KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions

Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
The Journal of Cell Biology (Impact Factor: 9.69). 11/2007; 179(2):247-54. DOI: 10.1083/jcb.200705175
Source: PubMed

ABSTRACT Cerebral cavernous malformation (CCM), a disease associated with defective endothelial junctions, result from autosomal dominant CCM1 mutations that cause loss of KRIT-1 protein function, though how the loss of KRIT-1 leads to CCM is obscure. KRIT-1 binds to Rap1, a guanosine triphosphatase that maintains the integrity of endothelial junctions. Here, we report that KRIT-1 protein is expressed in cultured arterial and venous endothelial cells and is present in cell-cell junctions. KRIT-1 colocalized and was physically associated with junctional proteins via its band 4.1/ezrin/radixin/moesin (FERM) domain. Rap1 activity regulated the junctional localization of KRIT-1 and its physical association with junction proteins. However, the association of the isolated KRIT-1 FERM domain was independent of Rap1. Small interfering RNA-mediated depletion of KRIT-1 blocked the ability of Rap1 to stabilize endothelial junctions associated with increased actin stress fibers. Thus, Rap1 increases KRIT-1 targeting to endothelial cell-cell junctions where it suppresses stress fibers and stabilizes junctional integrity.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Graphical Abstract Highlights d Endocardial CCM signaling regulates cardiac jelly during heart development d CCM signaling controls endothelial KLF and ADAMTS gene expression d MEKK3 signaling controls endothelial KLF and ADAMTS expression in response to flow d CCM signaling regulates endothelial gene expression through the MEKK3 pathway In Brief The cerebral cavernous malformation pathway is necessary for cardiovascular development and to prevent vascular malformations later in life. How this pathway regulates endothelial cell function remains unclear. Zhou et al. demonstrate that CCM signaling inhibits the MEKK3 signaling pathway to control endothelial gene expression during cardiovascular development.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmaceutical manipulation of cAMP levels exerts beneficial effects through the regulation of the exchange protein activated by cAMP (EPAC) and protein kinase A (PKA) signalling routes. Recent attention has turned to the specific regulation of EPAC isoforms (EPAC1 and EPAC2) as a more targeted approach to cAMP-based therapies. For example, EPAC2-selective agonists could promote insulin secretion from pancreatic β cells, whereas EPAC1-selective agonists may be useful in the treatment of vascular inflammation. By contrast, EPAC1 and EPAC2 antagonists could both be useful in the treatment of heart failure. Here we discuss whether the best way forward is to design EPAC-selective agonists or antagonists and the current strategies being used to develop isoform-selective, small-molecule regulators of EPAC1 and EPAC2 activity. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Trends in Pharmacological Sciences 03/2015; 396(4). DOI:10.1016/ · 9.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hemodynamic shear stress from blood flow on the endothelium critically regulates vascular function in many physiological and pathological situations. Endothelial cells adapt to shear stress by remodeling their cytoskeletal components and subsequently by changing their shape and orientation. We demonstrate that beta 1 integrin activation is critically controlled during the mechanoresponse of endothelial cells to shear stress. Indeed, we show that overexpression of the CCM complex, an inhibitor of beta 1 integrin activation, blocks endothelial actin rearrangement and cell reorientation in response to shear stress similarly to beta 1 integrin silencing. Conversely, depletion of CCM2 protein leads to an elongated "shear-stress-like" phenotype even in the absence of flow. Taken together, our findings reveal the existence of a balance between positive extracellular and negative intracellular signals, i.e. shear stress and CCM complex, for the control of beta 1 integrin activation and subsequent adaptation of vascular endothelial cells to mechanostimulation by fluid shear stress.
    12/2014; 3(12):1228-1235. DOI:10.1242/bio.201410132