure.

    Evidence In vivo mouse models, phosphorylation and ubiquitination assays, adipocyte-specific knockout/overexpression

    PMID:32242025 PMID:32275885

    Open questions at the time
    • Stimuli selecting these substrates over canonical MKKs unknown
    • Structural determinants of substrate selection undefined
  14. 2022 Medium

    Defined additional dimerization-blocking inhibitors (GSTM2, MVP) and conserved a CaMKII-Sarm1/TIR-1-ASK1-p38 neuroprotective axis, reinforcing N-terminal dimerization as a druggable activation node.

    Evidence Co-IP and dimerization assays with conditional knockout mice; C. elegans genetic epistasis screen

    PMID:34656650 PMID:35285800 PMID:35387478

    Open questions at the time
    • Whether endogenous GSTM2/MVP set ASK1 tone in human disease unclear
    • Conservation of CaMKII-Sarm1-ASK1 axis in mammals not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many competing activating and inhibitory inputs are integrated to set ASK1 signalosome output, and what governs the choice between canonical MKK substrates and non-canonical substrates (cTnT, EB1, HDAC6, IRF3), remains unresolved.
  • No unified quantitative model of ASK1 activation thresholds
  • Determinants of substrate selectivity unknown
  • Full-length signalosome structure unsolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-5357801 Programmed Cell Death 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 1
Partners
DAXXGSTM2LRRK2MVPPDK1TNFAIP3TRAF6TXN
Complex memberships
ASK1 signalosome (ASK1 homo-oligomer)

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MAP3K5/ASK1 activates both JNK and p38 kinase signaling pathways. A novel interacting protein (MAPKKK6) was identified by yeast two-hybrid screening using MAPKKK5 as bait, and their interaction was confirmed by co-immunoprecipitation in 293 cells. Yeast two-hybrid screen, co-immunoprecipitation Biochemical and biophysical research communications Medium 9875215
1999 ASK1 mediates apoptotic cell death induced by genotoxic stress (cisplatin) upstream of caspase activation, acting through the SEK1/MKK4 and MKK3/MKK6 pathways to activate JNK1 and p38. Overexpression of kinase-negative ASK1 (K709R) suppressed caspase activation and apoptosis. Dominant-negative overexpression, immune complex kinase assay, caspase activity assay Oncogene Medium 9926932
1999 TRAF2, TRAF5, and TRAF6 associate with ASK1, and a catalytically-inactive ASK1 mutant blocks SAPK/JNK activation by these TRAFs. ASK1 is a common mediator of TRAF-regulated SAPK and apoptosis signaling downstream of TNF receptors. Co-immunoprecipitation, dominant-negative overexpression, JNK activation assay Oncogene Medium 10523862
2000 Constitutively active ASK1 (ASK1DeltaN) induces neurite outgrowth and neuronal differentiation in PC12 cells through activation of p38 (and to a lesser extent JNK), not ERK. ASK1DeltaN also promoted survival of PC12 cells under serum-starved conditions. Constitutively active mutant overexpression, p38 inhibitor (SB203580), MEK inhibitor controls, morphological/biochemical differentiation assays The Journal of biological chemistry Medium 10734135
2001 Constitutively active ASK1 induces keratinocyte differentiation through the ASK1-p38 MAP kinase cascade, as shown by induction of differentiation markers (transglutaminase-1, loricrin, involucrin) that was blocked by p38 inhibitors SB202190 and SB203580. Ceramide-induced differentiation increased ASK1 expression and activity. Constitutively active ASK1 overexpression, p38 inhibitor treatment, differentiation marker assays The Journal of biological chemistry Medium 11029458
2001 ASK1 possesses a kinase-independent, caspase-independent cell death function activated by interaction with Daxx. The N-terminal domain of ASK1 (lacking the kinase domain) was constitutively active in producing crumpled nuclei, distinct from caspase-dependent fragmented nuclei caused by ASK1 kinase activity. Co-transfection, domain deletion mutants, caspase inhibitor, morphological assays The Journal of biological chemistry Medium 11493600
2001 ASK1-JNK pathway stabilizes c-Myc protein by phosphorylating Ser-62 and Ser-71, attenuating degradation of ubiquitinated c-Myc without affecting its ubiquitination, thus promoting c-Myc-dependent apoptosis. Overexpression, site-directed mutagenesis of c-Myc, pulse-chase, kinase assay Biochemical and biophysical research communications Medium 11243879
