Abstract

Loss of function mutations in CCM genes and gain of function mutation in the MAP3K3 gene encoding MEKK3 cause cerebral cavernous malformation (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 cause 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 that contributes to vessel stability. Loss of STK24/25 causes MEKK3 activation leading to CCM lesion formation.

Authors

Xi Yang, Shi-Ting Wu, Rui Gao, Rui Wang, Yixuan Wang, Zhenkun Dong, Lu Wang, Chunxiao Qi, Xiaohong Wang, M. Lienhard Schmitz, Renjing Liu, Zhiming Han, Lu Wang, Xiangjian Zheng

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