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GPIb-dependent Platelet Activation Is Dependent on Src Kinases but Not MAP Kinase or cGMP-dependent Kinase

GPIb-dependent Platelet Activation Is Dependent on Src Kinases but Not MAP Kinase or cGMP-dependent Kinase

Stuart J Marshall, Yotis A Senis, Jocelyn M Auger, Robert Feil, Franz Hofmann, Gary Salmon, J Thomas Peterson, Frank Burslem, Steve P Watson

Blood. 2004 Apr 1;103(7):2601-9.

PMID: 14684423

Abstract:

Glycoprotein Ib-IX-V (GPIb-IX-V) mediates platelet tethering to von Willebrand factor (VWF), recruiting platelets into the thrombus, and activates integrin alphaIIbbeta3 through a pathway that is dependent on Src kinases. In addition, recent reports indicate that activation of alphaIIbbeta3 by VWF is dependent on protein kinase G (PKG) and mitogen-activated protein (MAP) kinases. The present study compares the importance of these signaling pathways in the activation of alphaIIbbeta3 by GPIb-IX-V. In contrast to a recent report, VWF did not promote an increase in cyclic guanosine monophosphate (cGMP), while agents that elevate cGMP, such as the nitrous oxide (NO) donor glyco-SNAP-1 (N-(beta-D-glucopyranosyl)-N2-acetyl-S-nitroso-D,L-penicillaminamide) or the type 5 phosphosdiesterase inhibitor, sildenafil, inhibited rather than promoted activation of alphaIIbbeta3 by GPIb-IX-V and blocked aggregate formation on collagen at an intermediate rate of shear (800 s(-1)). Additionally, sildenafil increased blood flow in a rabbit model of thrombus formation in vivo. A novel inhibitor of the MAP kinase pathway, which is active in plasma, PD184161, had no effect on aggregate formation on collagen under flow conditions, whereas a novel inhibitor of Src kinases, which is also active in plasma, PD173952, blocked this response. These results demonstrate a critical role for Src kinases but not MAP kinases in VWF-dependent platelet activation and demonstrate an inhibitory role for cGMP-elevating agents in regulating this process.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP305820751	PD173952		305820-75-1	Price

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