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