Science and Research

Release of STK24/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation

Loss-of-function mutations in cerebral cavernous malformation (CCM) genes and gain-of-function mutation in the MAP3K3 gene encoding MEKK3 cause CCM. Deficiency of CCM proteins leads to the activation of MEKK3-KLF2/4 signaling, but it is not clear how this occurs. Here, we demonstrate that deletion of the CCM3 interacting kinases STK24/25 in endothelial cells causes defects in vascular patterning during development as well as CCM lesion formation during postnatal life. While permanent deletion of STK24/25 in endothelial cells caused developmental defects of the vascular system, inducible postnatal deletion of STK24/25 impaired angiogenesis in the retina and brain. More importantly, deletion of STK24/25 in neonatal mice led to the development of severe CCM lesions. At the molecular level, a hybrid protein consisting of the STK kinase domain and the MEKK3 interacting domain of CCM2 rescued the vascular phenotype caused by the loss of ccm gene function in zebrafish. Our study suggests that CCM2/3 proteins act as adapters to allow recruitment of STK24/25 to limit the constitutive MEKK3 activity, thus contributing to vessel stability. Loss of STK24/25 causes MEKK3 activation, leading to CCM lesion formation.

    • Yang, X.
  • Wu, S. T.
  • Gao, R.
  • Wang, R.
  • Wang, Y.
  • Dong, Z.
  • Wang, L.
  • Qi, C.
  • Wang, X.
  • Schmitz, M. L.
  • Liu, R.
  • Han, Z.
  • Wang, L.
  • Zheng, X.
  • Keywords

      • Animals
  • Mice
  • *Hemangioma, Cavernous, Central Nervous System/genetics
  • Endothelial Cells
  • Zebrafish
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases/genetics
  • Angiogenesis
  • Genetic diseases
  • Stroke
  • Vascular Biology
  • Publication details
    DOI: 10.1172/jci.insight.160372
    Journal: JCI Insight
    Number: 5
    Work Type: Original
    Location: UGMLC
    Disease Area: General Lung and Other
    Partner / Member: JLU
    Access-Number: 36692953

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