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J. Biol. Chem., Vol. 280, Issue 15, 14462-14468, April 15, 2005

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Evidence for a Role of ADAM17 (TACE) in the Regulation of Platelet Glycoprotein V^*

Tamer Rabie, Amrei Strehl, Andreas Ludwig¶, and Bernhard Nieswandt||

From the Vascular Biology, Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg, 97078 Würzburg, Germany, and ^¶Institute of Biochemistry, Christian Albrecht University Kiel, 24098 Kiel, Germany

Glycoprotein V (GPV) is a subunit of the GPIb-IX-V receptor for von Willebrand factor and thrombin and has been shown to modulate platelet responses to the two strongest physiological agonists, thrombin and collagen. Thrombin directly cleaves GPV from the platelet surface, yielding a 69-kDa fragment GPV f1 of unknown function. We show here that a 82-kDa fragment of GPV is shed from the platelet surface upon cellular activation with phorbol 12-myristate 13-acetate or the collagen-related peptide. This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 (ADAM17 lacking Zn-binding domain; ADAM17^Zn/Zn). Furthermore, we show that recombinant ADAM17 ectodomain efficiently releases GPV from the platelet surface. GPV is known to be associated with the intracellular regulatory protein calmodulin, which has previously been shown to be involved in ADAM17-mediated shedding of L-selectin from the surface of leukocytes. As in these reports, inhibition of calmodulin led to rapid GPV shedding from the platelet surface, a process that was again blocked by GM6001 or ADAM17 inhibitors and that was absent in ADAM17^Zn/Zn mice. Inhibition of outside-in signaling through GPIIb/IIIa did not significantly affect GPV shedding, excluding an essential role of this pathway for the regulation of ADAM17 activity. These results demonstrate that GPV is cleaved upon agonist-induced platelet activation and show that ADAM17 is the major enzyme mediating this process.

Received for publication, January 3, 2005 , and in revised form, February 2, 2005.

^* This work was supported in part by the Deutsche Forschungsgemeinschaft Grants Ni556/4-1 (to B. N.) and LU 869/1-1 (to A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| Heisenberg Fellow of the Deutsche Forschungsgemeinschaft. To whom correspondence should be addressed. Tel.: 49-931-201-48996; Fax: 49-931-201-48123; E-mail: bernhard.nieswandt{at}virchow.uniwuerzburg.de.

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