Dataset Information

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

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.

SUBMITTER: Fisher OS

PROVIDER: S-EPMC4526114 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Fisher Oriana S OS Deng Hanqiang H Liu Dou D Zhang Ya Y Wei Rong R Deng Yong Y Zhang Fan F Louvi Angeliki A Turk Benjamin E BE Boggon Titus J TJ Su Bing B

Nature communications 20150803

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 ...[more]

PMID: 26235885

Similar Datasets

Project description:OBJECTIVE Vascular permeability and iron leakage are central features of cerebral cavernous malformation (CCM) pathogenesis. The authors aimed to correlate prospective clinical behavior of CCM lesions with longitudinal changes in biomarkers of dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM) assessed by MRI. METHODS Forty-six patients with CCMs underwent 2 or more permeability and/or susceptibility studies in conjunction with baseline and follow-up imaging and clinical surveillance during a mean 12.05 months of follow-up (range 2.4-31.27 months). Based on clinical and imaging features, cases/lesions were classified as stable, unstable, or recovering. Associated and predictive changes in quantitative permeability and susceptibility were investigated. RESULTS Lesional mean permeability and QSM values were not significantly different in stable versus unstable lesions at baseline. Mean lesional permeability in unstable CCMs with lesional bleeding or growth increased significantly (+85.9% change; p = 0.005), while mean permeability in stable and recovering lesions did not significantly change. Mean lesional QSM values significantly increased in unstable lesions (+44.1% change; p = 0.01), decreased slightly with statistical significance in stable lesions (-3.2% change; p = 0.003), and did not significantly change in recovering lesions. Familial cases developing new lesions during the follow-up period showed a higher background brain permeability at baseline (p = 0.001), as well as higher regional permeability (p = 0.003) in the area that would later develop a new lesion as compared with the homologous contralateral brain region. CONCLUSIONS In vivo assessment of vascular permeability and iron deposition on MRI can serve as objective and quantifiable biomarkers of disease activity in CCMs. This may be applied in natural history studies and may help calibrate clinical trials. The 2 techniques are likely applicable in other disorders of vascular integrity and iron leakage such as aging, hemorrhagic microangiopathy, and traumatic brain injury.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets