MEKK3 binds to CCM2; this interaction limits the ability of MEKK3 signaling to increase expression of the transcription factors KLF2 and KLF4 (Cuttano et al., 2016; Hong et al., 2020; Lopez-Ramirez et al., 2019; Renz et al., 2015; Zhou et al., 2015, 2016), which in turn promote CCM lesion formation by altering gene expression (Hong et al., 2020). Here, MAP3K3 is linked to cerebral cavernous malformation.