Affinage

MAP3K8

Mitogen-activated protein kinase kinase kinase 8 · UniProt P41279

Length
467 aa
Mass
52.9 kDa
Annotated
2026-06-10
85 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K8 (TPL-2/Cot) is a serine/threonine MAP kinase kinase kinase that couples innate immune receptor engagement to MAPK output, directly phosphorylating and activating the MAP kinase kinases that drive ERK1/2 and JNK/SAPK signaling (PMID:8631303). In resting cells the kinase is held inactive within a stoichiometric complex: NF-κB1 p105 binds TPL-2 through dual contacts—its 497–534 region engaging the TPL-2 C-terminus and its death domain engaging the kinase domain—to suppress MEK kinase activity and stabilize the protein, while ABIN-2 provides additional stability such that its loss collapses steady-state TPL-2 levels (PMID:9950430, PMID:12832462, PMID:15169888). Activating signals from TLRs, TNF, CD40, and IL-1R relieve this restraint through the IKK complex, which phosphorylates p105 PEST serines to trigger proteasomal degradation and TPL-2 release, and additionally phosphorylates TPL-2 Ser400; S400 phosphorylation cooperates with Ser443 autophosphorylation to recruit 14-3-3, which is required to stimulate MEK kinase activity and downstream ERK1/2 activation (PMID:15485931, PMID:17709378, PMID:22988300, PMID:24912162, PMID:22733995). Beyond the MKK1/2-ERK axis, TPL-2 is the MAP3K for the MKK3/6-p38α module downstream of TLR4 and TNF (PMID:27402796). These pathways shape macrophage and dendritic cell function: TPL-2/ERK signaling suppresses IFN-β and IL-12 via an ERK1/2-TCF-FOS transcriptional axis (PMID:19667062, PMID:35082159), controls Cox-2/PGE2 production in lung macrophages (PMID:33443087), and, through a MAP-kinase-independent route, drives DMXL1 phosphorylation and V-ATPase assembly to acidify phagosomes for bacterial killing (PMID:33881780). TPL-2 stability is further constrained by BCL-3-promoted nuclear shuttling and proteasomal turnover (PMID:31772019). Oncogenic activation arises from C-terminal truncation, which removes the autoinhibitory tail, S400, and 14-3-3 dependence to render the kinase constitutively active (PMID:9087424, PMID:24912162); such truncating MAP3K8 rearrangements drive constitutive MEK-ERK signaling and confer MEK/ERK-inhibitor sensitivity in spitzoid melanoma and other tumors (PMID:30833747, PMID:31186280).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1994 Medium

    Before its biochemical activity was known, genetic epistasis placed Tpl-2 within mitogenic Ras/Raf signaling, establishing it as a transducer of proliferative MAPK signals.

    Evidence Dominant-negative Ras/Raf-1 co-transfection epistasis in cell lines

    PMID:7937886

    Open questions at the time
    • Direct kinase substrates not yet defined
    • Physiological activating receptor not identified
    • Relies on overexpressed dominant-negative constructs
  2. 1996 High

    Established the core molecular activity—that TPL-2 is a MAP3K that directly phosphorylates the MAP kinase kinases MEK-1 and SEK-1 to activate both ERK and JNK/SAPK cascades.

    Evidence In vitro kinase assay with immunoprecipitated TPL-2 and recombinant GST-MEK-1/SEK-1; transfection in COS-1 and Jurkat cells

    PMID:8631303

    Open questions at the time
    • Regulation of basal activity unaddressed
    • Physiological versus overexpression substrate preference unclear
  3. 1997 High

    Revealed intrinsic autoinhibition—the C-terminal tail folds back on the kinase domain to suppress activity, defining the molecular basis later exploited by oncogenic truncation.

    Evidence In vitro kinase comparison of wild-type vs truncated Tpl-2; GST pulldown of tail with kinase domain in Sf9 cells; transgenic mice

    PMID:9087424

    Open questions at the time
    • Trans-acting regulators of the tail not yet known
    • Did not identify the phosphorylation events controlling the tail
  4. 1999 High

    Connected TPL-2 to NF-κB by showing it phosphorylates p105 to promote its degradation, linking the kinase to two transcriptional outputs.

    Evidence Co-IP, wild-type vs kinase-inactive TPL-2, p105 phosphorylation/degradation assays

    PMID:9950430

    Open questions at the time
    • Whether p105 also regulates TPL-2 reciprocally not yet shown
    • Kinase responsible for p105 phosphorylation in vivo unresolved
  5. 2003 High

    Defined p105 as a bidirectional partner that both inhibits TPL-2 MEK kinase activity through dual-domain binding and stabilizes the protein, explaining the inactive resting state and oncogene insensitivity.

