Map3k6, short for mitogen-activated protein kinase kinase kinase 6, is involved in multiple biological processes. It has known functions in angiogenesis and affects vascular endothelial growth factor expression [2]. It is also part of signaling pathways such as the MAPK/ERK pathway [7]. In the MAPK/ERK pathway, its regulation can impact melanin production [7].

Mutations in Map3k6 have been associated with several diseases. In mixed-phenotype acute leukemia (MPAL), Map3k6 was among the genes with mutations detected in 18 patients analyzed, indicating its potential role in this type of leukemia [1]. In a Swedish kindred, a heterozygous variant in Map3k6 was identified in a neurovascular disease causing stroke, cognitive impairment, and tremor, though functional data was lacking [2]. In gastric cancer, germline mutations in Map3k6 were associated with familial gastric cancer in one study, but another study suggested it may not be a gastric cancer predisposition gene as deleterious variants were also common in the general population [4,5]. Additionally, salidroside was found to down-regulate Map3k6 in gastric cancer cells, suppressing their growth [3]. In NCI-H1975 cells, organophosphate flame retardants induced apoptosis through a pathway involving Map3k6 [6].

In conclusion, Map3k6 is involved in important biological functions like angiogenesis and signaling pathways. Its mutations are associated with diseases such as leukemia, neurovascular disorders, and gastric cancer. Studies on Map3k6, including those from genetic models, contribute to understanding the mechanisms of these diseases, potentially leading to new therapeutic strategies.

References:

1. Hennawi, Marah, Pakasticali, Nagehan, Tashkandi, Hammad, Hussaini, Mohammad. 2022. Genomic Landscape of Mixed-Phenotype Acute Leukemia. In International journal of molecular sciences, 23, . doi:10.3390/ijms231911259. https://pubmed.ncbi.nlm.nih.gov/36232559/

2. Ilinca, Andreea, Englund, Elisabet, Samuelsson, Sofie, Lindgren, Arne G, Puschmann, Andreas. 2021. MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor. In Neurology. Genetics, 7, e548. doi:10.1212/NXG.0000000000000548. https://pubmed.ncbi.nlm.nih.gov/33728376/

3. Wang, Xiaoping, Zhang, Zhendong, Cao, Xiaolan. 2024. Salidroside inhibited the proliferation of gastric cancer cells through up-regulating tumor suppressor miR-1343-3p and down-regulating MAP3K6/MMP24 signal molecules. In Cancer biology & therapy, 25, 2322206. doi:10.1080/15384047.2024.2322206. https://pubmed.ncbi.nlm.nih.gov/38436092/

4. Gaston, Daniel, Hansford, Samantha, Oliveira, Carla, Huntsman, David, Bedard, Karen. 2014. Germline mutations in MAP3K6 are associated with familial gastric cancer. In PLoS genetics, 10, e1004669. doi:10.1371/journal.pgen.1004669. https://pubmed.ncbi.nlm.nih.gov/25340522/

5. Weren, Robbert D A, van der Post, Rachel S, Vogelaar, Ingrid P, Hoogerbrugge, Nicoline, Ligtenberg, Marjolijn J L. 2018. Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility. In Journal of medical genetics, 55, 669-674. doi:10.1136/jmedgenet-2017-104962. https://pubmed.ncbi.nlm.nih.gov/29330337/

6. Meng, Yuan, Xu, Xiaojuan, Niu, Dong, Zhang, Hua, Yin, Daqiang. 2022. Organophosphate flame retardants induce oxidative stress and Chop/Caspase 3-related apoptosis via Sod1/p53/Map3k6/Fkbp5 in NCI-1975 cells. In The Science of the total environment, 819, 153160. doi:10.1016/j.scitotenv.2022.153160. https://pubmed.ncbi.nlm.nih.gov/35051466/

7. Liu, Xuexian, Zhang, Pengqian, Ji, Kaiyuan, Hu, Shuaipeng, Fan, Ruiwen. 2017. Cyclin-dependent kinase 5 regulates MAPK/ERK signaling in the skin of mice. In Acta histochemica, 120, 15-21. doi:10.1016/j.acthis.2017.10.009. https://pubmed.ncbi.nlm.nih.gov/29132690/