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Nat Commun. 2015 Aug 3;6:7937. doi: 10.1038/ncomms8937.

Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex.

Author information

1
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
2
Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
3
Department of Immunobiology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
4
Departments of Hematology and Dermotology, XiangYa Hospital, Central South University, Changsha 410008, China.
5
Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

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.

PMID:
26235885
PMCID:
PMC4526114
DOI:
10.1038/ncomms8937
[Indexed for MEDLINE]
Free PMC Article

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