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A more recent version of this article appeared on September 30, 2005
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M500146200v1
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Papers In Press, published online ahead of print June 13, 2005
J. Biol. Chem, 10.1074/jbc.M500146200
Submitted on January 5, 2005
Accepted on June 13, 2005

A new functional role of the fibrinogen RGD motif as the molecular switch that selectively triggers integrin alpha IIbbeta 3-dependent RhoA activation during cell spreading

Alexandre Salsmann, Elisabeth Schaffner-Reckinger, Fabrice Kabile, Sébastien Plançon, and Nelly Kieffer

Laboratoire de Biologie et Physiologie Intégrée (CNRS/GDRE-ITI), Centre Universitaire, Luxembourg, Grand Duchy L-1511

Corresponding Author: kieffer{at}cu.lu

A number of RGD-type integrins rely on a synergistic site in addition to the canonical RGD site for ligand binding and signaling, although it is still unclear whether these two recognition sites function independently, synergistically or competitively. Experimental evidence has suggested that fibrinogen binding to the RGD-type integrin alpha IIbbeta 3 occurs exclusively through the synergistic gamma 400-411 sequence, thus questioning the functional role of the RGD recognition site. Here we have investigated the respective role of the fibrinogen gamma 400-411 sequence and the RGD motif in the molecular events leading to ligand-induced alpha IIbbeta 3-dependent CHO cell or platelet spreading, by using intact fibrinogen and well characterized plasmin-generated fibrinogen fragments containing either the RGD motif (fragment C) or the gamma 400-411 sequence (fragment D), and CHO cells expressing resting wild type (alpha IIbbeta 3wt), constitutively active (alpha IIbbeta 3T562N) or non-functional (alpha IIbbeta 3D119Y) receptors. Our data provide evidence that the gamma 400-411 site by itself is able to initiate alpha IIbbeta 3 clustering and recrutement of intracellular proteins to early focal complexes, mediating cell attachment, FAK phosphorylation and Rac1 activation, while the RGD motif subsequently acts as a molecular switch on the beta 3 subunit to trigger cell spreading. More importantly, we show that the premier functional role of the RGD site is not to reinforce cell attachment, but rather to imprint a conformational change on the beta 3 subunit leading to maximal RhoA activation and actin cytoskeleton organization in CHO cells as well as in platelets. Finally, alpha IIbbeta 3-dependent RhoA stimulation and cell spreading, but not cell attachment, are Src-dependent and PI3 kinase-independent and are inhibited by the Src antagonist PP2.


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