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

Authors:
Glading A, Han J, Stockton RA, Ginsberg MH
In:
Source: J Cell Biol
Publication Date: (2007)
Issue: 179(2): 247-54
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Endothelial, aortic, cow (bAEC)
Species: bovine
Tissue Origin: aortic
Platform:
Nucleofector® I/II/2b
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.