The HHD of CCM2 binds the N-terminus of MEKK3, an upstream kinase in the p38 and ERK5 MAP kinase (MAPK) pathways and this interaction appears necessary to prevent hyperactive MEKK3–MEK5–ERK5 signalling which contributes to CCM pathogenesis [70–72]. Here, MAP2K5 is linked to cerebral cavernous malformation.