Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
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Target Concepts:
Gene/Protein
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Query: UNIPROT:P42345 (
mTOR
)
26,049
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Oxysterol-binding protein-related protein 2
(
ORP2
), a cholesterol-PI(4,5)P
2
countercurrent transporter, was recently identified as a novel regulator of plasma membrane (PM) cholesterol and PI(4,5)P
2
content in HeLa cells. Here, we investigate the role of
ORP2
in endothelial cell (EC) cholesterol and PI(4,5)P
2
distribution, angiogenic signaling, and angiogenesis. We show that
ORP2
knock-down modifies the distribution of cholesterol accessible to a D4H probe, between late endosomes and the PM. Depletion of
ORP2
from ECs inhibits their angiogenic tube formation capacity, alters the gene expression of angiogenic signaling pathways such as VEGFR2, Akt,
mTOR
, eNOS, and Notch, and reduces EC migration, proliferation, and cell viability. We show that
ORP2
regulates the integrity of VEGFR2 at the PM in a cholesterol-dependent manner, the depletion of
ORP2
resulting in proteolytic cleavage by matrix metalloproteinases, and reduced activity of VEGFR2 and its downstream signaling. We demonstrate that
ORP2
depletion increases the PM PI(4,5)P
2
coincident with altered F-actin morphology, and reduces both VEGFR2 and cholesterol in buoyant raft membranes. Moreover,
ORP2
knock-down suppresses the expression of the lipid raft-associated proteins VE-cadherin and caveolin-1. Analysis of the retinal microvasculature in
ORP2
knock-out mice generated during this study demonstrates the subtle alterations of morphology characterized by reduced vessel length and increased density of tip cells and perpendicular sprouts. Gene expression changes in the retina suggest disturbance of sterol homeostasis, downregulation of VE-cadherin, and a putative disturbance of Notch signaling. Our data identifies
ORP2
as a novel regulator of EC cholesterol and PI(4,5)P
2
homeostasis and cholesterol-dependent angiogenic signaling.
...
PMID:ORP2, a cholesterol transporter, regulates angiogenic signaling in endothelial cells. 3291 3
