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First published online October 30, 2006
doi: 10.1242/10.1242/jcs.03195

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Disabled-2 is a novel IIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation

¹ Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan 333, Taiwan, Republic of China
² School of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan, Republic of China
³ Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
⁴ Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110, USA
⁵ Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan, Republic of China
⁶ Graduate Institute of Medical Biotechnology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shen, Taoyuan 333, Taiwan, Republic of China

^* Authors for correspondence (e-mail: ctseng{at}mail.cgu.edu.tw; liaoch{at}mail.cgu.edu.tw)

Accepted 27 July 2006

Platelet aggregation plays a pivotal role in the haemostatic process and is involved in the pathological counterpart of arterial thrombosis. We have shown that the adapter protein disabled-2 (DAB2) is expressed abundantly in platelets. In this study, DAB2 was found to distribute in the platelet -granules and was released from the granular compartment upon platelet activation. The secreted DAB2 binds to the extracellular region of IIbß3 integrin on the platelet surface through the phosphotyrosine-binding domain. The DAB2-platelet interactions result in the inhibition of agonist-induced platelet aggregation with the exception of thrombin, a DAB2 protease that renders DAB2 inactive. Biochemical and mutational analysis revealed that the DAB2 cell-adhesion Arg-Gly-Asp (RGD) motif (amino acid residues 64-66) and the IIb-integrin–fibrinogen-binding region (amino acid residues 171-464) are important for the DAB2-platelet interactions. Such interactions compete for the binding of IIb integrin with fibrinogen and provide a mechanism for DAB2 to inhibit platelet aggregation. Accordingly, the synthetic RGD-motif-containing DAB2 peptide PDARGDKM also elicited anti-platelet aggregation activity. These findings demonstrate for the first time that DAB2 is an IIb-integrin-binding protein that plays a novel role in the control of platelet-fibrinogen interactions and platelet aggregation.

Key words: Disabled-2, Fibrinogen, IIbß3 Integrin, Platelet aggregation, RGD motif

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