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

Journal of Cell Science
Justyna LisowskaEva Faurobert

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 contr...Continue Reading

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Citations

Feb 2, 2020·The Journal of Biological Chemistry·Valerie L SuDavid A Calderwood
Aug 26, 2019·Translational Stroke Research·Lisa McKerracherIssam A Awad
Oct 9, 2019·International Journal of Molecular Sciences·Francesco Vieceli Dalla SegaSaverio Francesco Retta
Nov 26, 2020·Open Biology·Valerie L Su, David A Calderwood
Sep 3, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Concetta ScimoneAntonina Sidoti
Dec 18, 2021·Journal of Cell Science·Harsha Swamy, Angela J Glading

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