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J. Biol. Chem., Vol. 280, Issue 7, 6028-6035, February 18, 2005

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Annexin A5 Down-regulates Surface Expression of Tissue Factor

A NOVEL MECHANISM OF REGULATING THE MEMBRANE RECEPTOR REPERTOIR^*

Susana Ravassa¶, Abdelkader Bennaghmouch||, Heidi Kenis, Theo Lindhout, Tilman Hackeng, Jagat Narula**, Leo Hofstra||, and Chris Reutelingsperger

From the Departments of Biochemistry and ^||Cardiology of the Cardiovascular Research Institute Maastricht, University of Maastricht, P. O. Box 616, 6200 MD Maastricht, The Netherlands and the ^**Department of Medicine-Cardiology, University of California, Irvine, California 92612

Phosphatidylserine (PtdSer) is exposed on the external leaflet of the plasma membrane during apoptosis. The protein annexin A5 (anxA5) shows high affinity for PtdSer. When anxA5 binds to the PtdSer-expressing membranes during apoptosis, it crystallizes as an extended two-dimensional network and activates thereby a novel portal of cell entry that results in the internalization of the PtdSer-expressing membrane patches. This novel pathway of cell entry is potentially involved in the regulation of the surface expression of membrane receptors. In this study we report the regulation of surface expression of the initiator of blood coagulation tissue factor (TF) by this novel pathway of cell entry. AnxA5 induces the internalization of tissue factor expressed on the surface of apoptotic THP-1 macrophages. This down-regulation depends on the abilities of anxA5 to bind to PtdSer and to form a two-dimensional crystal at the membrane. We furthermore show that THP-1 cells produce and externalize anxA5 that cause the internalization of TF in an autocrine type of mechanism. We extended our in vitro work to the in vivo situation and show in a mouse model that anxA5 causes the down-regulation of TF expression by smooth muscle cells of the media of the carotid artery that was mechanically injured. In conclusion, anxA5 down-regulates surface-expressed TF by activating the novel portal of cell entry. This mechanism may be part of a more general autocrine function of anxA5 to regulate the plasma membrane receptor repertoir under stress conditions associated with the surface expression of PtdSer.

Received for publication, October 14, 2004 , and in revised form, November 23, 2004.

^* This work was supported in part by the Dutch Organization for Scientific Research (NWO) Grants 902-26-184, 014-080-103, and 912-03-013. 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.

These authors contributed equally to this work.

^¶ Supported by a grant from the Navarra Government (Beca para el perfeccionamiento de doctores).

To whom correspondence should be addressed. Tel.: 31-43-388-1533; Fax: 31-43-388-4159; E-mail: c.reutelingsperger{at}bioch.unimaas.nl.

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