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MAP3K8

Official Full Name
mitogen-activated protein kinase kinase kinase 8
Organism
Homo sapiens
GeneID
1326
Background
This gene is an oncogene that encodes a member of the serine/threonine protein kinase family. The encoded protein localizes to the cytoplasm and can activate both the MAP kinase and JNK kinase pathways. This protein was shown to activate IkappaB kinases, and thus induce the nuclear production of NF-kappaB. This protein was also found to promote the production of TNF-alpha and IL-2 during T lymphocyte activation. This gene may also utilize a downstream in-frame translation start codon, and thus produce an isoform containing a shorter N-terminus. The shorter isoform has been shown to display weaker transforming activity. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2011]
Synonyms
COT; EST; ESTF; TPL2; AURA2; MEKK8; Tpl-2; c-COT;
Protein Sequence
MEYMSTGSDNKEEIDLLIKHLNVSDVIDIMENLYASEEPAVYEPSLMTMCQDSNQNDERSKSLLLSGQEVPWLSSVRYGTVEDLLAFANHISNTAKHFYGQRPQESGILLNMVITPQNGRYQIDSDVLLIPWKLTYRNIGSDFIPRGAFGKVYLAQDIKTKKRMACKLIPVDQFKPSDVEIQACFRHENIAELYGAVLWGETVHLFMEAGEGGSVLEKLESCGPMREFEIIWVTKHVLKGLDFLHSKKVIHHDIKPSNIVFMSTKAVLVDFGLSVQMTEDVYFPKDLRGTEIYMSPEVILCRGHSTKADIYSLGATLIHMQTGTPPWVKRYPRSAYPSYLYIIHKQAPPLEDIADDCSPGMRELIEASLERNPNHRPRAADLLKHEALNPPREDQPRCQSLDSALLERKRLLSRKELELPENIADSSCTGSTEESEMLKRQRSLYIDLGALAGYFNLVRGPPTLEYG
Open
Disease
Indeterminate colitis
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8), also known as TPL2 (Tumor Progression Locus 2) or COT (Cancer Osaka Thyroid), is located at chromosome 10p11.23. The gene comprises 16 exons and encodes a protein with a molecular weight of approximately 58 kDa, classified within the serine/threonine kinase family. Structurally, the MAP3K8 protein contains an N-terminal coiled-coil domain, a central kinase domain, and a C-terminal autoinhibitory domain. Two main protein isoforms are transcribed: the full-length isoform (isoform 1) and a truncated isoform (isoform 2). The full-length isoform contains both the complete kinase and regulatory domains, with kinase activity suppressed by the C-terminal domain. In contrast, the truncated isoform initiates translation from a downstream start codon (Met48), lacking part of the N-terminal regulatory sequence, resulting in heightened transforming activity.

MAP3K8 is typically complexed with its regulatory partner NFKB1/p105 under basal conditions. Upon stimulation (e.g., LPS or TNF-α), p105 is phosphorylated by IKKβ and degraded, releasing MAP3K8 and activating its kinase function.

Biological Function and Signaling Regulation

As an upstream kinase in the MAPK signaling cascade, MAP3K8 plays a pivotal role in inflammation and immune regulation. Its downstream signaling branches include:

ERK Pathway Activation:

MAP3K8 directly phosphorylates and activates MAP2K1/2 (MEK1/2), which in turn activates ERK1/2. In macrophages, this pathway is essential for LPS/TLR4-induced TNF-α production. Studies show that MAP3K8-deficient mice fail to secrete TNF-α upon LPS challenge, leading to reduced sensitivity to endotoxin shock.

JNK/NF-κB Pathway Modulation:

In specific cell types such as T cells, MAP3K8 activates JNK and NF-κB, although the regulatory effect is context-dependent. During helper T cell differentiation, MAP3K8 promotes IFN-γ expression while inhibiting IL-17, thereby modulating the Th1/Th17 balance.

Negative Regulation of Type I Interferons:

Recent findings indicate that MAP3K8 negatively regulates IFN-α/β production by suppressing IRF3/7 activity, a mechanism critical for host defense against intracellular bacterial infections such as Listeria monocytogenes.

In studies of bovine endometritis, pathogenic bacteria such as E. coli activate the MAP3K8-MEK-ERK cascade via the LPS-TLR4 axis, leading to the secretion of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. Notably, miR-26a plays a protective role in this disease. Its expression is significantly downregulated in inflamed endometrial tissue, whereas MAP3K8 mRNA and protein levels are concurrently elevated. Mechanistic studies have shown that miR-26a directly targets the 3'UTR of MAP3K8 mRNA, inhibiting its translation. In bovine endometrial epithelial cells (bEECs), overexpression of miR-26a significantly reduces LPS-induced MAP3K8 expression, ERK phosphorylation, and inflammatory cytokine secretion, while inhibition of miR-26a exacerbates the inflammatory response. This regulatory axis has been further validated in a mouse model of endometritis, providing a potential therapeutic target for antibiotic-free livestock farming.

