The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling

Title: The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling
Authors: Constantinescu-Bercu, A
Wang, YA
Woollard, K
Mangin, P
Vanhoorelbeke, K
Crawley, JTB
Salles-Crawley, II
Item 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.
Issue Date: 16-Dec-2020
URI: http://hdl.handle.net/10044/1/86644
DOI: 10.1101/2020.12.16.423021
Publisher: Cold Spring Harbor Laboratory
Copyright Statement: © 2020 The Author(s). It is made available under a CC BY ND 4.0 International license.
Publication Status: Published
Open Access location: https://www.biorxiv.org/content/10.1101/2020.12.16.423021v1.full.pdf
Appears in Collections:Department of Immunology and Inflammation



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