    Evidence In vitro kinase assay, domain-mapping Co-IP, C-terminal deletion mutants

    PMID:12832462

    Open questions at the time
    • Did not establish the signal that disrupts the inhibitory interaction
  6. 2004 High

    Established the activation switch: IKK-driven p105 proteolysis releases TPL-2, and the freed pool carries the MEK kinase activity, while ABIN-2 was identified as a third stabilizing subunit.

    Evidence Co-IP, IKK blockade, reconstitution of NF-κB1-deficient macrophages with IKK-site mutant p105, RNAi/pulse-chase for ABIN-2

    PMID:15169888 PMID:15485931

    Open questions at the time
    • Whether release alone is sufficient for full activation unresolved
    • Direct phosphorylation of TPL-2 itself not yet demonstrated
  7. 2007 High

    Showed that release from p105 is necessary but not sufficient—LPS-induced Ser400 phosphorylation is a second obligatory activation step, and its loss in truncations links to oncogenesis.

    Evidence S400A mutagenesis, retroviral reconstitution in Nfkb1-/- and Map3k8-/- macrophages, in vitro MEK kinase assay

    PMID:17709378

    Open questions at the time
    • Kinase phosphorylating S400 not identified
    • Downstream consequence of S400-P not mechanistically explained
  8. 2012 High

    Identified IKK2 as the S400 kinase and showed IKK controls both activation steps (p105 proteolysis and S400 phosphorylation) across multiple TLR ligands and TNF, unifying the upstream input.

    Evidence In vitro kinase assay with recombinant IKK2; SSAA p105 knock-in mouse; multiple TLR ligands; IKK2 inhibition

    PMID:22733995 PMID:22988300

    Open questions at the time
    • How S400 phosphorylation mechanistically stimulates catalysis not yet resolved
  9. 2014 High

    Resolved the activation mechanism: IKK-phosphorylated S400 plus S443 autophosphorylation recruit 14-3-3, which is required to stimulate MEK kinase activity, and truncation bypasses this 14-3-3 dependence.

    Evidence Co-IP of TPL-2/14-3-3, S400/S443 mutagenesis, in vitro MEK-1 kinase assay, reconstitution in Map3k8-/- macrophages

    PMID:24912162

    Open questions at the time
    • Structural basis of 14-3-3-induced activation not determined
  10. 2016 High

    Broadened TPL-2 output beyond ERK by demonstrating it is the MAP3K for the MKK3/6-p38α axis downstream of TLR4 and TNF.

    Evidence Quantitative phosphoproteomics in Map3k8-D270A kinase-dead vs wild-type macrophages

