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Molecular and Cellular Biology, May 2003, p. 3623-3635, Vol. 23, No. 10
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.10.3623-3635.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

FAP-1 Association with Fas (Apo-1) Inhibits Fas Expression on the Cell Surface

Ruttenberg Cancer Center,¹ Department of Molecular and Developmental Biology, Mount Sinai School of Medicine, New York, New York 10029,³ Department of Pathology, Columbia University, New York, New York 10032²

Received 22 October 2002/ Returned for modification 11 December 2002/ Accepted 18 February 2003

As revealed by intracellular pools of nonactive Fas (Apo-1), export of Fas to the cell surface is often impaired in human tumors, thereby inactivating Fas ligand-mediated apoptosis. Here, we demonstrate that association with Fas-associated phosphatase 1 (FAP-1) attenuates Fas export to the cell surface. Forced expression of FAP-1 reduces cell surface Fas levels and increases the intracellular pool of Fas within the cytoskeleton network. Conversely, expression of dominant-negative forms of FAP-1, or inhibition of FAP-1 expression by short interfering RNA, efficiently up-regulates surface expression of Fas. Inhibition of Fas surface expression by FAP-1 depends on its association with the C terminus of Fas. Mutation within amino acid 275 results in decreased association with FAP-1 and greater export of Fas to the cell surface in melanomas, normal fibroblasts, or Fas null cells. Identifying the role of FAP-1 in binding to, and consequently inhibition of, Fas export to the cell surface provides novel insight into the mechanism underlying the regulation of Fas trafficking, which is commonly impaired in advanced tumors with FAP-1 overexpression.

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