Article

KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell-cell junctions. J Cell Biol

Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 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.

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Available from: Rebecca Stockton
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    • "Src activity has been reported to inhibit the Rho/Rock pathway[47], a pathway also inhibited by Pak2/Pak4[48], Rasip1/Arhgap29[11], and the cerebral cavernous malformation (CCM) proteins, CCM1 and CCM2[15,17]. Interestingly, Rap1 is known to affect the function of Rasip1/Arhgap29[49], and CCM1 is an effector for Rap1[50]. In addition, Src activation blocks the activity of Rasa1[51], while stimulating Pak2/Pak4 activation and Raf activation[9]. "
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    • "Proteins of the CCM complex assemble around the transmembrane protein heart of glass (HEG) (Kleaveland et al., 2009). The entire CCM protein complex is involved in endothelial junctional stabilization and directly interacts with the vascular endothelial-Cadherin complex (Glading et al., 2007). In addition, the CCM complex represses the activity of b1 integrin by stabilizing KRIT1- binding integrin-cytoplasmic-domain-associated protein 1 (ICAP1) (Faurobert et al., 2013; Macek Jilkova et al., 2014), a specific inhibitor of b1 integrin (Millon-Fré millon et al., 2008) that associates with KRIT1 (Zhang et al., 2001; Zawistowski et al., 2002). "
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    • "Interestingly, cell–cell and cell–ECM adhesions are also coordinated by an intracellular node, the CCM complex comprising CCM1 and CCM2 (Faurobert and Albiges-Rizo, 2010; Draheim et al., 2014). It regulates VE-cadherin-dependent cell–cell interactions (Glading et al., 2007; Dejana and Orsenigo, 2013), b1 integrin-dependent cell–ECM adhesion (Faurobert et al., 2013) and acto-myosin remodeling (Whitehead et al., 2009; Stockton et al., 2010). The loss-of-function of CCM proteins in humans leads to Cerebral Cavernous Malformations corresponding to stacks of dilated blood vessels lacking mural cells and from where blood extravasates, damaging the adjacent neural tissue (Fischer et al., 2013; Draheim et al., 2014). "
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