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Nature Communications published online paper about MEKK3 from professor Bing Su laboratory
Date:2015-08-04

Nature Communications published online one paper, entitled “Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex”, from professor Bing Su laboratory in Shanghai Institute of Immunology, Shanghai Jiao Tong University school of medicine. Cerebral Cavernous Malformation (CCM) is a cerebrovascular dysplasia and its clinical manifestations are intracranial hemorrhage, stroke, epilepsy and even sudden death. CCM is caused by mutations of three autosomal genes encoding CCM1/KRIT1, CCM2/OSM and CCM3/PDCD10 respectively. CCM2 loss is associated with the CCM disease, manifesting as cerebrovascular lesions that can lead to focal neurological defects and stroke. MEKK3, a highly conserved Serine/Threonine protein kinase belonging to MAP3K superfamily, is essential for embryonic cardiovascular development in mice. MEKK3 can interact with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are still unknown. Professor Bing Su laboratory found that Mekk3 deficiency in endothelial cells could lead to embryonic lethality because of impaired embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage, as well as other organs haemorrhages. They discover the interaction of MEKK3 N-terminal helix and PB1 domain with the CCM2 harmonin homology domain (HHD) and determine a 2.35 Å co-crystal structure. Structure-directed disruption of the MEKK3:CCM2 interaction with a competitive cell-permeable peptide leads to brain vascular leakage, which resembles that of endothelial Mekk3 deficient mice. Mekk3 deficient endothelial cells show increased Rho-ROCK signaling. Moreover, ROCK inhibitor can rescue the survival of inducible endothelial Mekk3 deficient mice and restore brain vascular permeability. This study showed that regulation of Rho-ROCK signaling by CCM2:MEKK3 complex is required for maintenance of neurovascular integrity, unraveling a mechanism by which CCM2 loss leads to CCM disease.

 

This study was finished cooperatively by the PhD student Hanqiang Deng in Shanghai Institute of Immunology, Dr. Oriana Fisher from Titus J. Boggon lab and Dou Liu from Bing Su lab in Yale University school of medicine. Other members from Bing Su lab, Dr. Ya Zhang, Dr. Rong Wei, Dr. Yong Deng and Dr. Fan Zhang have also done much works in this project. Dr. Angeliki Louvi and Benjamin E. Turk in Yale University school of medicine also contributed to this study.

 

This research was supported by National Natural Sciences Foundation of China Key Program (Grant No. 81430033), National Natural Sciences Foundation of China General Program (Grant No. 31470845), the Key Project of Science and Technology of Shanghai (Grant No. 13JC1404700) and NIH fund (Grant No. R01GM114621).

(by Hanqiang Deng)

                 

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