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
  • Immunoprecipitation
  • Flow Cytometry
  • Cadherins/genetics
  • Cadherins/metabolism
  • rho-Associated Kinases/genetics
  • rho-Associated Kinases/metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Zebrafish
  • Reverse Transcriptase Polymerase Chain Reaction
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism*
  • KRIT1 Protein/genetics
  • KRIT1 Protein/metabolism*
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Animals
  • Fluorescent Antibody Technique
  • Cattle
  • Antigens, CD/genetics
  • Antigens, CD/metabolism
  • Blotting, Western
(all 22)
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
Figure Gallery (2 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
s843TgTransgenic Insertion
    ty219c
      Point Mutation
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      rock1MO1-rock1MRPHLNO
      rock1MO2-rock1MRPHLNO
      rock2aMO4-rock2aMRPHLNO
      rock2bMO3-rock2bMRPHLNO
      1 - 4 of 4
      Show
      Fish
      Antibodies
      Orthology
      Gene Orthology
      rock1
      rock2a
      rock2b
      1 - 3 of 3
      Show
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
      Show
      Mapping
      No data available