2002 Reduced thioredoxin (Trx) binds to and inhibits ASK1. Upon oxidation (via H2O2 or TNF), Trx is released from ASK1. Single-Cys Trx mutants (C32S or C35S) that constitutively bind ASK1 promoted ASK1 ubiquitination and degradation, inhibiting JNK activation and apoptosis in a redox-independent manner. The double mutant (Trx-CS) lost ASK1-binding and inhibitory activity. Co-immunoprecipitation, overexpression of Trx mutants, ubiquitination assay, JNK activation assay, caspase-3 assay Circulation research High 12089063
2002 ASK1 is activated and autophosphorylated following cerebral ischemia/reperfusion in rat hippocampus, peaking at 30 min reperfusion. Both activation and autophosphorylation were suppressed by the antioxidant N-acetylcysteine, indicating redox-dependent regulation. In vitro kinase assay, immunoprecipitation, Western blot, antioxidant treatment in vivo Neuroscience letters Medium 12165419
2002 ALG-2 interacts with the C-terminus (aa 941–1375) of ASK1, and co-transfection with ALG-2 causes nuclear localization of ASK1 and inhibits ASK1-mediated JNK activation. ALG-2 variant with deletion of Gly-121/Phe-122 failed to bind ASK1, demonstrating specificity. Co-immunoprecipitation, subcellular localization (immunofluorescence), JNK activation assay, in vitro binding FEBS letters Medium 12372597
2003 ASK1 specifically interacts with cardiac troponin T (cTnT) via its C-terminal domain, phosphorylates cTnT at T194/S198 in vitro and in vivo, and ROS-induced ASK1 activation causes cTnT phosphorylation and contractile dysfunction in cardiomyocytes. Constitutively active ASK1 overexpression inhibited sarcomere shortening and calcium transients. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of cTnT, cardiomyocyte contractility assay The American journal of pathology High 12819028
2003 ASK1 regulates influenza virus infection-induced apoptosis: IV infection activated ASK1, phosphorylated JNK and p38, and ASK1-knockout MEFs showed reduced JNK/p38 activation and were defective in caspase-3 activation and cell death after IV infection. ASK1 knockout mouse-derived MEFs, kinase assays, caspase-3 activation assay Biochemical and biophysical research communications Medium 12878192
2003 ASK1 mediates anandamide-induced PC12 cell death through p38 MAPK and JNK activation, upstream of mitochondrial cytochrome c release and caspase activation. Dominant-negative ASK1 (K709M) inhibited p38/JNK activation and cell death. Dominant-negative overexpression, pharmacological inhibitors, cytochrome c release assay Journal of neurochemistry Medium 12641726
2003 The ASK1-SEK1-JNK1-HIPK1 pathway mediates Daxx phosphorylation at Ser667 during glucose deprivation, causing Daxx translocation from nucleus to cytoplasm where it binds ASK1 and promotes ASK1 oligomerization. JNK binding domain overexpression blocked Daxx relocalization and ASK1 oligomerization. In vivo labeling, immune complex kinase assay, immunofluorescence, protein interaction assay, site-directed mutagenesis The Journal of biological chemistry Medium 12968034
2003 CIIA (a novel antiapoptotic protein) binds ASK1 and inhibits oligomerization-induced ASK1 activation. CIIA antisense abolished its inhibitory effect on ASK1 activation, DNA fragmentation, and apoptosis. Co-immunoprecipitation, antisense oligonucleotides, ASK1 oligomerization assay, apoptosis assay The Journal of cell biology Medium 14557248
2004 Ca2+ influx activates p38 MAP kinase via CaMKII phosphorylation of ASK1. p38 activation by membrane depolarization in primary neurons was impaired in ASK1-deficient mice. Constitutively active CaMKII-induced p38 activation required endogenous ASK1. ASK1-knockout mouse neurons, constitutively active CaMKII overexpression, in vitro phosphorylation assay EMBO reports High 14749717
2005 Hsp90 and Akt form a ternary complex with ASK1 via the middle domain of Hsp90. Akt phosphorylates ASK1 at Ser83, and this phosphorylation is required for Hsp90-mediated inhibition of ASK1-p38 signaling. In resting endothelial cells, Akt binds the N-terminal domain of ASK1; upon H2O2 stimulation it shifts to the C-terminal domain of ASK1. Co-immunoprecipitation, domain-mapping, Akt knockout cells, in vitro kinase assay, pharmacological inhibitors Oncogene High 15782121
2005 Raf-1 kinase domain interacts with ALG-2, and both Raf-1 and ASK1 phosphorylate ALG-2. Raf-1 blocks ASK1-dependent ALG-2 phosphorylation, suggesting a mechanism for Raf-1's anti-apoptotic function through interference with the ASK1-ALG-2 axis. Yeast two-hybrid, in vitro kinase assay, co-immunoprecipitation Biochemical and biophysical research communications Medium 15925322
