Rap1 and its effector KRIT1/CCM1 regulate β-catenin signaling

Abstract

SUMMARYKRIT1, also called CCM1, is a member of a multiprotein complex that contains the products of the CCM2 and PDCD10 (also known as CCM3) loci. Heterozygous loss of any of the genes that encode these proteins leads to cerebral cavernous malformations (CCM), which are vascular lesions that are found in around 0.5% of humans. KRIT1 mediates the stabilization of -catenin-containing endothelial cell-cell junctions downstream of the Rap1 GTPase. Here, we report that Rap1 and KRIT1 are negative regulators of canonical -catenin signaling in mice and that hemizygous Krit1 deficiency exacerbates -catenin-driven pathologies. Depletion of endothelial KRIT1 caused -catenin to dissociate from vascular endothelial (VE)-cadherin and to accumulate in the nucleus with consequent increases in -catenin-dependent transcription. Activation of Rap1 inhibited -catenindependent transcription in confluent endothelial cells; this effect required the presence of intact cell-cell junctions and KRIT1. These effects of KRIT1 were not limited to endothelial cells; the KRIT1 protein was expressed widely and its depletion increased -catenin signaling in epithelial cells. Moreover, a reduction in KRIT1 expression also increased -catenin signaling in vivo. Hemizygous deficiency of Krit1 resulted in a ~1.5-fold increase in intestinal polyps in the Apc Min/+ mouse, which was associated with increased -catenin-driven transcription. Thus, KRIT1 regulates -catenin signaling,and Krit1 +/-mice are more susceptible to -catenin-driven intestinal adenomas.

Oxidative stress and inflammation in cerebral cavernous malformation disease pathogenesis: Two sides of the same coin

“…However, no study has so far undertaken the difficult work of organizing and prioritizing the identified signaling pathways in the context of the natural history of CCM, thus each pathway presently stands as a separate entity, independent of the others. Among others, it has been shown that CCM proteins regulate cadherin-mediated cell-cell junctions (Glading et al, 2007, Glading and Ginsberg, 2010, Lampugnani et al, 2010), integrin-mediated cell-matrix adhesion (Faurobert et al, 2013, Liu et al, 2013, Macek Jilkova et al, 2014), and Rho GTPase-regulated cytoskeleton dynamics (Borikova et al, 2010, Crose et al, 2009, Richardson et al, 2013, Stockton et al, 2010, Whitehead et al, 2009, Zheng et al, 2010). …”

“…The initial identification of KRIT1 as a Rap1 GTPase effector that interacts with the endothelial adherens junction (AJ) complex involving VE-cadherin, p120-catenin and β-catenin, and the discovery that loss of this protein promotes the weakening of VE-cadherin-mediated cell-cell adhesion and consequent dysfunction of the endothelial barrier, led to the original hypothesis that loss of blood-brain barrier (BBB) function contributes to the formation of CCM (Glading et al, 2007, Glading and Ginsberg, 2010). Though the interface for this interaction remains unclear, the binding of the small GTPase Rap1 to the FERM domain of KRIT1 is thought to promote the interaction of KRIT1 with the AJ (Glading et al, 2007).…”

Control of vascular permeability by adhesion molecules

“…128 Our lab has shown that loss of the junctional scaffolding protein KRIT1 leads to loss of VE-cadherin adhesion and increased nuclear b¡catenin in vitro, and increased vascular permeability in vivo. 129,130 Thus modification of interendothelial cell contacts is capable of switching the predominant mechanism of b¡catenin signaling from junctional to nuclear.…”

Concepts and hypothesis: integrin cytoplasmic domain-associated protein-1 (ICAP-1) as a potential player in cerebral cavernous malformation

“…It has recently been reported that CCM1 protein is required for the stabilizing effect of Rap1 on endothelial junctions and vascular integrity [29,30]. Depletion of endothelial CCM1 abrogates Rap1-mediated integrity of endothelial junctions containing b-catenin.…”