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Published online October 22, 2007
doi:10.1083/jcb.200705175
The Journal of Cell Biology, Vol. 179, No. 2, 247-254
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Glading et al.
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Report

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

Angela Glading, Jaewon Han, Rebecca A. Stockton, and Mark H. Ginsberg

Department of Medicine, University of California, San Diego, La Jolla, CA 92093

Correspondence to M.H. Ginsberg: mhginsberg{at}ucsd.edu

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.

A. Glading, J. Han, and R.A. Stockton contributed equally to this paper.

Dr. Han died on 4 July 2006.

Abbreviations used in this paper: 8-pCPT-2'-O-Me-cAMP, 8-pCPT-2'-O-methyladenosine-3',5'-cAMP; BAEC, bovine aortic endothelial cell; CCM, cerebral cavernous malformation; CS, calf serum; FERM, band 4.1/ezrin/radixin/moesin; FN, fibronectin; GAP, GTPase activating protein; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HUVEC, human umbilical vein endothelial cell; ICAP1{alpha}, integrin cytoplasmic domain-associated protein-1{alpha}; NGS, normal goat serum.


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