    PMID:27402796

    Open questions at the time
    • Why MKK4 is not a substrate unexplained
    • Determinants of MKK3/6 versus MKK1/2 selectivity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Multiple TPL-2 functions reported in non-macrophage and tumor contexts (NFAT/IL-2 in T cells, p53/PP2A regulation, caspase-9/Tvl-1 apoptosis, GPR30-driven progesterone, ovarian and HTLV-1 contexts) remain mechanistically siloed and not integrated into a unified signaling model.
  • Whether these context-specific roles share the p105/14-3-3 activation logic is untested
  • Direct substrates in T cells and reproductive tissue not biochemically defined
  • Relationship between MAP-kinase-dependent and -independent (DMXL1/V-ATPase) outputs not fully mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3
Partners
BCL3CHUK/IKBKB (IKK)DMXL1NFKB1TNIP2TP53TRAF2YWHA (14-3-3)
Complex memberships
TPL-2/NF-κB1 p105/ABIN-2 ternary complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 TPL-2/MAP3K8 directly phosphorylates and activates MEK-1 and SEK-1 (MAP kinase kinases) in vitro, functioning as a MAP kinase kinase kinase that activates both the ERK and JNK/SAPK pathways. In vitro kinase assay with immunoprecipitated TPL-2 and recombinant GST-MEK-1/SEK-1 fusion proteins; transfection of COS-1 and Jurkat T cells showing ERK-1 and SAP kinase activation The EMBO journal High 8631303
1994 MAP3K8/Tpl-2-induced MAPK activation is blocked by dominant-negative mutants of Ras and Raf-1, and kinase-deficient Tpl-2 down-regulates mitogenic signals from v-Ha-Ras or v-Raf, placing Tpl-2 in the Ras/Raf-1 signaling complex. Dominant-negative mutant co-transfection epistasis in cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 7937886
1997 C-terminal truncation of Tpl-2 increases catalytic activity ~7-fold and enhances MAPK/SAPK pathway activation 2-3 fold; the C-terminal tail interacts with the truncated kinase domain (GST fusion co-expression in Sf9 cells) and mediates autoinhibitory intramolecular interactions that down-regulate kinase activity. In vitro kinase assay comparing wild-type and truncated Tpl-2; GST pulldown of C-terminal tail with truncated protein in Sf9 cells; transgenic mouse model Genes & development High 9087424
1999 TPL-2 forms a complex with the C-terminus of NF-κB1 p105; TPL-2 expression causes phosphorylation and increased degradation of p105 while maintaining p50 production, thereby releasing associated Rel subunits to generate active nuclear NF-κB. Kinase-inactive TPL-2 blocks TNF-α-induced p105 degradation. Co-immunoprecipitation; transfection with wild-type and kinase-inactive TPL-2; p105 phosphorylation and degradation assays Nature High 9950430
2003 NF-κB1 p105 negatively regulates TPL-2 MEK kinase activity through two distinct interactions: the TPL-2 C-terminus binds p105 residues 497–534, while the TPL-2 kinase domain interacts with the p105 death domain. Binding to the p105 death domain inhibits TPL-2 MEK kinase activity in vitro, and both interactions are required for full inhibition in cells. C-terminally truncated oncogenic TPL-2 is insensitive to this inhibition. TPL-2 stability in vivo depends on its high-affinity stoichiometric association with p105. In vitro kinase assay; co-immunoprecipitation mapping of binding domains; cotransfection experiments with C-terminal deletion mutants Molecular and cellular biology High 12832462
2004 LPS stimulation releases both forms of TPL-2 from the p105 complex, and TPL-2 MEK kinase activity is restricted to the p105-free pool. IKK complex phosphorylation of two serines in the p105 PEST region triggers proteasome-mediated p105 proteolysis, which is essential for TPL-2 release and subsequent activation of MEK and ERK. Expression of a p105 point mutant not susceptible to signal-induced proteolysis impairs LPS-induced TPL-2 activation; wild-type but not mutant p105 reconstitutes LPS-stimulated MEK/ERK signaling in NF-κB1-deficient macrophages. Co-immunoprecipitation; pharmacological IKK blockade; reconstitution in primary NF-κB1-deficient macrophages with wild-type vs. IKK-site mutant p105; proteasome inhibitors Molecular and cellular biology High 15485931
