Two different groups independently reported that familial CCM caused by the loss of function mutations in CCM genes resulted in an increased activation of the MEKK3/MEK5/ERK5/KLF2/KLF4 pathway and the development of CCM lesions that were ameliorated by the endothelial loss of Mekk3, Klf2, or Klf4 [66,77]. Here, MAP3K3 is linked to cerebral cavernous malformation.