2006 Calcineurin directly dephosphorylates ASK1 at Ser967 (identified by yeast two-hybrid with calcineurin B as bait), promoting dissociation of 14-3-3 proteins from ASK1 and ASK1 activation. Calcineurin and ASK1 cooperatively enhanced cardiomyocyte apoptosis. Reciprocally, ASK1 negatively regulated calcineurin-NFAT signaling through JNK- and p38-mediated NFAT phosphorylation. Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, in vitro phosphatase assay with purified proteins, ASK1-deficient MEFs, dominant-negative ASK1 Molecular and cellular biology High 16648474
2007 Crystal structure of the human ASK1 catalytic domain in complex with staurosporine revealed that ASK1 forms a tight head-to-tail dimer (Kd ~0.2 μM). Three autophosphorylation sites (Thr813, Thr838, Thr842) were identified by mass spectrometry and shown to regulate ASK1 signaling by reporter gene assays, though site-directed mutants showed catalytic activities similar to wild-type, suggesting a regulatory mechanism independent of kinase activity. X-ray crystallography, analytical ultracentrifugation, mass spectrometry, site-directed mutagenesis, reporter gene assay Structure High 17937911
2007 ASK1 deficiency in mice resulted in dramatically reduced wounding-induced macrophage infiltration/activation and subsequent hair regrowth. Intracutaneous transplantation of cytokine-activated bone marrow-derived macrophages rescued hair growth in ASK1-deficient mice, placing ASK1 upstream of macrophage recruitment in inflammatory wound responses. ASK1-knockout mice, oligonucleotide microarray, bone marrow macrophage transplantation The Journal of cell biology Medium 17389227
2009 PIM1 phosphorylates ASK1 specifically at Ser83 in vitro and in vivo, binds ASK1 by co-immunoprecipitation, decreases ASK1 kinase activity under oxidative stress, and inhibits ASK1-mediated JNK and p38 phosphorylation and caspase-3 activation. PIM1 knockdown reduced Ser83 phosphorylation and increased cell death after H2O2. In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, caspase-3 activation assay Oncogene High 19749799
2009 DAB2IP acts as a scaffold protein interacting with ASK1 through its C2 domain to enhance ASK1 activation, leading to JNK pathway activation and apoptosis. DAB2IP loss in prostate cancer led to ASK1-JNK inactivation and accelerated tumor growth in vivo. Gain/loss-of-function studies, structural domain analysis, in vivo xenograft Proceedings of the National Academy of Sciences of the United States of America Medium 19903888
2009 PDK1 and ASK1 directly interact via the PDK1 PH domain and ASK1 C-terminal regulatory domain, and they reciprocally phosphorylate each other: PDK1 phosphorylates ASK1 at Ser967 (a 14-3-3 binding site) to suppress ASK1 activity, while ASK1 phosphorylates PDK1 at Ser394 and Ser398 to inhibit PDK1. The interaction is decreased by ASK1-activating stimuli. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, domain-mapping The Journal of biological chemistry High 19920149
2009 JAK2 phosphorylates ASK1 at Tyr718, enhancing its association with SOCS1 and subsequent ASK1 degradation. SHP2 dephosphorylates ASK1 at Tyr718 (confirmed by substrate-trapping mutant), dissociating SOCS1 from ASK1 and enabling TNF-induced ASK1 activation and apoptosis. Co-immunoprecipitation, JAK2-specific inhibitor, SHP2 substrate-trapping mutant, SHP2-KO cells, JAK2 overexpression with in vitro kinase assay The Journal of biological chemistry High 19287004
2011 Somatic mutations in MAP3K5 (e.g., I780F) identified in melanoma exomes reduced kinase activity in in vitro kinase assays and reduced phosphorylation of downstream MAP kinases when overexpressed in HEK293T cells. Loss of heterozygosity suggested these are inactivating mutations. Exome sequencing, in vitro kinase assay, overexpression in HEK293T cells with downstream phosphorylation readout Nature genetics Medium 22197930
2013 The MAP3K5 R256C melanoma mutation attenuates MKK4 activation through increased binding of the inhibitory protein thioredoxin (TRX), resulting in increased melanoma cell proliferation and anchorage-independent growth. Functional kinase assays, co-immunoprecipitation with TRX, proliferation and soft-agar growth assays The Journal of investigative dermatology Medium 24008424
