@article{LisowskaRoedelManetetal.2018,
  author    = {Lisowska, Justyna and R{\"o}del, Claudia Jasmin and Manet, Sandra and Miroshnikova, Yekaterina A. and Boyault, Cyril and Planus, Emmanuelle and De Mets, Richard and Lee, Hsiao-Hui and Destaing, Olivier and Mertani, Hichem and Boulday, Gwenola and Tournier-Lasserve, Elisabeth and Balland, Martial and Abdelilah-Seyfried, Salim and Albiges-Rizo, Corinne and Faurobert, Eva},
  title     = {The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity},
  series = {Journal of cell science},
  volume    = {131},
  journal   = {Journal of cell science},
  number    = {15},
  publisher = {Company biologists LTD},
  address   = {Cambridge},
  issn      = {0021-9533},
  doi       = {10.1242/jcs.216093},
  pages     = {15},
  year      = {2018},
  abstract  = {Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of ccm1 mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the ccm1 mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.},
  language  = {en}
}