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

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 mai...

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Detalles Bibliográficos
Autores principales: Glading, Angela, Han, Jaewon, Stockton, Rebecca A., Ginsberg, Mark H.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064761/
https://www.ncbi.nlm.nih.gov/pubmed/17954608
http://dx.doi.org/10.1083/jcb.200705175
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author Glading, Angela
Han, Jaewon
Stockton, Rebecca A.
Ginsberg, Mark H.
author_facet Glading, Angela
Han, Jaewon
Stockton, Rebecca A.
Ginsberg, Mark H.
author_sort Glading, Angela
collection PubMed
description 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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spelling pubmed-20647612008-04-22 KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions Glading, Angela Han, Jaewon Stockton, Rebecca A. Ginsberg, Mark H. J Cell Biol Research Articles 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. The Rockefeller University Press 2007-10-22 /pmc/articles/PMC2064761/ /pubmed/17954608 http://dx.doi.org/10.1083/jcb.200705175 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Glading, Angela
Han, Jaewon
Stockton, Rebecca A.
Ginsberg, Mark H.
KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title_full KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title_fullStr KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title_full_unstemmed KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title_short KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell–cell junctions
title_sort krit-1/ccm1 is a rap1 effector that regulates endothelial cell–cell junctions
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064761/
https://www.ncbi.nlm.nih.gov/pubmed/17954608
http://dx.doi.org/10.1083/jcb.200705175
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