2016 ASK1 controls mitotic spindle orientation and positioning by phosphorylating EB1 at Ser40, Thr154, and Thr206, enhancing EB1 binding to the plus ends of astral microtubules, stabilizing them, and enabling spindle-cortex interaction for spindle movement. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, live-cell imaging, microtubule co-sedimentation Cell discovery High 27721984
2016 ASK1 regulates brown and beige adipocyte function through a PKA-ASK1-p38 axis activated by cAMP signaling, contributing to cell-autonomous induction of Ucp1 expression. Global and fat-specific ASK1 deficiency led to impaired thermogenesis and oxygen consumption. ASK1-knockout mice (global and fat-specific), gene expression analysis, oxygen consumption measurement Nature communications Medium 27045525
2016 DUSP22 acts as a scaffold protein for the ASK1-MKK7-JNK signaling pathway, selectively associating with ASK1, MKK7, and JNK1/2. DUSP22 increased JNK phosphorylation and apoptosis in a concentration-dependent biphasic manner (scaffold behavior) independently of its phosphatase activity. Co-immunoprecipitation, JNK phosphorylation assay, apoptosis assay, phosphatase-inactive mutant PloS one Medium 27711255
2017 TNFAIP3 (A20) deubiquitinase directly interacts with and deubiquitinates ASK1 in hepatocytes, suppressing ASK1 activation. Hepatocyte-specific Tnfaip3 ablation exacerbated NASH-related phenotypes in an ASK1-dependent manner. Co-immunoprecipitation, deubiquitination assay, hepatocyte-specific knockout mice, rescue experiments Nature medicine High 29227477
2017 TRIM48 promotes ASK1 activation by inducing K48-linked polyubiquitination and proteasomal degradation of PRMT1, which is an ASK1-negative regulator that enhances ASK1's interaction with Trx. TRIM48 knockdown suppressed oxidative stress-induced ASK1 activation and cell death. Pull-down screen, co-immunoprecipitation, ubiquitination assay, siRNA knockdown, xenograft model Cell reports Medium 29186683
2017 LRRK2 directly phosphorylates ASK1 at Thr832 (adjacent to the autophosphorylation site Thr845) and acts as a scaffolding protein interacting with each component of the ASK1-MKK3/6-p38 pathway through its specific domains, increasing proximity to downstream targets and promoting neuronal cell death. Co-immunoprecipitation, in vitro kinase assay, domain-binding assays, neuronal stem cells from PD patients Biochimica et biophysica acta. Molecular cell research Medium 28888991
2017 Cold stress-induced ferroptosis activates the ASK1-p38 MAPK pathway through MEK activity, iron ions, and lipid peroxide. The ferroptosis inducer erastin also activates the ASK1-p38 axis downstream of lipid peroxide accumulation, leading to ASK1-dependent cell death. Chemical inhibitors (MEK, iron chelators, lipid peroxide inhibitors), ASK1-deficient cell lines, cell death assays EMBO reports Medium 28887319
2017 ASK1 phosphorylates IRF3, resulting in reduced Ucp1 expression in adipocytes. Adipocyte-specific ASK1 knockout increased UCP1 in inguinal fat and elevated energy expenditure, while ASK1 overexpression attenuated cold-induced UCP1. Adipocyte-specific knockout/overexpression mice, phosphorylation assay for IRF3, UCP1 expression analysis Nature communications Medium 32242025
2019 TRAF1 promotes myocardial ischemia/reperfusion injury through activation of ASK1-mediated JNK/p38 MAPK cascades. TRAF1 deficiency in mice protected against I/R injury and inflammation. TRAF1-knockout mice, I/R model, co-immunoprecipitation (implied), Western blot for pathway activation Journal of the American Heart Association Medium 31650881
2020 ASK1 phosphorylates HDAC6, blocking its ubiquitination by von Hippel-Lindau and preventing proteasomal degradation of HDAC6, which promotes HDAC6 accumulation and connecting cilia disassembly in the oxygen-induced retinopathy model. In vivo mouse model, co-immunoprecipitation, phosphorylation assay, ubiquitination assay, HDAC6 knockout/depletion Developmental cell High 32275885
2021 GSTM2 directly binds the N-terminal region of ASK1 and inhibits ASK1 N-terminal dimerization, suppressing ASK1 phosphorylation and downstream JNK/p38 signaling. GSTM2 deficiency aggravated NASH phenotypes while its overexpression was protective. Co-immunoprecipitation, in vitro binding assay, gain/loss-of-function in vivo, ASK1 phosphorylation assay Journal of hepatology Medium 34656650
