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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3284-3290.
Prepublished online as a Blood First Edition Paper on December 14, 2006; DOI 10.1182/blood-2006-10-051664.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Structure-function analysis reveals discrete ß3 integrin inside-out and outside-in signaling pathways in platelets
Zhiying Zou1,
Hong Chen1,
Alec A. Schmaier1,
Richard O. Hynes2, and
Mark L. Kahn1
1 Division of Cardiology and Department of Medicine, University of Pennsylvania, Philadelphia;
2 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge
A unique aspect of integrin receptor function is the transmission of bidirectional signals. In platelets  IIbß3 integrins require "inside-out" signals to bind fibrinogen and form thrombi. Following ligand binding, IIbß3 integrins generate "outside-in" signals that contribute to thrombus stability. Because integrin cytoplasmic tails are short and lack enzymatic activity, bidirectional signals are believed to be mediated by interactions with intracellular proteins, but the molecular basis for integrin signal transduction remains poorly understood. In the present study we have used retroviral vectors to express IIbß3 integrins with mutant ß3 tails in mouse platelets and test mechanisms of bidirectional signaling. Using this approach we identify mutations (eg, ß3Y747A) that confer loss of signaling in both directions and others (eg, ß3T762A) that confer a selective loss of outside-in signals. These results reveal the presence of discrete bidirectional signaling pathways controlled by integrin ß subunits in platelets and describe a high-throughput means of further investigating these pathways in vivo.
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