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


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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    • "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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    • "Junction Architecture b-catenin junction architecture and signaling Takeichi, 1988; Clevers, 2006; Dejana, 2010 p120 VE-cadherin stabilization and signaling Reynolds and Carnahan, 2004; Xiao et al., 2007; McCrea et al., 2009 plakoglobin junction architecture and signaling Lampugnani et al., 1995; Nottebaum et al., 2008 a-catenin, a-actinin, eplin, N-WASP cytoskeletal anchorage and organization Hartsock and Nelson, 2008; Knudsen et al., 1995; Abe and Takeichi, 2008; Chervin-Pé tinot et al., 2012; Rajput et al., 2013 Junction Stability and Cytoskeleton Organization Tiam activation of Rac, junction stability Lampugnani et al., 2002; Cain et al., 2010 Rap1, Raf1, MAGI junction stability and maturation Sakurai et al., 2006; Glading et al., 2007; Wimmer et al., 2012 Phosphatases Junction Stability VE-PTP VE-cadherin dephosphorylation, permeability control, leukocyte diapedesis Nottebaum et al., 2008; Nawroth et al., 2002; Broermann et al., 2011 PTP1B, PTP2A, SHP2, DEP-1, RPTP-m permeability control Grinnell et al., 2010, 2012; Ukropec et al., 2000; Ká sa et al., 2013; Hatanaka et al., 2012; Lampugnani et al., 2006; Orsenigo et al., 2012, Sui et al., 2005 Csk Src inactivation, inhibition of cell growth Baumeister et al., 2005 Cell Polarity PAR3/PAR6/aPKC cell polarity, lumen formation Lampugnani et al., 2010; McCaffrey and Macara, 2012; Iden et al., 2006; Koh et al., 2008 CCM1/Krit1 cell polarity, junction stability Lampugnani et al., 2010; Glading et al., 2007 Growth Factor Receptors VEGFR2 contact inhibition of cell growth, permeability control Nottebaum et al., 2008; Weis et al., 2004; Lampugnani et al., 2006; Gavard and Gutkind, 2006 FGF-R cell motility and growth Murakami et al., 2008; Giampietro et al., 2012 TGFb-R inhibition of cell motility Rudini et al., 2008; Rezaei et al., 2012 Induction of Permeability b-arrestin1, b-arrestin2, Caveolin1 junction permeability Gavard and Gutkind, 2006; Hebda et al., 2013; Kronstein et al., 2012 Other Functions PECAM mechanosensor Conway and Schwartz, 2012; Tzima et al., 2005 PI3 kinase, Akt, Shc signal transduction Taddei et al., 2008; Zanetti et al., 2002 Src, FAK increase in permeability Weis et al., 2004; Wallez et al., 2007; Chen et al., 2012 We report here some of the best-studied partners of VE-cadherin and adherens junctions. We apologize if, for space constraints, the table is not exhaustive. "
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