2021 OTUB1 directly binds TRAF6 and suppresses its K63-linked polyubiquitination, thereby inhibiting TRAF6-mediated ASK1 activation and downstream signaling. Hepatocyte-specific Otub1 overexpression protected against NASH. Immunoprecipitation-mass spectrometry, ubiquitination assay, co-immunoprecipitation, gain/loss-of-function in vivo Hepatology Medium 34591986
2022 In C. elegans, CaMKII (UNC-43) activates the Sarm1/TIR-1-ASK1/NSY-1-p38 MAPK pathway to protect against axon degeneration caused by mitochondrial loss. Disruption of a calsyntenin/Mint/kinesin trafficking complex activates this pathway through L-type voltage-gated calcium channels. Unbiased genetic screen in C. elegans, loss-of-function genetics, epistasis analysis eLife Medium 35285800
2022 Major vault protein (MVP) binds ASK1 via its α-helical domain and inhibits ASK1 dimerization and phosphorylation, suppressing ASK1-MKK4-JNK signaling and MMP-9 production in macrophages. A 62-amino-acid peptide (MVP-[686-747]) recapitulated this inhibitory function. Co-immunoprecipitation, ASK1 dimerization assay, phosphorylation assay, myeloid-specific MVP knockout mice Arteriosclerosis, thrombosis, and vascular biology Medium 35387478

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochimica et biophysica acta 402 18206122
2002 Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. Circulation research 318 12089063
2004 The ASK1-MAP kinase cascades in mammalian stress response. Journal of biochemistry 270 15598880
2002 Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice. Antioxidants & redox signaling 212 12215209
2007 Pathophysiological roles of ASK1-MAP kinase signaling pathways. Journal of biochemistry and molecular biology 203 17244475
2003 Roles of MAPKKK ASK1 in stress-induced cell death. Cell structure and function 198 12655147
2017 The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis. Nature medicine 166 29227477
2009 DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis. Proceedings of the National Academy of Sciences of the United States of America 166 19903888
1999 ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 160 9926932
2011 Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing. Nature genetics 154 22197930
2004 Involvement of ASK1 in Ca2+-induced p38 MAP kinase activation. EMBO reports 153 14749717
2005 Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 143 15782121
2000 Apoptosis signal-regulating kinase 1 (ASK1) induces neuronal differentiation and survival of PC12 cells. The Journal of biological chemistry 143 10734135
2006 The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Current molecular medicine 132 16472116
2010 Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO molecular medicine 126 21064192
2018 ASK1 contributes to fibrosis and dysfunction in models of kidney disease. The Journal of clinical investigation 120 30024858
2012 Activation mechanisms of ASK1 in response to various stresses and its significance in intracellular signaling. Advances in biological regulation 117 23031789
2001 Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. The Journal of biological chemistry 116 11029458
2012 Therapeutic targets in the ASK1-dependent stress signaling pathways. Proceedings of the Japan Academy. Series B, Physical and biological sciences 113 23060232
2017 Cold stress-induced ferroptosis involves the ASK1-p38 pathway. EMBO reports 110 28887319
2012 MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Annals of the rheumatic diseases 105 23087182
1999 Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1). Oncogene 98 10523862
2020 ASK1 inhibition: a therapeutic strategy with multi-system benefits. Journal of molecular medicine (Berlin, Germany) 96 32060587
2017 Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction. Redox biology 96 28954246
2009 PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene 95 19749799
2014 ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. American journal of physiology. Renal physiology 92 25298527
2007 Structural and functional characterization of the human protein kinase ASK1. Structure (London, England : 1993) 92 17937911
2003 ASK1-p38 MAPK/JNK signaling cascade mediates anandamide-induced PC12 cell death. Journal of neurochemistry 83 12641726
2006 Direct interaction and reciprocal regulation between ASK1 and calcineurin-NFAT control cardiomyocyte death and growth. Molecular and cellular biology 80 16648474
2015 ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice. Diabetes 79 26180085
