[HTML][HTML] Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

OS Fisher, H Deng, D Liu, Y Zhang, R Wei… - Nature …, 2015 - nature.com
OS Fisher, H Deng, D Liu, Y Zhang, R Wei, Y Deng, F Zhang, A Louvi, BE Turk, TJ Boggon
Nature communications, 2015nature.com
Abstract Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial
form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic
angiogenesis in mice and interacts physically with CCM2, but how this interaction is
mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3
plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3
knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain …
Abstract
Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.
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