2004 ABIN-2 forms a ternary complex with TPL-2 and NF-κB1 p105. ABIN-2 is required for TPL-2 protein stability: RNAi depletion of ABIN-2 dramatically reduces steady-state TPL-2 protein without affecting TPL-2 mRNA or p105 levels, and ABIN-2 increases TPL-2 half-life. LPS activation of TPL-2 correlates with its release from ABIN-2. Affinity purification identifying ABIN-2 as novel p105-associated protein; co-immunoprecipitation of endogenous proteins in bone marrow-derived macrophages; RNA interference; pulse-chase half-life experiments Molecular and cellular biology High 15169888
2007 LPS stimulation induces phosphorylation of serine 400 in the TPL-2 C-terminal tail. Mutation of S400 to alanine blocks LPS-stimulated TPL-2 MEK kinase activity and ERK activation independently of p105 release, demonstrating that S400 phosphorylation is a second required regulatory step for TPL-2 activation. C-terminal truncations that remove S400 may contribute to oncogenic activation. Site-directed mutagenesis (S400A); retroviral reconstitution in Nfkb1-/- and Map3k8-/- macrophages; in vitro MEK kinase assay Molecular and cellular biology High 17709378
2012 IκB kinase 2 (IKK2) directly phosphorylates TPL-2 on serine 400, providing the transphosphorylation signal required for TPL-2 activation of ERK-1/2 independently of p105 regulation. The IKK complex therefore controls both key regulatory steps of TPL-2 activation: p105 proteolysis and TPL-2 S400 phosphorylation. In vitro kinase assay with recombinant IKK2 and TPL-2 substrates; site-directed mutagenesis; pharmacological IKK2 inhibition in macrophages Molecular and cellular biology High 22988300
2014 IKK-mediated phosphorylation of TPL-2 S400 cooperates with TPL-2 S443 autophosphorylation to trigger TPL-2 association with 14-3-3 proteins. 14-3-3 binding to the phosphorylated C-terminus stimulates TPL-2 MEK-1 kinase activity and is essential for ERK-1/2 activation and LPS-induced TNF production. C-terminal deletion of TPL-2 renders its kinase activity independent of 14-3-3, contributing to oncogenic transformation. Co-immunoprecipitation of TPL-2 and 14-3-3; site-directed mutagenesis of S400 and S443; in vitro MEK-1 kinase assay; retroviral reconstitution in Map3k8-/- macrophages Proceedings of the National Academy of Sciences of the United States of America High 24912162
2012 IKK-induced proteolysis of NF-κB1 p105 (via IKK phosphorylation of p105 PEST serines) is essential for TPL-2/ERK activation by multiple TLR ligands (LPS, CpG, Pam3CSK, poly(I·C), flagellin, R848) and by TNF. Mutation of the IKK target serines on p105 (SSAA) blocks agonist-induced TPL-2 release from p105 and ERK activation. TPL-2/ERK activation creates a negative feedback loop to suppress IL-12 expression. Knock-in mouse model (Nfkb1-SSAA/SSAA); macrophage stimulation with multiple TLR ligands; ERK phosphorylation assays; gene expression analysis Molecular and cellular biology High 22733995
2016 TPL-2 catalytic activity is required for phosphorylation of MKK3 and MKK6 activation loops (but not MKK4) downstream of TLR4 and TNF stimulation in macrophages, placing TPL-2 as the MAP3K for the MKK3/6-p38α axis in addition to the MKK1/2-ERK axis. MKK3/6 activation also requires IKK phosphorylation of NF-κB1 p105. TNF activation of p38α is substantially dependent on TPL-2 via MKK3/6. Quantitative mass spectrometry of protein phosphorylation in wild-type vs. Map3k8-D270A/D270A (kinase-dead) macrophages following LPS/TNF/bacterial stimulation The Biochemical journal High 27402796
1998 TPL-2 activates the NFAT transcription factor and induces IL-2 expression in T-cell lines via convergence of the MAPK and calcineurin/NFAT pathways. NFATp (but not NFATc or NFATx) undergoes nuclear translocation when co-expressed with wild-type Tpl-2. Kinase-dead Tpl-2 K167M inhibits anti-CD3-stimulated NFAT activation in Jurkat cells. TPL-2 also activates NF-κB to cooperate in IL-2 promoter induction. Transfection with dominant-negative signaling molecules; NFAT-driven reporter assays; nuclear translocation assay; specific isoform co-expression Proceedings of the National Academy of Sciences of the United States of America Medium 9520452
2002 TPL-2/Cot interacts with TRAF2 (co-immunoprecipitation and co-localization), functioning downstream of TRAF2, and contributes to LMP1-induced NF-κB signaling. Catalytically inactive TPL-2 suppresses LMP1- and CD40-induced NF-κB activation. TPL-2 modulates both IκBα and p105 functions in this pathway. Co-immunoprecipitation; co-localization; dominant-negative kinase-dead TPL-2 transfection; NF-κB reporter assay Journal of virology Medium 11932422
