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RhoA and the Function of Platelet Integrin
 IIb 3
Lijun Leng,
Hirokazu Kashiwagi,
Xiang-Dong Ren, and
Sanford J. Shattil
From the Departments of Vascular Biology and Molecular and
Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
Integrins respond to "inside-out" signals, which enable them
to bind adhesive ligands, and ligand binding initiates
"outside-in" signals that mediate anchorage-dependent cellular
responses. RhoA is a GTPase that regulates certain actin
rearrangements and transcriptional events. It has also been implicated
in integrin signaling, but the exact relationship is not understood. To
examine this further, platelets were incubated with C3 exoenzyme to
adenine diphosphate (ADP)-ribosylate and inactivate RhoA,
and the function of integrin  IIb 3 was
studied. Despite inactivation of  90% of RhoA, platelets exhibited
normal inside-out signaling, as monitored by agonist-induced binding of
a fibrinogen-mimetic anti-IIb3 antibody
and normal fibrinogen-dependent aggregation. On the other hand, RhoA
inactivation decreased the adhesion of agonist-stimulated platelets to
fibrinogen (P < .04) and the formation of vinculin-rich focal
adhesions in platelets that did adhere (P < .001). These
effects were selective because fibrin clot retraction, a response also
dependent on IIb3 and actin
contractility, was unaffected by C3, as was the content of F-actin in
resting or agonist-stimulated platelets. Similar results were obtained
in a Chinese hamster ovary (CHO) cell model system of
IIb3: C3 exoenzyme (or overexpression of
dominant-negative N19RhoA) failed to influence integrin activation
state, but it blocked the formation of focal adhesions in cells spread
on fibrinogen. These studies establish that RhoA plays a highly
selective role in IIb3 signaling, and
they identify a subset of responses to integrin ligation that may be
uniquely dependent on the actin rearrangements regulated by this
GTPase.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4206-4215
© 1998 by The American Society of Hematology.
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