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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2014 ; 289
(23
): 16114-28
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Endorepellin evokes autophagy in endothelial cells
#MMPMID24737315
Poluzzi C
; Casulli J
; Goyal A
; Mercer TJ
; Neill T
; Iozzo RV
J Biol Chem
2014[Jun]; 289
(23
): 16114-28
PMID24737315
show ga
Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan
perlecan, possesses angiostatic activity via dual receptor antagonism, through
concurrent binding to the ?2?1 integrin and vascular endothelial growth factor
receptor 2 (VEGFR2). Here, we discovered that soluble endorepellin induced
autophagy in endothelial cells by modulating the expression of Beclin 1, LC3, and
p62, three established autophagic markers. Moreover, endorepellin evoked
expression of the imprinted tumor suppressor gene Peg3 and its co-localization
with Beclin 1 and LC3 in autophagosomes, suggesting a major role for this gene in
endothelial cell autophagy. Mechanistically, endorepellin induced autophagy by
down-regulating VEGFR2 via the two LG1/2 domains, whereas the C-terminal LG3
domain, the portion responsible for binding the ?2?1 integrin, was ineffective.
Endorepellin also induced transcriptional activity of the BECN1 promoter in
endothelial cells, and the VEGFR2-specific tyrosine kinase inhibitor, SU5416,
blocked this effect. Finally, we found a correlation between endorepellin-evoked
inhibition of capillary morphogenesis and enhanced autophagy. Thus, we have
identified a new role for this endogenous angiostatic fragment in inducing
autophagy through a VEGFR2-dependent but ?2?1 integrin-independent pathway. This
novel mechanism specifically targets endothelial cells and could represent a
promising new strategy to potentiate the angiostatic effect of endorepellin and
perhaps other angiostatic matrix proteins.
|Apoptosis Regulatory Proteins/metabolism
[MESH]
|Autophagy/*physiology
[MESH]
|Beclin-1
[MESH]
|Cells, Cultured
[MESH]
|Class III Phosphatidylinositol 3-Kinases/metabolism
[MESH]