2005 MAP3K8/Tpl-2 is recruited to the CD40 receptor complex through TRAF-binding sites in CD40 (TRAF-dependent association). Catalytically inactive Tpl-2 suppresses CD40-mediated IKK activation and NF-κB induction. Tpl2-/- fibroblasts are deficient in CD40 but not TNF signaling. Tpl-2 functions distal to TRAFs but proximal to the TAK1/TAB1 complex. Co-immunoprecipitation of Tpl-2 with CD40 complex; kinase-dead dominant-negative transfection; Tpl2-/- fibroblast genetic experiments; epistasis with TAK1/TAB1 Biochemical and biophysical research communications Medium 15670770
2009 TPL-2 negatively regulates LPS- and CpG-induced IFN-β production in macrophages and myeloid DCs via ERK-dependent induction of c-Fos. In the absence of TPL-2 signaling, IFN-β is increased while IL-10 is decreased. The negative regulation requires protein synthesis and is independent of IL-10. Map3k8-/- macrophages and myeloid DCs; retroviral transduction of ERK-dependent transcription factor c-Fos into TPL-2-deficient cells; cytokine secretion assays The Journal of experimental medicine High 19667062
2010 Arginine availability facilitates TPL-2 activation downstream of TLR4 by preventing dephosphorylation and inactivation of TPL-2 in LPS-stimulated macrophages, thereby enabling ERK1/2 activation and TNF-α production. Arginine starvation impairs LPS-induced ERK1/2 activation in vivo. Arginine depletion/supplementation experiments in cultured macrophages and in mice; ERK1/2 and TPL-2 phosphorylation assays; in vivo arginine supplementation Science signaling Medium 20716763
2001 Tpl-2 induces apoptosis by promoting assembly of a complex containing caspase-9, the ankyrin repeat protein Tvl-1, and procaspase-3, leading to caspase-9-dependent caspase-3 activation. Co-expression with Tvl-1 enhances this effect; procaspase-3 conditionally associates with Tvl-1 in response to Tpl-2 apoptotic signals. Co-immunoprecipitation of complex components; caspase activity assays; co-transfection in non-transformed cells Journal of cellular physiology Medium 11267997
2019 BCL-3, a nuclear IκB protein, promotes TPL-2 degradation by increasing TPL-2 nuclear localization. TPL-2 is a nucleocytoplasmic shuttling protein, and the nucleus is the primary site for its proteasomal degradation after TLR stimulation. BCL-3 interacts with TPL-2 and promotes nuclear retention, thereby limiting MAPK activity. Bcl3-/- macrophages have increased TPL-2 stability, elevated MAPK activity, and lower TLR stimulation threshold for cytokine production. Bcl3-/- macrophages; co-immunoprecipitation of BCL-3 and TPL-2; subcellular fractionation; nuclear localization imaging; proteasome inhibitor experiments Proceedings of the National Academy of Sciences of the United States of America High 31772019
2021 TPL-2 catalytic activity induces phagosome acidification and proteolysis in macrophages through a MAP kinase-independent mechanism. TPL-2 stimulates phosphorylation of DMXL1 (a V-ATPase regulator), promoting V-ATPase assembly on phagosomes. Blocking TPL-2 catalytic activity reduces V-ATPase proton pump subunit abundance on phagosomes and impairs killing of S. aureus and C. rodentium. Map3k8-D270A/D270A kinase-dead macrophages; quantitative phagosome proteomics; latex bead phagosome assay; bacterial killing assay; V-ATPase assembly analysis; DMXL1 phosphorylation The EMBO journal High 33881780
2009 Tpl-2 wild-type protein interacts with p53 in vitro and in cells. Overexpression of Tpl-2 inhibits EGF-induced p53 phosphorylation (Ser15) by upregulating protein phosphatase 2A activity. Mutation S413A in Tpl-2 abrogates suppression of p53 activity and EGF-induced c-fos promoter/AP-1 transactivation. Co-immunoprecipitation of Tpl-2 and p53 in vitro and ex vivo; site-directed mutagenesis (S413A); p53 phosphorylation and transcriptional activity assays Carcinogenesis Medium 19221002
2022 TPL-2 (MAP3K8) activation promotes Th1-like differentiation and constitutively activates MEK-ERK signaling in HTLV-1-infected T cells. HTLV-1 Tax, Fosl2, and c-Jun collaboratively induce chromatin remodeling at the MAP3K8 enhancer locus, driving MAP3K8 overexpression. MEK inhibitors suppress the MAP3K8-MEK signaling cascade and mitigate inflammatory pathogenesis ex vivo. Chromatin accessibility profiling (ATAC-seq); transcriptomic analysis; chromatin immunoprecipitation; MEK inhibitor treatment in ex vivo culture; overexpression of Tax, Fosl2, c-Jun Nature communications Medium 41213906
