{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n MAP3K21, also known as MLK4, is a mixed‐lineage kinase that orchestrates diverse signaling cascades with context‐dependent effects on cell fate, tumor progression, immune responses, and even metabolic regulation. In glioblastoma stem cells, MLK4 is overexpressed in the mesenchymal subtype and drives NF‑κB signaling via phosphorylation of IKKα, thereby promoting self‑renewal, motility, tumorigenesis, and radioresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In macrophages, MLK4 interacts with Toll‑like receptor 4 to inhibit LPS‑induced activation of MAP kinases and TNF‑α production, functioning as a negative regulator of inflammatory signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of colorectal cancer, MLK4 appears to play a dual role. On one hand, constitutively active MLK4 alleles enhance transformation and tumorigenicity through activation of the MEK/ERK pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while on the other hand, loss of MLK4 expression is associated with poorer overall and progression‑free survival, particularly in KRAS‑mutated tumors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In breast cancer—especially in the triple‑negative subtype—MLK4 is frequently upregulated. High MLK4 expression drives NF‑κB activation, promotes a mesenchymal phenotype, and enhances proliferation and invasiveness"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while its role in regulating the DNA damage response contributes to chemoresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In hepatocellular carcinoma, overexpression of MLK4 correlates with aggressive tumor growth and metastasis via increased reactive oxygen species production and subsequent activation of p38, JNK, and ERK pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In gastric carcinoma cells, reconstitution of MLK4 function has been shown to inhibit cell viability, migration, and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in pancreatic cancer cells, MLK4 is recruited by the IL‑17 receptor IL‑17RB, where it phosphorylates the receptor to trigger subsequent ubiquitination and assembly of an NF‑κB activator complex that promotes oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond oncogenesis, a coding variant in MAP3K21 has been significantly associated with pediatric adiposity, suggesting that MLK4 may also play a role in metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore MAP3K21/MLK4 as a multifaceted regulator of NF‑κB, MAPK, and DNA damage response pathways. Its activity can promote aggressive traits—in part by enhancing mesenchymal features, survival, and chemoresistance in cancer cells—or, in other contexts, its loss correlates with adverse outcomes. This context‐dependent functionality highlights MLK4 as a promising target for therapeutic intervention across various disease states.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sung-Hak Kim, Ravesanker Ezhilarasan, Emma Phillips, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2016.01.005"}], "href": "https://doi.org/10.1016/j.ccell.2016.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26859459"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26859459"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alim Seit-Nebi, Wei Cheng, Hong Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLK4 has negative effect on TLR4 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cmi.2011.15"}], "href": "https://doi.org/10.1038/cmi.2011.15"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21602844"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21602844"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Miriam Martini, Mariangela Russo, Simona Lamba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase MLK4 is activated in colorectal cancers where it synergistically cooperates with activated RAS signaling in driving tumorigenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-3074"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-3074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23319808"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23319808"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lydia Brandl, David Horst, Thomas G P Grünewald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical Evidence on the Interaction Between MLK4, KRAS and Microsatellite Instability to Determine the Prognosis of Early-Stage Colorectal Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.33594/000000175"}], "href": "https://doi.org/10.33594/000000175"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31701729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31701729"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Anna A Marusiak, Monika K Prelowska, Dawid Mehlich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of MLK4 promotes migratory and invasive potential of breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-018-0618-0"}], "href": "https://doi.org/10.1038/s41388-018-0618-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30552384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30552384"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Dawid Mehlich, Michał Łomiak, Aleksandra Sobiborowicz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MLK4 regulates DNA damage response and promotes triple-negative breast cancer chemoresistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-021-04405-0"}], "href": "https://doi.org/10.1038/s41419-021-04405-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34839359"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34839359"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yu Li, Haibo Zuo, Hongjian Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decrease of MLK4 prevents hepatocellular carcinoma (HCC) through reducing metastasis and inducing apoptosis regulated by ROS/MAPKs signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2019.108749"}], "href": "https://doi.org/10.1016/j.biopha.2019.108749"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31071576"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31071576"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yu Xi, Jianhua Niu, Dongmei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixed lineage kinase-4 promotes gastric carcinoma tumorigenesis through suppression of the c-Jun N-terminal kinase signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Ther Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/etm.2018.6618"}], "href": "https://doi.org/10.3892/etm.2018.6618"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30233678"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30233678"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Heng-Hsiung Wu, Lung-Hung Tsai, Chun-Kai Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of initial key steps of IL-17 receptor B oncogenic signaling for targeted therapy of pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.abc2823"}], "href": "https://doi.org/10.1126/scitranslmed.abc2823"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33658352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33658352"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ke Mao, Meixian Zhang, Jinshuai Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Coding Variants are Relevant to the Expression of Obesity-Related Genes for Pediatric Adiposity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Obesity (Silver Spring) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/oby.23046"}], "href": "https://doi.org/10.1002/oby.23046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34494379"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34494379"}]}]}]}