VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin

Nat Cell Biol. 2006 Nov;8(11):1223-34. doi: 10.1038/ncb1486. Epub 2006 Oct 22.

Abstract

How vascular endothelial growth factor (VEGF) induces vascular permeability, its first described function, remains poorly understood. Here, we provide evidence of a novel signalling pathway by which VEGF stimulation promotes the rapid endocytosis of a key endothelial cell adhesion molecule, VE-cadherin, thereby disrupting the endothelial barrier function. This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor. Rac activation, in turn, promotes the p21-activated kinase (PAK)-mediated phosphorylation of a highly conserved motif within the intracellular tail of VE-cadherin. Surprisingly, this results in the recruitment of beta-arrestin2 to serine-phosphorylated VE-cadherin, thereby promoting its internalization into clathrin-coated vesicles and the consequent disassembly of intercellular junctions. Ultimately, this novel biochemical route by which VEGF promotes endothelial permeability through the beta-arrestin2-dependent endocytosis of VE-cadherin may help identify new therapeutic targets for the treatment of many human diseases that are characterized by vascular leakage.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Arrestins / genetics
  • Arrestins / physiology*
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cadherins / pharmacokinetics*
  • Cell Line
  • Cell Membrane Permeability / drug effects*
  • Conserved Sequence / genetics
  • Endocytosis / drug effects*
  • Endocytosis / physiology
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Humans
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-vav / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / physiology
  • RNA, Small Interfering / genetics
  • Sequence Homology, Amino Acid
  • Serine / genetics
  • Serine / metabolism
  • Transfection
  • Vascular Endothelial Growth Factor A / pharmacology*
  • beta-Arrestins
  • p21-Activated Kinases

Substances

  • Antigens, CD
  • Arrestins
  • Cadherins
  • Proto-Oncogene Proteins c-vav
  • RNA, Small Interfering
  • VAV2 protein, human
  • Vascular Endothelial Growth Factor A
  • beta-Arrestins
  • cadherin 5
  • Green Fluorescent Proteins
  • Serine
  • Proto-Oncogene Proteins pp60(c-src)
  • PAK2 protein, human
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases

Associated data

  • RefSeq/NM_001795
  • RefSeq/NM_009500
  • RefSeq/NM_145429
  • RefSeq/NP_001001601
  • RefSeq/NP_001001649
  • RefSeq/NP_001783
  • RefSeq/NP_004351
  • RefSeq/NP_033998
  • RefSeq/NP_989558
  • RefSeq/XP_226213
  • RefSeq/XP_523383