2022 TPL-2 inhibition of IFN-β in TLR4-stimulated macrophages is mediated via an ERK1/2-TCF-FOS axis. TPL-2 activates ERK1/2, which phosphorylates ELK1 (a ternary complex factor) and induces TCF target genes including FOS. TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via secondary transcription factors. Loss of FOS recapitulates a significant fraction of TPL-2 transcriptional regulation. Transcriptomic comparison of wild-type vs. Map3k8-D270A/D270A macrophages; TCF-deficient macrophages; Fos-/- macrophages; bioinformatics motif analysis; ELK1 phosphorylation assay Journal of immunology (Baltimore, Md. : 1950) High 35082159
2020 MAP3K8 regulates Cox-2 expression and PGE2 production in macrophages in the lung. Map3k8 deficiency in mice reduces Cox-2 expression and PGE2 levels; macrophage-specific deletion of Map3k8 is sufficient to exacerbate pulmonary fibrosis. Exogenous PGE2 administration rescues the exacerbated fibrotic phenotype of Map3k8-/- mice. Conditional macrophage-specific Map3k8 knockout (LysM-Cre); bone marrow transplantation; bleomycin fibrosis model; Cox-2 and PGE2 measurements; PGE2 rescue experiment Journal of immunology (Baltimore, Md. : 1950) High 33443087
2018 Hypoxia increases MAP3K8 expression via HIF-1 (hypoxia-induced factor) transcriptional activation, upstream of the p38 MAPK pathway in monocyte-derived dendritic cells. MAP3K8 knockdown or pharmacological inhibition reduces hypoxia-potentiated TNF-α secretion and p38 MAPK phosphorylation. siRNA knockdown of MAP3K8 in human moDCs; MAP3K8 inhibitor; TNF-α ELISA; p38 phosphorylation assay; HIF-ChIP or HIF-target analysis Bioscience reports Medium 30463908
2019 MAP3K8 fusions in spitzoid melanoma invariably encode the intact kinase domain but lack the autoinhibitory C-terminal exon (exon 1-8 fusions), resulting in constitutively active kinase. These truncating rearrangements activate MEK signaling and confer sensitivity to MEK inhibition. RNA sequencing identification of fusion transcripts; clinical MEK inhibitor treatment with tumor response; FISH break-apart assay Nature medicine Medium 30833747
2019 Truncating MAP3K8 rearrangements in driver-negative melanoma cell lines result in increased levels of truncated, constitutively active MAP3K8 protein, oncogenic ERK dependency, resistance to BRAF inhibition, and sensitivity to MEK or ERK1/2 inhibition. Endogenous MAP3K8 rearranged melanoma cell lines; FISH validation; western blot of truncated protein; MEK/ERK inhibitor sensitivity assays; BRAF inhibitor resistance assay Molecular cancer research : MCR Medium 31186280
2015 MAP3K8 overexpression in high-grade serous ovarian carcinoma cells controls cancer cell proliferation and migration by regulating G1/S transition key players and adhesion dynamics, primarily via the MEK pathway. MAP3K8 knockdown/overexpression in ovarian cancer cells; patient-derived xenografts; MEK pathway inhibitor experiments; cell cycle and migration assays Nature communications Medium 26456302
2015 MAP3K8 mediates E2 (estradiol)-stimulated progesterone production in mouse corpus luteum via GPR30 (G protein-coupled receptor 30), stimulating ERK phosphorylation downstream. siRNA knockdown of MAP3K8 or pharmacological MAP3K8 inhibition significantly blocks progesterone synthesis and neutralizes E2's enhancing effect on progesterone production. siRNA knockdown; MAP3K8 inhibitor; hormone assays; ERK phosphorylation; co-expression with GPR30 Molecular endocrinology (Baltimore, Md.) Medium 25763610
2018 The TPL-2/NF-κB1 p105/ABIN-2 complex has a distinct substrate specificity profile from the isolated TPL-2 kinase domain, determined by positional scanning peptide library. The complex also shows significantly altered sensitivities to existing ATP-competitive TPL-2 inhibitors compared to the isolated kinase domain, suggesting allosteric inhibitor opportunities. Positional scanning peptide library; high-throughput mass spectrometry kinase activity assay; comparison of complex vs. isolated kinase domain with multiple inhibitors The Biochemical journal Medium 29229763

