PUBLICATION

Cerebral Cavernous Malformation 1/2 complex controls ROCK1 and ROCK2 complementary functions for endothelial integrity

Authors
Lisowska, J., Rödel, C.J., Manet, S., Miroshnikova, Y.A., Boyault, C., Planus, E., De Mets, R., Lee, H.H., Destaing, O., Mertani, H., Boulday, G., Tournier-Lasserve, E., Balland, M., Abdelilah-Seyfried, S., Albiges-Rizo, C., Faurobert, E.
ID
ZDB-PUB-180722-18
Date
2018
Source
Journal of Cell Science   131(15): (Journal)
Registered Authors
Abdelilah-Seyfried, Salim
Keywords
CCM, Endothelial integrity, Mechanotransduction, ROCK
MeSH Terms
  • Animals
  • Antigens, CD/genetics
  • Antigens, CD/metabolism
  • Blotting, Western
  • Cadherins/genetics
  • Cadherins/metabolism
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Cattle
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Immunoprecipitation
  • KRIT1 Protein/genetics
  • KRIT1 Protein/metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Zebrafish
  • rho-Associated Kinases/genetics
  • rho-Associated Kinases/metabolism*
PubMed
30030370 Full text @ J. Cell Sci.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes