Map3k3, also known as Mitogen-activated protein kinase kinase kinase 3, is ubiquitously expressed and activated by various extracellular stimuli. It belongs to the serine/threonine protein kinase family and plays a role in regulating processes like cell proliferation, differentiation, and in pathways such as NF-κB, ERK1/2, JNK, p38, and Hippo-YAP [4,5,6]. It is also involved in angiogenesis and endothelial cell function, thus having significance in vascular-related biology. Genetic models, such as mouse models, are valuable for studying its functions.

In the context of cerebral and spinal cord cavernous malformations (CCMs), somatic mutations in Map3k3, especially the c.1323C>G (p.Ile441Met) mutation, have been identified. Around 40% of patients with sporadic CCMs have this specific Map3k3 mutation [1,3]. Mouse models with Map3k3I441M uniquely expressed in CNS endothelium developed pathological phenotypes similar to human CCMs, revealing that a single genetic hit in Map3k3 can cause CCMs. The lesions initiated with endothelial expansion followed by blood-brain barrier disruption, and could be alleviated by rapamycin treatment [1]. Additionally, in vitro and in vivo experiments showed that overexpression of the Map3k3 mutation perturbed angiogenesis. Also, single-cell RNA sequencing in Map3k3I441M mice found enrichment of the apoptosis pathway in a subset of brain endothelial cells, and Map3k3I441M overexpression activated p38 signaling associated with endothelial cell apoptosis [2].

In conclusion, Map3k3 is a key regulator in multiple cellular processes and signaling pathways. Its role in CCMs, as revealed through mouse models, has provided insights into the pathogenesis of this vascular disorder. These findings suggest that targeting Map3k3 could potentially be a therapeutic strategy for CCMs, and further understanding its functions may offer more opportunities for treating related diseases.

References:

1. Ren, Jian, Huang, Yazi, Ren, Yeqing, Hong, Tao, Ge, Woo-Ping. . Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations. In Brain : a journal of neurology, 146, 3634-3647. doi:10.1093/brain/awad104. https://pubmed.ncbi.nlm.nih.gov/36995941/

2. Huo, Ran, Yang, Yingxi, Sun, Yingfan, Wang, Jiguang, Cao, Yong. 2023. Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation. In Angiogenesis, 26, 295-312. doi:10.1007/s10456-023-09866-9. https://pubmed.ncbi.nlm.nih.gov/36719480/

3. Weng, Jiancong, Yang, Yingxi, Song, Dong, Wang, Jiguang, Cao, Yong. 2021. Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. In American journal of human genetics, 108, 942-950. doi:10.1016/j.ajhg.2021.04.005. https://pubmed.ncbi.nlm.nih.gov/33891857/

4. Park, Sanghyun, Ryu, Won-Ji, Kim, Tae Yeong, Kim, Min Hwan, Kim, Joon. 2024. Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation. In Experimental & molecular medicine, 56, 987-1000. doi:10.1038/s12276-024-01210-5. https://pubmed.ncbi.nlm.nih.gov/38622197/

5. Jia, Wei, Dong, Yuling, Tao, Lin, Yuan, Xianglin, Li, Feng. 2015. MAP3K3 overexpression is associated with poor survival in ovarian carcinoma. In Human pathology, 50, 162-9. doi:10.1016/j.humpath.2015.12.011. https://pubmed.ncbi.nlm.nih.gov/26997451/

6. Zhang, Ying, Wang, Sha-Sha, Tao, Lin, Jia, Wei, Li, Feng. 2019. Overexpression of MAP3K3 promotes tumour growth through activation of the NF-κB signalling pathway in ovarian carcinoma. In Scientific reports, 9, 8401. doi:10.1038/s41598-019-44835-7. https://pubmed.ncbi.nlm.nih.gov/31182739/