Figure 5.

MEKK3 signaling regulated by CCM2 in the CSC complex (a) and disrupted signaling due to CCM protein depletion (b). CCM2 binds to and inhibits MEKK3, preventing its ability to phosphorylate downstream kinases. MEKK3-MEK5-ERK5-KLF2/4 is an underlying signaling cascade for angiogenesis, ensuring cell–cell junctional integrity and promoting endothelial barrier. Conversely, p38 mitogen-activated protein kinase (MAPK) activation mediated by MEKK3 is required to control pro-survival and pro-apoptotic stimuli. CCM proteins strictly control both signaling cascades, in order to avoid MEKK3 hyperactivation, which may result in excessive cell proliferation, dysfunctional migration, EndMT, and altered response to apoptosis, all features characterizing CCM lesions.