2007 ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds. The Journal of cell biology 75 17389227
2003 Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. The Journal of biological chemistry 75 12968034
2006 The ASK1-MAP kinase pathways in immune and stress responses. Microbes and infection 74 16517200
2012 Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury. Cell death and differentiation 73 22976835
2008 14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy. Biochemical pharmacology 72 18342293
2019 Liver ASK1 protects from non-alcoholic fatty liver disease and fibrosis. EMBO molecular medicine 69 31595673
2017 Kaempferol Attenuates Cardiac Hypertrophy via Regulation of ASK1/MAPK Signaling Pathway and Oxidative Stress. Planta medica 68 28219095
2005 CaMKII activates ASK1 and NF-kappaB to induce cardiomyocyte hypertrophy. Biochemical and biophysical research communications 65 15629441
2009 Differential expression of apoptotic genes PDIA3 and MAP3K5 distinguishes between low- and high-risk prostate cancer. Molecular cancer 64 20035634
2012 Aquaporin 1, Nox1, and Ask1 mediate oxidant-induced smooth muscle cell hypertrophy. Cardiovascular research 63 22997161
2017 TRIM48 Promotes ASK1 Activation and Cell Death through Ubiquitination-Dependent Degradation of the ASK1-Negative Regulator PRMT1. Cell reports 61 29186683
2016 ASK1 signalling regulates brown and beige adipocyte function. Nature communications 61 27045525
2020 ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model. JCI insight 60 31996485
2020 ASK1-Mediated Phosphorylation Blocks HDAC6 Ubiquitination and Degradation to Drive the Disassembly of Photoreceptor Connecting Cilia. Developmental cell 59 32275885
2016 ASK1: a new therapeutic target for kidney disease. American journal of physiology. Renal physiology 59 27226108
2014 Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer's disease. International journal of molecular sciences 59 24481061
2021 Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling. Journal of hepatology 57 34656650
1998 MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochemical and biophysical research communications 57 9875215
2016 Pleiotropic properties of ASK1. Biochimica et biophysica acta. General subjects 56 27693599
2003 ASK1 associates with troponin T and induces troponin T phosphorylation and contractile dysfunction in cardiomyocytes. The American journal of pathology 56 12819028
2004 ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14-q15 and 6q23 amplifications. Genes, chromosomes & cancer 54 15034865
2001 A kinase-independent function of Ask1 in caspase-independent cell death. The Journal of biological chemistry 53 11493600
2003 ASK1 regulates influenza virus infection-induced apoptotic cell death. Biochemical and biophysical research communications 50 12878192
2017 ASK1 in neurodegeneration. Advances in biological regulation 48 28882588
2019 Ask1 and Akt act synergistically to promote ROS-dependent regeneration in Drosophila. PLoS genetics 44 30677014
2009 Targeting ASK1 in ER stress-related neurodegenerative diseases. Expert opinion on therapeutic targets 44 19456270
2020 ASK1 inhibits browning of white adipose tissue in obesity. Nature communications 43 32242025
2019 TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling. Journal of the American Heart Association 43 31650881
2017 ASK1-dependent endothelial cell activation is critical in ovarian cancer growth and metastasis. JCI insight 41 28931753
2016 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells. Biochemical and biophysical research communications 41 26773495
2012 Association of DJ-1/PTEN/AKT- and ASK1/p38-mediated cell signalling with ischaemic cardiomyopathy. Cardiovascular research 41 23015639
2023 ASK1-K716R reduces neuroinflammation and white matter injury via preserving blood-brain barrier integrity after traumatic brain injury. Journal of neuroinflammation 40 37875988
2003 Identification of a novel antiapoptotic protein that antagonizes ASK1 and CAD activities. The Journal of cell biology 39 14557248
2022 Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria. eLife 38 35285800
2021 Serum deprivation-response protein induces apoptosis in hepatocellular carcinoma through ASK1-JNK/p38 MAPK pathways. Cell death & disease 38 33931585
2007 TNF-alpha suppresses prolyl-4-hydroxylase alpha1 expression via the ASK1-JNK-NonO pathway. Arteriosclerosis, thrombosis, and vascular biology 38 17478756
