Affinage

MAP3K6

Mitogen-activated protein kinase kinase kinase 6 · UniProt O95382

Length
1288 aa
Mass
142.6 kDa
Annotated
2026-06-10
11 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K6 (ASK2) is a stress-associated MAP kinase kinase kinase that functions primarily as a partner and regulator of ASK1 (MAP3K5) within a hetero-oligomeric signalosome that controls JNK signaling and apoptosis (PMID:9875215, PMID:19935702). It was identified through its physical interaction with ASK1, and unlike ASK1 it is a weak activator of JNK and does not engage ERK or p38 pathways on its own (PMID:9875215). Endogenous ASK2 forms hetero-oligomers with ASK1, and co-expression mutually stabilizes both proteins (PMID:17714688). ASK2 sets the activation threshold of the complex by binding 14-3-3 proteins through phosphorylated S964; loss of this engagement (S964A mutant or ASK2 knockdown) strips 14-3-3 from ASK1, enhancing ASK1 T838 phosphorylation and downstream JNK activation, thereby coupling ASK2 S964 phosphorylation to signal relay through the ASK1 signalosome (PMID:19935702). Functionally, ASK2 cooperates with ASK1 to drive pro-apoptotic activity in epithelial cells and acts as a tumor suppressor whose expression is lost in human cancers (PMID:19214184), and it acts as a positive regulator of apoptosis in neuronal cells, where its depletion lowers BAX and caspase-3 and raises Bcl-2 (PMID:41782555). The structural basis of the ASK1–ASK2 complex and the upstream kinase responsible for S964 phosphorylation have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1998 Medium

    Establishing that MAP3K6 is an ASK1-interacting MAP3K with restricted pathway output defined it as a partner kinase rather than a broadly acting stress kinase.

    Evidence Yeast two-hybrid with ASK1 bait plus co-IP in 293 cells and MAPK pathway activation assays

    PMID:9875215

    Open questions at the time
    • Functional consequence of the ASK1 interaction not defined
    • No upstream activator identified
    • Single lab, overexpression-based
  2. 2007 Medium

    Showing endogenous ASK2–ASK1 hetero-oligomerization with mutual protein stabilization moved the interaction from an artifact of overexpression to a physiological complex with anti-apoptotic stabilization effects.

    Evidence Co-IP, overexpression/knockdown, caspase-3/PARP cleavage assays, subcellular fractionation

    PMID:17714688

    Open questions at the time
    • Mechanism of mutual stabilization unknown
    • Mitochondrial vs nuclear functional roles not separated
    • No structural detail of the hetero-oligomer
  3. 2009 High

    Identifying ASK2 S964 phosphorylation as the controller of dual 14-3-3 engagement explained how ASK2 sets the activation threshold of the ASK1 signalosome and downstream JNK output.

    Evidence Co-IP, S964A site-directed mutagenesis, siRNA knockdown, ASK1-T838 and JNK phosphorylation readouts

    PMID:19935702

    Open questions at the time
    • Upstream kinase phosphorylating S964 not identified
    • Stoichiometry of dual 14-3-3 engagement unresolved
    • In vitro reconstitution lacking
  4. 2009 High

    Demonstrating that ASK2 cooperates with ASK1 to drive epithelial apoptosis and suppress tumor initiation assigned a physiological, disease-relevant role to the complex.

    Evidence Genetic mouse models, loss-of-function studies, human cancer tissue expression analysis, apoptosis and cytokine assays

    PMID:19214184

    Open questions at the time
    • Molecular link between signalosome activity and tumor suppression not fully mapped
    • Cell-type opposing roles (epithelial vs inflammatory) mechanism unresolved
    • No mutational disease evidence in humans
  5. 2026 Medium

    Knockdown studies in neuronal cells extended ASK2's pro-apoptotic role beyond epithelium, establishing it as a positive regulator of neuronal apoptosis.

