{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n MAP3K8 (also known as TPL2 or COT) is a serine/threonine kinase that plays a pivotal role in transducing signals from multiple receptors – including Toll‐like receptors, TNF receptor superfamily members, and CD40 – to downstream MAP kinase modules. In innate immune cells such as macrophages and B cells, MAP3K8 is maintained in an inactive state through its high‐affinity association with the NF‐κB precursor p105; receptor stimulation triggers IκB kinase–dependent phosphorylation and degradation of p105, thereby liberating MAP3K8 to activate the MEK–ERK cascade (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " This activation is essential for the production and release of key inflammatory mediators – for example, ERK‐dependent signals downstream of MAP3K8 regulate the transcription of cytokines such as TNF‑α and COX‑2, and they also modulate events such as the cell surface trafficking and processing of TNF‑α via phosphorylation of TACE (a disintegrin and metalloproteinase) (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, MAP3K8 integrates signals from Akt – which enhances its capacity to promote NF‑κB–dependent gene transcription – thereby linking growth factor and inflammatory signaling (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition to its role in normal immune responses, aberrant regulation of MAP3K8 has oncogenic implications. For instance, in cholangiocarcinoma, IL‑6–mediated downregulation of miR‑370 leads to the derepression of MAP3K8 expression, contributing to tumor growth (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and its expression is also featured in gene signatures associated with aggressive migration and metastasis in breast cancer (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, studies in immune cells have underscored that MAP3K8 is required for robust ERK activation downstream of TLR stimulation, thereby controlling the balance of pro‐ and anti‐inflammatory cytokines (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Its activity and stability are also modulated by upstream kinases – with p38γ/δ being necessary to maintain its steady‐state levels – ensuring that MAP3K8 functions as a finely tuned rheostat in cellular signaling (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these functions position MAP3K8 as a central integrator of receptor signals that coordinate inflammatory responses and influence cancer cell behavior.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael R Waterfield, Minying Zhang, Lourdes P Norman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(03)00070-4"}], "href": "https://doi.org/10.1016/s1097-2765(03"}, {"type": "t", "text": "00070-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12667451"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12667451"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michael Waterfield, Wei Jin, William Reiley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IkappaB kinase is an essential component of the Tpl2 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.24.13.6040-6048.2004"}], "href": "https://doi.org/10.1128/MCB.24.13.6040-6048.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15199157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15199157"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Aristides G Eliopoulos, Calin D Dumitru, Chun-Chi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/emboj/cdf478"}], "href": "https://doi.org/10.1093/emboj/cdf478"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12234923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12234923"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Simon Rousseau, Matoula Papoutsopoulou, Antony Symons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.018671"}], "href": "https://doi.org/10.1242/jcs.018671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18187448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18187448"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lawrence P Kane, Marianne N Mollenauer, Zheng Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.22.16.5962-5974.2002"}], "href": "https://doi.org/10.1128/MCB.22.16.5962-5974.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12138205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12138205"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "F Meng, H Wehbe-Janek, R Henson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1210648"}], "href": "https://doi.org/10.1038/sj.onc.1210648"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17621267"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17621267"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Wies van Roosmalen, Sylvia E Le Dévédec, Ofra Golani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI74440"}], "href": "https://doi.org/10.1172/JCI74440"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25774502"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25774502"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ashish Banerjee, Raffi Gugasyan, Martin McMahon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0511113103"}], "href": "https://doi.org/10.1073/pnas.0511113103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16484370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16484370"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ana Risco, Carlos del Fresno, Agnes Mambol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1207290109"}], "href": "https://doi.org/10.1073/pnas.1207290109"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22733747"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22733747"}]}]}]}