Source papers

Stage 0 corpus · 85 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. The EMBO journal 263 8631303
1999 TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105. Nature 184 9950430
2004 Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IkappaB kinase-induced proteolysis of NF-kappaB1 p105. Molecular and cellular biology 172 15485931
1993 Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proceedings of the National Academy of Sciences of the United States of America 155 7681591
2009 TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. The Journal of experimental medicine 141 19667062
2012 IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunological reviews 121 22435554
2010 Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase. Cell research 121 21135874
1997 Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Genes & development 116 9087424
2022 ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression. International journal of biological sciences 107 35982895
2003 NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Molecular and cellular biology 107 12832462
1994 Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 107 7937886
2014 Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis 90 24517997
2013 TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production. Journal of immunology (Baltimore, Md. : 1950) 85 23842752
2009 Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta production. Journal of immunology (Baltimore, Md. : 1950) 82 19933865
2004 ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability. Molecular and cellular biology 82 15169888
2019 Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nature medicine 74 30833747
1999 Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 74 10490831
1998 Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB. Oncogene 66 9840924
1998 The Tpl-2 protooncoprotein activates the nuclear factor of activated T cells and induces interleukin 2 expression in T cell lines. Proceedings of the National Academy of Sciences of the United States of America 59 9520452
2016 miR-144-3p serves as a tumor suppressor for renal cell carcinoma and inhibits its invasion and metastasis by targeting MAP3K8. Biochemical and biophysical research communications 58 27717821
1996 Involvement of the Tpl-2/cot oncogene in MMTV tumorigenesis. Oncogene 56 8934549
2012 Coordinate regulation of TPL-2 and NF-κB signaling in macrophages by NF-κB1 p105. Molecular and cellular biology 55 22733995
2019 Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 54 31719662
2016 TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. The Biochemical journal 52 27402796
2002 The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2. Journal of virology 49 11932422
2016 Identification of altered microRNAs and mRNAs in the cumulus cells of PCOS patients: miRNA-509-3p promotes oestradiol secretion by targeting MAP3K8. Reproduction (Cambridge, England) 48 27001999
2016 miR-589-5p inhibits MAP3K8 and suppresses CD90+ cancer stem cells in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 48 27835990
2017 microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways. Oncotarget 47 28186962
2004 Mutational activation of the MAP3K8 protooncogene in lung cancer. Genes, chromosomes & cancer 47 15287022
1993 Genomic organization and expression of Tpl-2 in normal cells and Moloney murine leukemia virus-induced rat T-cell lymphomas: activation by provirus insertion. Journal of virology 47 8510223
2022 Shexiang Baoxin Pill attenuates myocardial ischemia/reperfusion injury by activating autophagy via modulating the ceRNA-Map3k8 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 42 35849969
2015 MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas. Nature communications 42 26456302
2010 TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Science signaling 42 20716763
2007 Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. Molecular and cellular biology 41 17709378
2012 IκB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400. Molecular and cellular biology 40 22988300
2009 Cot/Tpl-2 protein kinase as a target for the treatment of inflammatory disease. Current topics in medicinal chemistry 39 19689369
2011 NF-κB1 inhibits TLR-induced IFN-β production in macrophages through TPL-2-dependent ERK activation. Journal of immunology (Baltimore, Md. : 1950) 34 21217011
2014 Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase. Journal of immunology (Baltimore, Md. : 1950) 33 24639351
2014 IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases. Proceedings of the National Academy of Sciences of the United States of America 32 24912162
2018 Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8. Bioscience reports 31 30463908
2011 TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. PloS one 27 21267413
2020 microRNA-381-3p Confers Protection Against Ischemic Stroke Through Promoting Angiogenesis and Inhibiting Inflammation by Suppressing Cebpb and Map3k8. Cellular and molecular neurobiology 25 32297103
2019 Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells. Bioinformatics (Oxford, England) 25 30481266
2011 Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease? Mucosal immunology 25 22157885
2021 TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria. The EMBO journal 23 33881780
2019 Pathologic Characteristics of Spitz Melanoma With MAP3K8 Fusion or Truncation in a Pediatric Cohort. The American journal of surgical pathology 23 31498175
2016 Map3k8 Modulates Monocyte State and Atherogenesis in ApoE-/- Mice. Arteriosclerosis, thrombosis, and vascular biology 22 27856455