    Evidence siRNA knockdown in mouse spinal cord neuronal cells with western blot for BAX, caspase-3, cleaved caspase-3, Bcl-2 and viability assay

    PMID:41782555

    Open questions at the time
    • Whether the neuronal effect requires ASK1 partnership not tested
    • Upstream stimulus driving apoptosis undefined
    • Single method type, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The kinase responsible for ASK2 S964 phosphorylation and the structural architecture of the ASK1–ASK2/14-3-3 complex remain unresolved.
  • Upstream regulatory kinase of S964 unknown
  • No structural model of the hetero-oligomeric signalosome
  • Direct substrate(s) of ASK2 kinase activity not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0016740 transferase activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Partners
MAP3K5YWHA (14-3-3)
Complex memberships
ASK1–ASK2 signalosome

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MAPKKK6 (MAP3K6) was identified as a novel MAP kinase kinase kinase that physically interacts with MAPKKK5/ASK1; the interaction was confirmed by co-immunoprecipitation after co-expression in 293 cells. Unlike ASK1, MAPKKK6 only weakly activated JNK and did not activate ERK or p38 kinase pathways. Yeast two-hybrid screening with ASK1 as bait, followed by co-immunoprecipitation in 293 cells; kinase pathway activation assays Biochemical and biophysical research communications Medium 9875215
2007 ASK2 (MAP3K6) forms homo-oligomers when ectopically expressed, but endogenous ASK2 and ASK1 form hetero-oligomers; co-expression of ASK2 and ASK1 stabilizes both proteins and reduces serum-starvation-induced caspase-3 activation and PARP cleavage. ASK2 localizes to the nucleus, cytoplasm, and mitochondria, similar to ASK1. Co-immunoprecipitation, overexpression and knockdown experiments, caspase-3/PARP cleavage assays, subcellular fractionation/localization Biochemical and biophysical research communications Medium 17714688
2009 ASK2 (MAP3K6) interacts with 14-3-3 proteins through phosphorylated S964. A 14-3-3-binding defective ASK2 mutant (S964A) and ASK2 knockdown both dramatically reduced ASK1 complexed with 14-3-3. ASK2 S964A-induced dissociation of 14-3-3 from ASK1 correlated with enhanced phosphorylation of ASK1 at T838 and increased JNK phosphorylation, indicating that ASK2 S964 phosphorylation controls signal relay to the ASK1 signalosome via dual engagement of 14-3-3. Co-immunoprecipitation, site-directed mutagenesis (S964A), siRNA knockdown, phosphorylation assays (ASK1-T838, JNK) Oncogene High 19935702
2009 ASK2 (MAP3K6), in cooperation with ASK1, functions as a tumor suppressor by exerting pro-apoptotic activity in epithelial cells. ASK1-dependent cytokine production in inflammatory cells, by contrast, promotes tumorigenesis. Loss of ASK2 expression was observed in human cancer cells and tissues, and genetic experiments demonstrated that ASK2 cooperates with ASK1 to suppress tumor initiation. Genetic mouse models, loss-of-function studies, expression analysis in human cancer tissues, apoptosis and cytokine assays The EMBO journal High 19214184
2026 MAP3K6 knockdown in mouse spinal cord neuronal cells promoted cell growth and inhibited apoptosis, decreasing pro-apoptotic proteins BAX, caspase-3, and cleaved caspase-3, and increasing anti-apoptotic Bcl-2, establishing MAP3K6 as a positive regulator of neuronal apoptosis. siRNA knockdown in mouse spinal cord neuronal cells, western blot for apoptosis markers (BAX, caspase-3, cleaved caspase-3, Bcl-2), cell viability assay The International journal of neuroscience Medium 41782555

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. The EMBO journal 112 19214184
1998 MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochemical and biophysical research communications 57 9875215
2014 Germline mutations in MAP3K6 are associated with familial gastric cancer. PLoS genetics 50 25340522
2022 Organophosphate flame retardants induce oxidative stress and Chop/Caspase 3-related apoptosis via Sod1/p53/Map3k6/Fkbp5 in NCI-1975 cells. The Science of the total environment 49 35051466
2018 Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility. Journal of medical genetics 37 29330337
2009 Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome. Oncogene 30 19935702
2007 Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling. Biochemical and biophysical research communications 18 17714688
2024 Salidroside inhibited the proliferation of gastric cancer cells through up-regulating tumor suppressor miR-1343-3p and down-regulating MAP3K6/MMP24 signal molecules. Cancer biology & therapy 14 38436092
2021 MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor. Neurology. Genetics 10 33728376
2024 Assessing sequence variation, haplotype analysis and molecular characterisation of aspartate kinase2 (ask2) gene regulating methionine biosynthesis in diverse maize inbreds. Molecular genetics and genomics : MGG 5 38349549
2026 High MAP3K6 expression in spinal cord injury tissues enhances neuronal apoptosis: insights from multi-omics data integrating WGCNA, machine learning and experimental validation. The International journal of neuroscience 0 41782555

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