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

Author

Listed:
  • Oriana S. Fisher

    (Yale University School of Medicine)

  • Hanqiang Deng

    (Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM))

  • Dou Liu

    (Yale University School of Medicine)

  • Ya Zhang

    (Yale University School of Medicine
    XiangYa Hospital, Central South University)

  • Rong Wei

    (Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)
    Yale University School of Medicine
    XiangYa Hospital, Central South University)

  • Yong Deng

    (Yale University School of Medicine)

  • Fan Zhang

    (Yale University School of Medicine
    XiangYa Hospital, Central South University)

  • Angeliki Louvi

    (Yale University School of Medicine)

  • Benjamin E. Turk

    (Yale University School of Medicine)

  • Titus J. Boggon

    (Yale University School of Medicine)

  • Bing Su

    (Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM)
    Yale University School of Medicine
    XiangYa Hospital, Central South University)

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.

Suggested Citation

  • Oriana S. Fisher & Hanqiang Deng & Dou Liu & Ya Zhang & Rong Wei & Yong Deng & Fan Zhang & Angeliki Louvi & Benjamin E. Turk & Titus J. Boggon & Bing Su, 2015. "Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8937
    DOI: 10.1038/ncomms8937
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