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J. Biol. Chem., Vol. 277, Issue 28, 25715-25721, July 12, 2002
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From the Departments of The affinity of integrin
Relationships between Rap1b, Affinity Modulation of
Integrin
IIb
3, and the Actin
Cytoskeleton*
,,,,
**
Cell Biology and
Molecular and Experimental Medicine, The Scripps Research
Institute, La Jolla, California 92037 and the Departments of
§ Pharmacology and ¶ Medicine, University of North
Carolina, Chapel Hill, North Carolina 27599
IIb
3 for fibrinogen is
controlled by inside-out signals that are triggered by agonists like
thrombin. Agonist treatment of platelets also activates Rap1b, a small
GTPase known to promote integrin-dependent adhesion of other
cells. Therefore, we investigated the role of Rap1b in
IIb3 function by viral transduction of
GFP-Rap1 chimeras into murine megakaryocytes, which exhibit inside-out
signaling similar to platelets. Expression of constitutively active
GFP-Rap1b (V12) had no effect on unstimulated megakaryocytes, but it
greatly augmented fibrinogen binding to IIb3 induced by a PAR4 thrombin receptor
agonist (p < 0.01). The Rap1b effect was
cell-autonomous and was prevented by pre-treating cells with
cytochalasin D or latrunculin A to inhibit actin polymerization. Rap1b-dependent fibrinogen binding to megakaryocytes was
blocked by POW-2, a novel monovalent antibody Fab fragment specific for high affinity murine IIb3. In contrast to
GFP-Rap1b (V12), expression of GFP-Rap1GAP, which deactivates
endogenous Rap1, inhibited agonist-induced fibrinogen binding
(p < 0.01), as did dominant-negative GFP-Rap1b (N17)
(p < 0.05). None of these treatments affected surface
expression of IIb3. These studies
establish that Rap1b can augment agonist-induced ligand binding to
IIb3 through effects on integrin
affinity, possibly by modulating IIb3
interactions with the actin cytoskeleton.
*
These studies were supported by research grants from the
National Institutes of Health (to L. V. P., G. C. W., and
S. J. S.) and by a postdoctoral fellowship from the American Heart
Association (to K. E.). This work was presented in part at the Annual
Meeting of the American Society of Hematology, December, 2002, Orlando, FL and published in abstract form (Bertoni, A., Tadokoro, S., Eto, K., Pampori, N., Parise, L., White, G. C., and Shattil, S. J. (2001) Blood 98, 752a).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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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