The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Cell Science Année : 2018

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Claudia Jasmin Rödel
  • Fonction : Auteur
Yekaterina A Miroshnikova
  • Fonction : Auteur
Hsiao-Hui Lee
  • Fonction : Auteur
Gweńola Boulday
Martial Balland
Salim Abdelilah-Seyfried
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-02324079 , version 1 (21-10-2019)

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Justyna Lisowska, Claudia Jasmin Rödel, Sandra Manet, Yekaterina A Miroshnikova, Cyril Boyault, et al.. The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity. Journal of Cell Science, 2018, 131 (15), pp.jcs216093. ⟨10.1242/jcs.216093⟩. ⟨hal-02324079⟩
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