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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 Curr+Biol
2017 ; 27
(14
): 2219-2225.e5
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gab.com Text
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English Wikipedia
VE-Cadherin Phosphorylation Regulates Endothelial Fluid Shear Stress Responses
through the Polarity Protein LGN
#MMPMID28712573
Conway DE
; Coon BG
; Budatha M
; Arsenovic PT
; Orsenigo F
; Wessel F
; Zhang J
; Zhuang Z
; Dejana E
; Vestweber D
; Schwartz MA
Curr Biol
2017[Jul]; 27
(14
): 2219-2225.e5
PMID28712573
show ga
Fluid shear stress due to blood flow on the vascular endothelium regulates blood
vessel development, remodeling, physiology, and pathology [1, 2]. A complex
consisting of PECAM-1, VE-cadherin, and vascular endothelial growth factor
receptors (VEGFRs) that resides at endothelial cell-cell junctions transduces
signals important for flow-dependent vasodilation, blood vessel remodeling, and
atherosclerosis. PECAM-1 transduces forces to activate src family kinases (SFKs),
which phosphorylate and transactivate VEGFRs [3-5]. By contrast, VE-cadherin
functions as an adaptor that interacts with VEGFRs through their respective
cytoplasmic domains and promotes VEGFR activation in flow [6]. Indeed, shear
stress triggers rapid increases in force across PECAM-1 but decreases the force
across VE-cadherin, in close association with downstream signaling [5].
Interestingly, VE-cadherin cytoplasmic tyrosine Y658 can be phosphorylated by
SFKs [7], which is maximally induced by low shear stress in vitro and in vivo
[8]. These considerations prompted us to address the involvement of VE-cadherin
cytoplasmic tyrosines in flow sensing. We found that phosphorylation of a small
pool of VE-cadherin on Y658 is essential for flow sensing through the junctional
complex. Y658 phosphorylation induces dissociation of p120ctn, which allows
binding of the polarity protein LGN. LGN is then required for multiple flow
responses in vitro and in vivo, including activation of inflammatory signaling at
regions of disturbed flow, and flow-dependent vascular remodeling. Thus,
endothelial flow mechanotransduction through the junctional complex is mediated
by a specific pool of VE-cadherin that is phosphorylated on Y658 and bound to
LGN.
|Antigens, CD/*genetics/metabolism
[MESH]
|Biomechanical Phenomena
[MESH]
|Cadherins/*genetics/metabolism
[MESH]
|Endothelium, Vascular/*physiology
[MESH]
|Humans
[MESH]
|Intercellular Junctions/metabolism
[MESH]
|Intracellular Signaling Peptides and Proteins/*genetics/metabolism
[MESH]