RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell-cell junctions

Coralie Dorard, Botond Cseh, Karin Ehrenreiter, Reiner Wimmer, Andrea Varga, Tatjana Hirschmugl, Barbara Maier, Karina Kramer, Sabine Fürlinger, Eszter Doma, Manuela Baccarini

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The endothelium functions as a semipermeable barrier regulating fluid homeostasis, nutrient, and gas supply to the tissue. Endothelial permeability is increased in several pathological conditions including inflammation and tumors; despite its clinical relevance, however, there are no specific therapies preventing vascular leakage. Here, we show that endothelial cell-restricted ablation of BRAF, a kinase frequently activated in cancer, prevents vascular leaking as well metastatic spread. BRAF regulates endothelial permeability by promoting the cytoskeletal rearrangements necessary for the remodeling of VE-Cadherin-containing endothelial cell–cell junctions and the formation of intercellular gaps. BRAF kinase activity and the ability to form complexes with RAS/RAP1 and dimers with its paralog RAF1 are required for proper permeability control, achieved mechanistically by modulating the interaction between RAF1 and the RHO effector ROKα. Thus, RAF dimerization impinges on RHO pathways to regulate cytoskeletal rearrangements, junctional plasticity, and endothelial permeability. The data advocate the development of RAF dimerization inhibitors, which would combine tumor cell autonomous effect with stabilization of the vasculature and antimetastatic spread.

Original languageEnglish
Pages (from-to)2277-2294
Number of pages18
JournalFEBS Journal
Volume286
Issue number12
DOIs
StatePublished - Jun 2019

Keywords

  • cell-cell adhesions
  • cytoskeletal rearrangements
  • RAF kinases
  • vascular permeability

Fingerprint

Dive into the research topics of 'RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell-cell junctions'. Together they form a unique fingerprint.

Cite this