TY  - JOUR
A1  - Han, Chao
A1  - Ren, Pengxuan
A1  - Mamtimin, Medina
A1  - Kruk, Linus
A1  - Sarukhanyan, Edita
A1  - Li, Chenyu
A1  - Anders, Hans-Joachim
A1  - Dandekar, Thomas
A1  - Krueger, Irena
A1  - Elvers, Margitta
A1  - Goebel, Silvia
A1  - Adler, Kristin
A1  - Münch, Götz
A1  - Gudermann, Thomas
A1  - Braun, Attila
A1  - Mammadova-Bach, Elmina
T1  - Minimal collagen-binding epitope of glycoprotein VI in human and mouse platelets
JF  - Biomedicines
N2  - Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.
KW  - GPVI
KW  - collagen
KW  - blood platelets
KW  - thrombosis
KW  - anti-thrombotic therapies
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304148
SN  - 2227-9059
VL  - 11
IS  - 2
ER  - 
TY  - JOUR
A1  - Dütting, Sebastian
A1  - Gaits-Iacovoni, Frederique
A1  - Stegner, David
A1  - Popp, Michael
A1  - Antkowiak, Adrien
A1  - van Eeuwijk, Judith M.M.
A1  - Nurden, Paquita
A1  - Stritt, Simon
A1  - Heib, Tobias
A1  - Aurbach, Katja
A1  - Angay, Oguzhan
A1  - Cherpokova, Deya
A1  - Heinz, Niels
A1  - Baig, Ayesha A.
A1  - Gorelashvili, Maximilian G.
A1  - Gerner, Frank
A1  - Heinze, Katrin G.
A1  - Ware, Jerry
A1  - Krohne, Georg
A1  - Ruggeri, Zaverio M.
A1  - Nurden, Alan T.
A1  - Schulze, Harald
A1  - Modlich, Ute
A1  - Pleines, Irina
A1  - Brakebusch, Cord
A1  - Nieswandt, Bernhard
T1  - A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
JF  - Nature Communications
N2  - Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard–Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.
KW  - megakaryocytes
KW  - blood platelets
KW  - regulatory circuit downstream
KW  - glycoprotein Ib
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170797
VL  - 8
IS  - 15838
ER  -