Imperial College London
Alternate

DrIsabelleSalles

Faculty of Medicine, Department of Immunology and Inflammation

Honorary Lecturer
 
 
 
//

Contact

 

+44 (0)20 3313 2298i.salles

 
 
//

Location

 

5S5Commonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Constantinescu-Bercu:2022:10.3324/haematol.2020.278242,
author = {Constantinescu-Bercu, A and Wang, YA and Woollard, KJ and Mangin, P and Vanhoorelbeke, K and Crawley, JTB and Salles-Crawley, II},
doi = {10.3324/haematol.2020.278242},
journal = {Haematologica},
pages = {933--946},
title = {The GPIbα intracellular tail – role in transducing VWF- and collagen/GPVI-mediated signaling},
url = {http://dx.doi.org/10.3324/haematol.2020.278242},
volume = {107},
year = {2022}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:p>The GPIbT-VWF A1 domain interaction is essential for platelet tethering under high shear. Synergy between GPIbα and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIbα transgenic mouse (GpIbαΔsig/Δsig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIbα intracellular tail that harbors the 14-3-3 and phosphoinositide-3 kinase binding sites. GPIbαΔsig/Δsig platelets bound VWF normally under flow. However, they formed fewer filopodia on VWF/botrocetin in the presence of a oIIbI3 blocker, demonstrating that despite normal ligand binding, VWF-dependent signaling is diminished. Activation of GpIbαΔsig/Δsig platelets with ADP and thrombin was normal, but GpIbαΔsig/Δsig platelets stimulated with collagen-related-peptide (CRP) exhibited markedly decreased P-selectin exposure and eIIbI3 activation, suggesting a role for the GpIbaaintracellular tail in GPVI-mediated signaling. Consistent with this, while haemostasis was normal in GPIbαΔsig/Δsig mice, diminished tyrosine-phosphorylation, (particularly pSYK) was detected in CRP-stimulated GpIbαΔsig/Δsig platelets as well as reduced platelet spreading on CRP. Platelet responses to rhodocytin were also affected in GpIbαΔsig/Δsig platelets but to a lesser extent than those with CRP. GpIbαΔsig/Δsig platelets formed smaller aggregates than wild-type platelets on collagen-coated microchannels at low, medium and high shear. In response to both VWF and collagen binding, flow assays performed with plasma-free blood or in the presence of bIIbI3- or GPVI-blockers suggested reduced bIIbI3 activation contributes to the phenotype of the GpIbαΔsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbiiin transducing
AU  - Constantinescu-Bercu,A
AU  - Wang,YA
AU  - Woollard,KJ
AU  - Mangin,P
AU  - Vanhoorelbeke,K
AU  - Crawley,JTB
AU  - Salles-Crawley,II
DO  - 10.3324/haematol.2020.278242
EP  - 946
PY  - 2022///
SN  - 0390-6078
SP  - 933
TI  - The GPIbα intracellular tail – role in transducing VWF- and collagen/GPVI-mediated signaling
T2  - Haematologica
UR  - http://dx.doi.org/10.3324/haematol.2020.278242
UR  - http://hdl.handle.net/10044/1/90389
VL  - 107
ER  -
Download