2021 OTUB1 alleviates NASH through inhibition of the TRAF6-ASK1 signaling pathways. Hepatology (Baltimore, Md.) 37 34591986
2022 Overlapping functions of YDA and MAPKKK3/MAPKKK5 upstream of MPK3/MPK6 in plant immunity and growth/development. Journal of integrative plant biology 34 35652263
2017 LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. Biochimica et biophysica acta. Molecular cell research 34 28888991
2016 Scaffold Role of DUSP22 in ASK1-MKK7-JNK Signaling Pathway. PloS one 34 27711255
2021 Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions. International journal of molecular sciences 33 34948191
2016 ASK1 controls spindle orientation and positioning by phosphorylating EB1 and stabilizing astral microtubules. Cell discovery 33 27721984
2009 Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation. The Journal of biological chemistry 33 19920149
2002 Interaction of ALG-2 with ASK1 influences ASK1 localization and subsequent JNK activation. FEBS letters 33 12372597
2017 ASK1 (MAP3K5) is transcriptionally upregulated by E2F1 in adipose tissue in obesity, molecularly defining a human dys-metabolic obese phenotype. Molecular metabolism 32 28702328
2001 ASK1-signaling promotes c-Myc protein stability during apoptosis. Biochemical and biophysical research communications 30 11243879
2013 Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ß cell exhaustion. Biochimica et biophysica acta 28 23416061
2013 Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses. Infection and immunity 27 24082073
2012 ASK1 promotes apoptosis of normal and malignant plasma cells. Blood 27 22723553
2023 Iron overload induces islet β cell ferroptosis by activating ASK1/P-P38/CHOP signaling pathway. PeerJ 25 37090106
2018 MiR17 improves insulin sensitivity through inhibiting expression of ASK1 and anti-inflammation of macrophages. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 25 29477089
2016 Effect of silibinin and vitamin E on the ASK1-p38 MAPK pathway in D-galactosamine/lipopolysaccharide induced hepatotoxicity. Experimental biology and medicine (Maywood, N.J.) 25 26941058
2021 Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia. Scientific reports 24 33972601
2020 ASK1/p38‑mediated NLRP3 inflammasome signaling pathway contributes to aberrant retinal angiogenesis in diabetic retinopathy. International journal of molecular medicine 24 33416127
2013 Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy. Pharmacogenomics 24 23556445
2009 JAK2 and SHP2 reciprocally regulate tyrosine phosphorylation and stability of proapoptotic protein ASK1. The Journal of biological chemistry 24 19287004
2005 Apoptosis-linked gene-2 connects the Raf-1 and ASK1 signalings. Biochemical and biophysical research communications 24 15925322
2020 Discovery and development of ASK1 inhibitors. Progress in medicinal chemistry 23 32362327
2017 Structural aspects of protein kinase ASK1 regulation. Advances in biological regulation 23 29066278
2018 Redox-Inactive Peptide Disrupting Trx1-Ask1 Interaction for Selective Activation of Stress Signaling. Biochemistry 22 29261301
2011 Dyrk1A Positively Stimulates ASK1-JNK Signaling Pathway during Apoptotic Cell Death. Experimental neurobiology 22 22110360
2022 Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling. Arteriosclerosis, thrombosis, and vascular biology 21 35387478
2021 Apocynin attenuates diabetic cardiomyopathy by suppressing ASK1-p38/JNK signaling. European journal of pharmacology 21 34348125
2020 FGF21 Induced by the ASK1-p38 Pathway Promotes Mechanical Cell Competition by Attracting Cells. Current biology : CB 21 33357449
2016 Deletion of ASK1 Protects against Hyperoxia-Induced Acute Lung Injury. PloS one 21 26807721
2002 Activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) following cerebral ischemia in rat hippocampus. Neuroscience letters 21 12165419
2017 Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors. European journal of medicinal chemistry 20 29348070
2013 Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin. The Journal of investigative dermatology 20 24008424
2023 MITOGEN-ACTIVATED PROTEIN KINASE3 enhances disease resistance of edr1 mutants by phosphorylating MAPKKK5. Plant physiology 19 37638889
2017 The Epstein-Barr Virus-encoded miR-BART22 targets MAP3K5 to promote host cell proliferative and invasive abilities in nasopharyngeal carcinoma. Journal of Cancer 19 28243335

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