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3385_Ch14 - Section III Inside-Out Signaling by Integrins...

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© 1999 by CRC Press LLC Section III Inside-Out Signaling by Integrins
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14 © 1999 by CRC Press LLC Chapter Studies of Integrin Signaling Through Platelet α IIb β 3 Takaaki Hato, Petra Maschberger, and Sanford J. Shattil Contents I. Introduction II. Inside-Out Signaling A. Affinity Modulation B. Avidity Modulation of α IIb β 3 in CHO Cells III. Outside-in Signaling A. CHO Cell Adhesion to Immobilized Ligands B. Analysis of Protein Tyrosine Phosphorylation/Kinase Activity C. Integrin-Dependent Morphological Changes References I. Introduction Integrin α IIb β 3 , which is expressed only in megakaryocytes and platelets, is essential for normal platelet adhesion and aggregation during hemostasis and for the devel- opment of occlusive, platelet-rich thrombi in vascular diseases. Studies in platelets over the past two decades have demonstrated that α IIb β 3 is engaged in bidirectional signaling. “Inside-out” signals convert the receptor from a low to a high affinity/avid- ity state. This enables platelets to bind soluble, multivalent adhesive ligands, such as fibrinogen and von Willebrand factor; in turn, these bridge the integrins on adjacent platelets, culminating in cell-cell aggregation. Inside-out signals also enable
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© 1999 by CRC Press LLC the receptor to recognize or to bind more tightly to Arg-Gly-Asp ligands immobilized in the vessel wall, thus contributing to firm platelet adhesion during hemostasis and thrombosis. 1 “Outside-in” signals are triggered by the binding of soluble and immo- bilized ligands to α IIb β 3 , and they are responsible for mediating or facilitating a number of important post-ligand binding events, including platelet spreading, cytoskeletal reorganization, exocytosis, and development of platelet membrane pro- coagulant activity. 2 Platelets are anucleate cells and consequently are not amenable to study by the usual recombinant methods. Accordingly, in the past several years, investigators have turned to model cell systems to study the adhesive and signaling functions of α IIb β 3 . 3-6 In such systems, α IIb β 3 and/or other recombinant molecules are expressed transiently or in a stable manner in tissue culture cells, and various aspects of bidirectional signaling are studied. These model systems have been quite useful in characterizing the signaling pathways that can interact with α IIb β 3 , and they have established the critical importance of the relatively short integrin cytoplasmic tails in bidirectional signaling. We have focused our own studies in this area on a CHO cell model system that was first popularized for α IIb β 3 by O’Toole and colleagues. 7,8 With this system, we have been able to reconstitute many of the signaling properties of α IIb β 3 normally found in platelets.
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