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Related Experiment Video

Updated: Apr 6, 2026

Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model

Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model

Published on: September 4, 2017

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

Oriana S Fisher¹, Hanqiang Deng², Dou Liu³

¹Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.

Nature Communications

|August 4, 2015

Summary

Loss of cerebral cavernous malformations 2 (CCM2) protein impairs neurovascular integrity. This study reveals CCM2 interacts with MEKK3 kinase, regulating Rho signaling essential for brain blood vessel stability.

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Last Updated: Apr 6, 2026

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Area of Science:

Molecular Biology
Neuroscience
Vascular Biology

Background:

Cerebral cavernous malformations 2 (CCM2) loss is linked to familial CCM disease.
Protein kinase MEKK3 (MAP3K3) is crucial for embryonic angiogenesis and interacts with CCM2.
The mechanism and relevance of the CCM2-MEKK3 interaction in cerebral vasculature remain unclear.

Purpose of the Study:

To investigate the role of MEKK3 in embryonic vascular development.
To elucidate the interaction between CCM2 and MEKK3.
To determine the functional significance of this interaction in maintaining neurovascular integrity.

Main Methods:

Generated inducible endothelial MEKK3 knockout mice.
Determined the cocrystal structure of CCM2 harmonin homology domain (HHD) and MEKK3 N terminus.
Assessed neurovascular integrity and Rho-ROCK signaling pathways.

Main Results:

Endothelial MEKK3 knockout in neonatal mice resulted in lethality due to intracranial hemorrhages and brain blood vessel leakage.
A direct interaction between CCM2 HHD and MEKK3 N terminus was confirmed via cocrystal structure.
MEKK3 deficiency and disruption of the MEKK3:CCM2 interaction both led to impaired neurovascular integrity and leakage, partly via Rho-ROCK signaling.

Conclusions:

MEKK3 plays an intrinsic role in embryonic vascular development and maintaining neurovascular integrity.
The CCM2:MEKK3 interaction is critical for regulating Rho signaling.
CCM2:MEKK3-mediated Rho signaling regulation is essential for maintaining neurovascular integrity, explaining how CCM2 loss contributes to CCM disease.