The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling
Author(s)
Type
Working Paper
Abstract
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 important for VWF-mediated signaling. GPIbαΔsig/Δsig platelets bound VWF normally under flow but formed fewer filopodia on VWF/botrocetin, demonstrating that the deleted region does not affect ligand binding but appreciably impairs VWF-dependent signaling. Notably, while haemostasis was normal in GPIbαΔsig/Δsig mice, GPIbαΔsig/Δsig platelets exhibited defective responses after collagen-related-peptide stimulation and formed smaller aggregates on collagen-coated microchannels at low and high shears. Flow assays performed with plasma-free blood or in the presence of αIIbβ3-or GPVI-blockers suggested reduced αIIbβ3 activation contributes to the phenotype of the GPIbαΔsig/Δsig platelets. Together, these results reveal a new role for the intracellular tail of GPIbα in transducing both VWF-GPIbα and collagen-GPVI signaling events in platelets.
Date Issued
2020-12-16
Date Acceptance
2021-06-10
Citation
2020
ISSN
0390-6078
Publisher
Cold Spring Harbor Laboratory
Journal / Book Title
Haematologica: the hematology journal
Copyright Statement
© 2020 The Author(s). It is made available under a CC BY ND 4.0 International license.
License URL
Identifier
https://www.biorxiv.org/content/10.1101/2020.12.16.423021v1
Publication Status
Published