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

J Cell Biol. 2007 Oct 22;179(2):247-54. doi: 10.1083/jcb.200705175.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CHO Cells
  • Cattle
  • Cell Membrane Permeability / drug effects
  • Cricetinae
  • Cricetulus
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism*
  • Humans
  • Intercellular Junctions / metabolism*
  • KRIT1 Protein
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / metabolism*
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • Antibodies, Monoclonal
  • KRIT1 Protein
  • KRIT1 protein, human
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • rap1 GTP-Binding Proteins