MAGI1 signaling in cerebral cavernous malformations (664.11)

Abstract

Cerebral Cavernous Malformations (CCMs) are vascular brain lesions affecting 0.5% of humans. Late stage lesions are clusters of grossly dilated capillaries lacking smooth muscle cell or pericyte support, and can cause hemorrhagic stroke. No treatment exists other than surgical removal of symptomatic lesions. CCMs occur sporadically through spontaneous mutations, or by familial autosomal dominant transmission of mutations in three genes : KRIT1, CCM2 or CCM3 (PDCD10). Our lab’s previous work showed that KRIT1 and CCM2 normally regulate endothelial permeability through regulation of RhoA and ROCK1/2. We now used proteomics and CHO cell co‐immunoprecipitations to identify a signalosome consisting of a unique brain microvascular endothelial cell‐specific splice variant of Rap1‐interacting junctional protein MAGI, “MAGI1C‐beta2”, that binds to KRIT1 and CCM2 through a PDZ domain to mediate translocation of two CCM proteins to endothelial junctions, and is required to maintain barrier function. We further identified a MAGI‐1 interacting protein , AMOT (angiomotin) as a convergence point for all three CCM protein signaling pathways, by showing that PDCD10 interacts directly with AMOT at junctional complex , while KRIT1 and CCM2 are localized there through MAGI1C‐beta2. Further, this intact CCM1‐2‐3/AMOT complex suppresses RhoA activation, providing a mechanistic explanation for some aspects of CCM lesion development.Grant Funding Source: NIH