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Title: Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

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.
 [1] ;  [2] ;  [3] ;  [3] ;  [2] ;  [3] ;  [3] ;  [3] ;  [1] ;  [1] ;  [2]
  1. Yale Univ., New Haven, CT (United States)
  2. Shanghai Jiao Tong Univ. School of Medicine (SJTU-SM), Shanghai (China)
  3. Yale Univ. School of Medicine, New Haven, CT (United States)
Publication Date:
OSTI Identifier:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 6; Journal Issue: 9
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org:
Country of Publication:
United States
biological sciences; biochemistry; cell biology