title: KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Glading
authors.forename: Jaewon
authors.initials: J
authors.lastname: Han
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Stockton
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016466:CHO Cells; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D000075927:KRIT1 Protein; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D020827:rap1 GTP-Binding Proteins