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J. Biol. Chem., Vol. 280, Issue 48, 40012-40024, December 2, 2005

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Binding of the Intracellular Fas Ligand (FasL) Domain to the Adaptor Protein PSTPIP Results in a Cytoplasmic Localization of FasL^*

Wiebke Baum1, Vladimir Kirkin, Sara B. Mateus Fernández, Robert Pick, Marcus Lettau, Ottmar Janssen, and Martin Zörnig2

From the Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, Frankfurt D-60596, Germany and Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Michaelisstrasse 5, Kiel D-24105, Germany

The tumor necrosis factor family member Fas ligand (FasL) induces apoptosis in Fas receptor-expressing target cells and is an important cytotoxic effector molecule used by CTL- and NK-cells. In these hematopoietic cells, newly synthesized FasL is stored in specialized secretory lysosomes and only delivered to the cell surface upon activation and target cell recognition. FasL contains an 80-amino acid-long cytoplasmic tail, which includes a proline-rich domain as a bona fide Src homology 3 domain-binding site. This proline-rich domain has been implicated in FasL sorting to secretory lysosomes, and it may also be important for reverse signaling via FasL, which has been described to influence T-cell activation. Here we report the identification of the Src homology 3 domain-containing adaptor protein PSTPIP as a FasL-interacting partner, which binds to the proline-rich domain. PSTPIP co-expression leads to an increased intracellular localization of Fas ligand, thereby regulating extracellular availability and cytotoxic activity of the molecule. In addition, we demonstrate recruitment of the tyrosine phosphatase PTP-PEST by PSTPIP into FasL·PSTPIP·PTP-PEST complexes which may contribute to FasL reverse signaling.

Received for publication, February 28, 2005 , and in revised form, September 2, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Zo 110/2-1/2 and a grant from the Heinrich und Erna Schaufler-Stiftung. 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 Present address: Institut für Normale und Pathologische Physiologie, Deutschhausstrasse 1-2, Marburg D-35037, Germany.

² To whom correspondence should be addressed. Tel.: 49-69-63395115; Fax: 49-69-63395297; E-mail: zoernig{at}em.uni-frankfurt.de.

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