Titel
RAF dimers control vascular permeability and cytoskeletal rearrangements at endothelial cell‐cell junctions
Autor*in
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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 /RAP 1 and dimers with its paralog RAF 1 are required for proper permeability control, achieved mechanistically by modulating the interaction between RAF 1 and the RHO effector ROK α. 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.
Stichwort
cell‐cell adhesionscytoskeletal rearrangementsRAF kinasesvascular permeability
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
phaidra.univie.ac.at/o:1094748
Erschienen in
Titel
The FEBS Journal
Band
286
Ausgabe
12
ISSN
1742-464X
Erscheinungsdatum
2019
Seitenanfang
2277
Seitenende
2294
Publication
Wiley
Fördergeber
Austrian Science Fund (FWF) — SFB021
Erscheinungsdatum
2019
Zugänglichkeit
Rechte
Rechteangabe
© 2019 The Authors
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