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J. Biol. Chem., Vol. 283, Issue 16, 10904-10918, April 18, 2008

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Engagement of Phospholipid Scramblase 1 in Activated Cells

IMPLICATION FOR PHOSPHATIDYLSERINE EXTERNALIZATION AND EXOCYTOSIS^*

Daniel Smr, Pavel Lebduka, L'ubica Dráberová, Jan Korb, and Petr Dráber¹

From the Department of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, CZ 14220 Prague 4, Czech Republic

Phosphatidylserine (PS) in quiescent cells is predominantly confined to the inner leaflet of the plasma membrane. Externalization of PS is a marker of apoptosis, exocytosis, and some nonapoptotic activation events. It has been proposed that PS externalization is regulated by the activity of PLSCR1 (phospholipid scramblase 1), a Ca²⁺-dependent endofacial plasma membrane protein, which is tyrosine-phosphorylated in activated cells. It is, however, unclear how the phosphorylation of PLSCR1 is related to its membrane topography, PS externalization, and exocytosis. Using rat basophilic leukemia cells as a model, we show that nonapoptotic PS externalization induced through the high affinity IgE receptor (FcRI) or the glycosylphosphatidylinositol-anchored protein Thy-1 does not correlate with enhanced tyrosine phosphorylation of PLSCR1. In addition, PS externalization in FcRI- or Thy-1-activated cells is not associated with alterations of PLSCR1 fine topography as detected by electron microscopy on isolated plasma membrane sheets. In contrast, activation by calcium ionophore A23187 [GenBank] induces changes in the cellular distribution of PLSCR1. We also show for the first time that in pervanadate-activated cells, exocytosis occurs even in the absence of PS externalization. Finally, we document here that tyrosine-phosphorylated PLSCR1 is preferentially located in detergent-insoluble membranes, suggesting its involvement in the formation of membrane-bound signaling assemblies. The combined data indicate that changes in the topography of PLSCR1 and its tyrosine phosphorylation, PS externalization, and exocytosis are independent phenomena that could be distinguished by employing specific conditions of activation.

Received for publication, December 20, 2007 , and in revised form, February 7, 2008.

^* This work was supported by Center of Molecular and Cellular Immunology Project 1M0506 and LC-545 from the 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 1QS500520551; and Institutional Project AVOZ50520514 from the Academy of Sciences of the Czech Republic. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by an International Research Scholar's award from the Howard Hughes Medical Institute. To whom correspondence should be addressed: Dept. of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeská 1083, Prague 4, CZ 142 20, Czech Republic. Tel.: 420-241062468; Fax: 420-241062214; E-mail: draberpe{at}img.cas.cz.

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