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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blood Vessels / embryology*
  • Blood Vessels / metabolism
  • Capillary Permeability / genetics
  • Cerebrovascular Circulation / genetics*
  • Crystallization
  • Hemangioma, Cavernous, Central Nervous System / genetics
  • Intracranial Hemorrhages / genetics*
  • MAP Kinase Kinase Kinase 3 / genetics*
  • MAP Kinase Kinase Kinase 3 / metabolism
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Neovascularization, Physiologic / genetics*
  • Signal Transduction
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / metabolism

Substances

  • Microfilament Proteins
  • osmosensing scaffold for MEKK3 protein, mouse
  • rho-Associated Kinases
  • MAP Kinase Kinase Kinase 3
  • Map3k3 protein, mouse
  • rho GTP-Binding Proteins