FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.
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.
Ruttenberg Cancer Center, Department of Molecular and Developmental Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
Vladimir N
VN
Ivanov
Pablo
P
Lopez Bergami
Gabriel
G
Maulit
Taka-Aki
TA
Sato
David
D
Sassoon
Ze'ev
Z
Ronai
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism*; D002469:Cell Separation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005799:Genes, Dominant; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D002352:Carrier Proteins; D008024:Ligands; D008164:Luminescent Proteins; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D012313:RNA; D054645:Protein Phosphatase 1; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases; C516743:Ptpn13 protein, mouse; D001616:beta-Galactosidase