Map3k3, also known as Mitogen-activated protein kinase kinase kinase 3, is ubiquitously expressed in numerous tissues. It is activated by various extracellular stimuli and plays a role in regulating processes such as cell proliferation, differentiation, and apoptosis. It is involved in multiple signaling pathways including ERK1/2, JNK, p38, and NF-κB pathways [3,4].

In the context of cerebral and spinal cord cavernous malformations (CCMs), a somatic mutation in Map3k3 [c.1323C>G (p.Ile441Met)] has been identified. About 40% of CCM patients carry this specific Map3k3 mutation. Mouse models with Map3k3I441M expressed in CNS endothelium developed pathological phenotypes similar to human CCMs. These models showed that CCMs initiate with endothelial expansion and blood-brain barrier disruption. Rapamycin, an mTOR inhibitor, can alleviate CCMs in these mouse models [1]. Additionally, in vitro and in vivo experiments with mouse models demonstrated that overexpression of the Map3k3 mutation perturbed angiogenesis, and activation of PI3K signaling enhanced and maintained CCM-like lesions [2].

In conclusion, Map3k3 is crucial in regulating multiple cellular processes through various signaling pathways. The study of Map3k3 using mouse models has provided valuable insights into the pathogenesis of CCMs, suggesting potential therapeutic strategies. These models have revealed the role of Map3k3 in the development of CCMs, highlighting its importance in this disease area.