Role in Tumorigenesis and Targeted Therapy

Aberrant activation of MAP3K8 is closely associated with the development of various cancers, most notably melanocytic tumors and lymphomas:

Spitz-lineage Melanocytic Tumors:

A 2022 report of 33 MAP3K8 fusion-positive cutaneous tumors highlighted distinct molecular and morphological features. Fusion genes, identified via RNA sequencing or FISH, comprised MAP3K8 exons 1–8 (encoding the full kinase domain) fused with 3' partner genes such as SVIL, DIP2C, or UBL3. These fusion proteins lack the C-terminal autoinhibitory domain, resulting in constitutive activation. Clinically, these tumors predominantly affected adolescents and young adults (median age: 18 years), commonly occurring on the lower limbs (55%). Histologically, they were categorized as Spitz nevi (5 cases), atypical Spitz tumors (13 cases), and malignant Spitz tumors (15 cases). Atypical/malignant tumors frequently showed epidermal ulceration (32%), dermal multinucleated giant cells (32%), and nests of pigmented cells (32%), with 77% exhibiting CDKN2A inactivation (loss of p16 expression). Despite some regional lymph node involvement, no distant metastasis was observed during follow-up, indicating relatively indolent biological behavior.

Lung and Thyroid Cancers:

MAP3K8 amplification occurs in approximately 5% of lung adenocarcinomas, particularly the bronchioloalveolar subtype, and is mutually exclusive with EGFR mutations. In thyroid cancer, MAP3K8 overexpression enhances tumor cell survival and drug resistance via NF-κB activation.

Inflammation-Associated Tumorigenesis:

In a chronic inflammatory microenvironment, sustained MAP3K8 activation can promote malignant transformation by enhancing cell proliferation (via ERK and NF-κB pathways), inhibiting apoptosis (through Bcl-2 upregulation), and increasing angiogenesis.

Table: Dual Roles of MAP3K8 in Human Diseases

Disease AreaMechanismMolecular FeaturesClinical Significance
Bovine EndometritisLPS-induced MAP3K8-MEK-ERK activationDownregulation of miR-26aNovel target for antibiotic-free therapy
Spitz TumorsMAP3K8-SVIL and other fusionsLoss of p16 (CDKN2A inactivation)Generally favorable prognosis
Lung AdenocarcinomaMAP3K8 gene amplificationMutual exclusivity with EGFR mutationsCandidate for targeted therapy
Autoimmune DiseasesTNF-α and IL-2 overproductionTh1/Th17 imbalanceSmall-molecule inhibitor development

Targeting Strategies and Clinical Applications

Therapeutic approaches targeting MAP3K8 include:

Small-Molecule Inhibitors: For example, BPS Bioscience developed a recombinant MAP3K8 protein with GST-His tags (BPS-40050), covering amino acids 30–397. This construct retains full kinase activity and has been used for in vitro activity assays and inhibitor screening, with a specific activity of 47 pmol/min/μg.

miRNA-Based Therapy:Strategies using miR-26a mimics have shown efficacy in reducing inflammatory damage in animal models of endometritis, offering a potential solution for antibiotic-free livestock farming.

Fusion Gene-Specific Inhibition: Allosteric inhibitors targeting MAP3K8 fusion proteins (e.g., disrupting SVIL-MAP3K8 dimerization) are currently under preclinical investigation.

MAP3K8 inhibitors have demonstrated promise in treating inflammatory diseases such as rheumatoid arthritis. However, their use in cancer therapy requires caution, as complete suppression of MAP3K8 may impair anti-tumor immunity by reducing TNF-α production. Future research will focus on developing microenvironment-responsive nanomedicines (targeted delivery to inflamed or tumor tissues), exploring combination therapies (e.g., MAP3K8 inhibitors with PD-1 antibodies), and tailoring treatment based on fusion partner types (such as SVIL vs. UBL3).

MAP3K8 serves as a molecular hub linking inflammation and cancer. Its complex functional profile—balancing pro-inflammatory and anti-infective roles, as well as tumor-promoting and immune-surveillance functions—poses unique challenges for targeted therapy. Comprehensive analysis of its signaling dynamics and interactome in specific microenvironments will be essential for precise therapeutic intervention.

References:

  1. Sibira R, Vu A, Giubellino A, Murugan P. Spitz melanoma with MAP3K8::ABLIM1 rearrangement: a case report with review of the literature. Diagn Pathol. 2024 Oct 3;19(1):133.
  2. Donati M, Mansour B, Hagstrom M, et al. Clinical, Morphological and Molecular Features of Spitz tumors. Cesk Patol. 2024;60(1):35-48.
  3. You Y, Wen D, Zeng L, et al. ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression. Int J Biol Sci. 2022 Aug 1;18(13):5001-5018.
  4. Gruosso T, Garnier C, Abelanet S, et al. MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas. Nat Commun. 2015 Oct 12;6:8583.
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