Abstract
The glycoprotein Ib–IX (GPIb-IX) complex mediates initial platelet adhesion to von Willebrand factor (VWF) immobilized on subendothelial matrix and endothelial surfaces, and transmits VWF binding-induced signals to stimulate platelet activation. GPIb-IX also functions as part of a mechanosensor to convert mechanical force received via VWF binding into intracellular signals, thereby greatly enhancing platelet activation. Thrombin binding to GPIb-IX initiates GPIb-IX signaling cooperatively with protease-activated receptors to synergistically stimulate the platelet response to low-dose thrombin. GPIb-IX signaling may also occur following the binding of other GPIb-IX ligands such as leukocyte integrin αMβ2 and red cell-derived semaphorin 7A, contributing to thrombo-inflammation. GPIb-IX signaling requires the interaction between the cytoplasmic domains of GPIb-IX and 14-3-3 protein and is mediated through Src family kinases, the Rho family of small GTPases, phosphoinositide 3-kinase-Akt-cGMP-mitogen-activated protein kinase, and LIM kinase 1 signaling pathways, leading to calcium mobilization, integrin activation, and granule secretion. This review summarizes the current understanding of GPIb-IX signaling.
Acknowledgements
We thank Dr. Randal Skidgel for critical reading of this manuscript.
Disclosure statement
The University of Illinois holds patents related to GPIb-IX and integrins. X.D. has equity interests in DuPage Medical Technology, Inc. which licenses the university patents. Other authors have no conflicts of interest to declare. This work was partially supported by National Heart, Lung and Blood Institute grants HL150797 (X.D), HL062350 (X.D.) and HL132019 (C.Z.).
Author contributions
YZ and SME wrote the initial draft. XD and CZ wrote the improved version based on the initial draft. All four authors participated in revisions and figure preparation.