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J. Biol. Chem., Vol. 277, Issue 17, 14738-14746, April 26, 2002
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From the Department of Medicine, Australian Centre for Blood
Diseases, Monash University, Box Hill Hospital, Arnold St., Box
Hill, Victoria 3128, Australia
The small GTPase RhoA modulates the adhesive
nature of many cell types; however, despite high levels of expression
in platelets, there is currently limited evidence for an important role
for this small GTPase in regulating platelet adhesion processes. In this study, we have examined the role of RhoA in regulating the adhesive function of the major platelet integrin,
RhoA Sustains Integrin
IIb
3
Adhesion Contacts under High Shear*
,
IIb
3. Our studies demonstrate that
activation of RhoA occurs as a general feature of platelet activation
in response to soluble agonists (thrombin, ADP, U46619, collagen),
immobilized matrices (von Willebrand factor (vWf), fibrinogen) and high
shear stress. Blocking the ligand binding function of integrin
IIb3, by pretreating platelets with c7E3
Fab, demonstrated the existence of integrin IIb3-dependent and
-independent mechanisms regulating RhoA activation. Inhibition of RhoA
(C3 exoenzyme) or its downstream effector Rho kinase (Y27632) had no
effect on integrin IIb3 activation induced by soluble agonists or adhesive substrates, however, both inhibitors reduced shear-dependent platelet adhesion on
immobilized vWf and shear-induced platelet aggregation in suspension.
Detailed analysis of the sequential adhesive steps required for stable platelet adhesion on a vWf matrix under shear conditions revealed that
RhoA did not regulate platelet tethering to vWf or the initial formation of integrin IIb3 adhesion
contacts but played a major role in sustaining stable platelet-matrix
interactions. These studies define a critical role for RhoA in
regulating the stability of integrin IIb3
adhesion contacts under conditions of high shear stress.
*
This work was supported in part by grants from the National
Health and Medical Research Council (NHMRC) of Australia and the National Heart Foundation of Australia.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of an NHMRC R. D. Wright Fellowship and a Monash
University (Australia) Logan Fellowship. To whom correspondence should
be addressed: Dept. of Medicine, Monash University, 5th Level, Clive
Ward Bldg., Box Hill Hospital, Arnold Street, Box Hill, Victoria 3128, Australia. Tel.: 61-3-9895-0350; Fax: 61-3-9895-0332; E-mail:
Simone.Schoenwaelder@med.monash.edu.au.
§
Recipient of the Australian Post-Graduate Research Award.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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