Hyperactivation of the MEKK3–MEK5–ERK5 kinase cascade, leading to upregulation of KLF2 and KLF4 (KLF2/4) transcription factors and changes in expression of their transcriptional targets such as ADAMTS4, thrombomodulin (TM), thrombospondin 1 (TSP1), bone morphogenic protein 6 (BMP6) and potentially SLC39 (figure 4), is now recognized as a key step in CCM disease [16,71,95–99]. Here, MAP3K3 is linked to cerebral cavernous malformation.