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@ARTICLE{Krueger:889872,
author = {Krueger, Irena and Gremer, Lothar and Mangels, Lena and
Klier, Meike and Jurk, Kerstin and Willbold, Dieter and
Bock, Hans H. and Elvers, Margitta},
title = {{R}eelin {A}mplifies {G}lycoprotein {VI} {A}ctivation and
{A}lpha{II}b {B}eta3 {I}ntegrin {O}utside-{I}n {S}ignaling
via {PLC} {G}amma 2 and {R}ho {GTP}ases},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {40},
number = {10},
issn = {1524-4636},
address = {Stanford, Calif.},
publisher = {HighWire},
reportid = {FZJ-2021-00480},
pages = {2391 - 2403},
year = {2020},
abstract = {Objective:Reelin, a secreted glycoprotein, was originally
identified in the central nervous system, where it plays an
important role in brain development and maintenance. In the
cardiovascular system, reelin plays a role in
atherosclerosis by enhancing vascular inflammation and in
arterial thrombosis by promoting platelet adhesion,
activation, and thrombus formation via APP (amyloid
precursor protein) and GP (glycoprotein) Ib. However, the
role of reelin in hemostasis and arterial thrombosis is not
fully understood to date.Approach and Results:In the present
study, we analyzed the importance of reelin for cytoskeletal
reorganization of platelets and thrombus formation in more
detail. Platelets release reelin to amplify alphaIIb beta3
integrin outside-in signaling by promoting platelet
adhesion, cytoskeletal reorganization, and clot retraction
via activation of Rho GTPases RAC1 (Ras-related C3 botulinum
toxin substrate) and RhoA (Ras homolog family member A).
Reelin interacts with the collagen receptor GP
(glycoprotein) VI with subnanomolar affinity, induces
tyrosine phosphorylation in a GPVI-dependent manner, and
supports platelet binding to collagen and GPVI-dependent
RAC1 activation, PLC gamma 2
(1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase
gamma-2) phosphorylation, platelet activation, and
aggregation. When GPVI was deleted from the platelet surface
by antibody treatment in reelin-deficient mice, thrombus
formation was completely abolished after injury of the
carotid artery while being only reduced in either
GPVI-depleted or reelin-deficient mice.Conclusions:Our study
identified a novel signaling pathway that involves
reelin-induced GPVI activation and alphaIIb beta3 integrin
outside-in signaling in platelets. Loss of both, GPVI and
reelin, completely prevents stable arterial thrombus
formation in vivo suggesting that inhibiting
reelin-platelet-interaction might represent a novel strategy
to avoid arterial thrombosis in cardiovascular disease.},
cin = {IBI-7},
ddc = {610},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {551 - Functional Macromolecules and Complexes (POF3-551)},
pid = {G:(DE-HGF)POF3-551},
typ = {PUB:(DE-HGF)16},
pubmed = {32787521},
UT = {WOS:000576399500009},
doi = {10.1161/ATVBAHA.120.314902},
url = {https://juser.fz-juelich.de/record/889872},
}