2015 A TPL2 (MAP3K8) disease-risk polymorphism increases TPL2 expression thereby leading to increased pattern recognition receptor-initiated caspase-1 and caspase-8 activation, signalling and cytokine secretion. Gut 22 26215868
2008 Tpl-2/Cot and COX-2 in breast cancer. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 22 18795070
2020 MAP3K8 Regulates Cox-2-Mediated Prostaglandin E2 Production in the Lung and Suppresses Pulmonary Inflammation and Fibrosis. Journal of immunology (Baltimore, Md. : 1950) 21 33443087
2019 ABIN-2, of the TPL-2 Signaling Complex, Modulates Mammalian Inflammation. Trends in immunology 20 31401161
2022 circNup188/miR-760-3p/Map3k8 axis regulates inflammation in cerebral ischemia. Molecular and cellular probes 17 35636640
2016 TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology. PLoS pathogens 17 27487182
2014 MAP3K8 (TPL2/COT) affects obesity-induced adipose tissue inflammation without systemic effects in humans and in mice. PloS one 16 24586913
2013 Ebola virus VP35 induces high-level production of recombinant TPL-2-ABIN-2-NF-κB1 p105 complex in co-transfected HEK-293 cells. The Biochemical journal 16 23557442
2012 MAP3K8 kinase regulates myeloma growth by cell-autonomous and non-autonomous mechanisms involving myeloma-associated monocytes/macrophages. British journal of haematology 15 23252623
2021 ZNF507 affects TGF-β signaling via TGFBR1 and MAP3K8 activation in the progression of prostate cancer to an aggressive state. Journal of experimental & clinical cancer research : CR 13 34537073
2014 Pharmacological inhibition of TPL2/MAP3K8 blocks human cytotoxic T lymphocyte effector functions. PloS one 13 24642963
2005 TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40. Biochemical and biophysical research communications 13 15670770
2019 Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations. Molecular cancer research : MCR 12 31186280
2019 The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus. Proceedings of the National Academy of Sciences of the United States of America 12 31772019
2017 Map3k8 controls granulocyte colony-stimulating factor production and neutrophil precursor proliferation in lipopolysaccharide-induced emergency granulopoiesis. Scientific reports 12 28694430
2015 Mitogen-Activated Protein Kinase 8 (MAP3K8) Mediates the Signaling Pathway of Estradiol Stimulating Progesterone Production Through G Protein-Coupled Receptor 30 (GPR30) in Mouse Corpus Luteum. Molecular endocrinology (Baltimore, Md.) 12 25763610
2023 Melatonin Protects the Apoptosis of Sheep Granulosa Cells by Suppressing Oxidative Stress via MAP3K8 and FOS Pathway. Genes 11 37239427
2022 TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages. Journal of immunology (Baltimore, Md. : 1950) 11 35082159
2001 Tpl-2 induces apoptosis by promoting the assembly of protein complexes that contain caspase-9, the adapter protein Tvl-1, and procaspase-3. Journal of cellular physiology 11 11267997
2024 Clinical, Morphologic, and Molecular Features of MAP3K8 Rearranged Spitz Neoplasms: A Retrospective Study Documenting That Bonafide Spitz Melanomas Are Rare. The American journal of surgical pathology 10 38233731
2014 Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C. PloS one 10 24819603
2023 Epigenetic Regulation of MAP3K8 in EBV-Associated Gastric Carcinoma. International journal of molecular sciences 9 36768307
2009 Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF. Carcinogenesis 9 19221002
2024 MAP3K8 is a potential therapeutic target in airway epithelial inflammation. Journal of inflammation (London, England) 7 39030600
2022 Enhanced expression of miR-26a ameliorates lipopolysaccharide-induced endometritis by targeting MAP3K8 to inactivate MAPK signaling pathway. Journal of reproductive immunology 7 36252394
2019 Induction of squamous cell carcinoma after MAP3K8 overexpression in murine salivry gland epithelial cells. Head & neck 7 30723988
2017 Mycobacteria induce TPL-2 mediated IL-10 in IL-4-generated alternatively activated macrophages. PloS one 7 28658262
2021 OVOL2 attenuates the expression of MAP3K8 to suppress epithelial mesenchymal transition in colorectal cancer. Pathology, research and practice 5 34098198
2017 TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus. PLoS pathogens 4 28759611
2007 A cis and trans adenine-dependent hairpin ribozyme against Tpl-2 target. Biochimie 4 17703868
2024 Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature. Diagnostic pathology 3 39363234
2019 Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) mediates the LH-induced stimulation of progesterone synthesis in the porcine corpus luteum. Reproduction, fertility, and development 3 31039922
2025 Dexmedetomidine Blocks the ERK Pathway by Inhibiting MAP3K8 to Achieve a Protective Effect in Lung Ischemia/Reperfusion Injury. The Kaohsiung journal of medical sciences 1 40372180
2025 Chromatin remodeling enhances MAP3K8 expression in HAM: a key pathogenesis for therapeutic intervention. Nature communications 1 41213906
2026 MiR-93-5p Loaded Lipid Nanoparticles Break the Dry Eye Vicious Cycle via Targeting MAP3K8. ACS applied materials & interfaces 0 41879739
2026 Improving Gut Microbiota and Growth Performance of Edible Crickets (Gryllus bimaculatus) by the Probiotic Lactiplantibacillus plantarum TPL-2 from the Guts of the Termite, Termes propinquus. Microorganisms 0 41900419
2024 Expression profiling and single nucleotide polymorphism of mitogen-activated protein kinase kinase kinase 8 MAP3K8 in white muscovy ducks (Cairina moschata). Gene 0 39209181
2018 Assaying kinase activity of the TPL-2/NF-κB1 p105/ABIN-2 complex using an optimal peptide substrate. The Biochemical journal 0 29229763

Missed literature

Know a paper Affinage missed for MAP3K8? Flag it for the maintainers and the community.

No submissions yet.