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J. Biol. Chem., Vol. 282, Issue 14, 10487-10497, April 6, 2007

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Non-apoptotic Phosphatidylserine Externalization Induced by Engagement of Glycosylphosphatidylinositol-anchored Proteins^*

Daniel Smr, L'ubica Dráberová, and Petr Dráber, Supported by an International Research Scholar award from Howard Hughes Medical Institute¹

From the Department of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, CZ 142 20 Prague 4, Czech Republic

The exposure of phosphatidylserine (PS) on the cell surface is a general marker of apoptotic cells. Non-apoptotic PS externalization is induced by several activation stimuli, including engagement of immunoreceptors. Immune cells can also be activated by aggregation of glycosylphosphatidylinositol-anchored proteins (GPI-APs). However, it is unknown whether cell triggering through these proteins, lacking transmembrane and cytoplasmic domains, also leads to PS externalization. Here we show that engagement of GPI-APs in rodent mast cells induces a rapid and reversible externalization of PS by a non-apoptotic mechanism. PS externalization triggered by GPI-AP-specific monoclonal antibodies was dependent on the activity of H⁺-ATP synthase and several other enzymes involved in mast cell signaling but was independent of cell degranulation, free cytoplasmic calcium up-regulation, and a decrease in lipid packing as determined by merocyanine 540 binding. Surprisingly, disruption of actin cytoskeleton by latrunculin B or plasma membrane integrity by methyl--cyclodextrin had opposite effects on PS externalization triggered through GPI-AP or the high affinity IgE receptor. We further show that PS externalization mediated by GPI-APs was also observed in some other cells, and its extent varied with antibodies used. Interestingly, effects of different antibodies on PS externalization were additive, indicating that independent stimuli converge onto a signaling pathways leading to PS externalization. Our findings identify the cell surface PS exposure induced through GPI-AP as a distinct mechanism of cell signaling. Such a mechanism could contribute to "inside-out" signaling in response to pathogens and other external activators and/or to initiation of other functions associated with PS externalization.

Received for publication, December 4, 2006 , and in revised form, January 22, 2007.

^* This work was supported in part by Center of Molecular and Cellular Immunology Project 1M6837805001 and Grant LC545 from Ministry of Education, Youth, and Sports of the Czech Republic, Grant Agency of the Czech Republic Grant 301/06/0361, Grant Agency of the Academy of Sciences of the Czech Republic Grant IAA5052310, and Institutional Project AVOZ50520514. 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.

¹ To whom correspondence should be addressed: Dept. of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeská 1083, CZ 142 20 Prague 4, Czech Republic. Tel.: 420-241062468; Fax: 420-241062214; E-mail: draberpe{at}biomed.cas.cz.

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