Programmed cell death plays an important role in a variety of physiological processes and its dysregulation contributes to many human diseases, including cancer, stroke, and autoimmunity. Fas/APO-1 (CD95), which is a member of tumor necrosis factor (TNF) receptor family, is a cell surface protein that triggers apoptosis and is expressed on activated cytolytic T-cells and various types of human cells including solid tumors of the breast, ovary, colon, prostate, liver, and kidney. Genetic defects that lead to loss of function of Fas or its ligand are responsible for autoimmune disease and a lymphoproliferative disorder in lpr/lpr and gld/gld mice. Furthermore, altered Fas protein production has been associated with Systemic Lupus Erythematosus (SLE) in humans. Recently we cloned Fas-associated proteins using a yeast two-hybrid approach and identified a protein tyrosine phosphatase (PTPase), which we have termed Fas-associated phosphatase-1 (FAP-1). The FAP-1 protein was biochemically confirmed to bind to the cytosolic tail of Fas but not to other members of the TNFR family. Control of protein phosphorylation on tyrosines is an important mechanism for the regulation of cellular proliferation, differentiation, and cell death. The physiological function of FAP-1 will be explored by: (i) gene transfer-mediated modulations of FAP-1 levels in cultured cells in vitro; (ii) testing the function of mutants of Fas and FAP-1 that fail to interact; (iii) biochemical studies of the effects of Fas-triggering on enzymatic activity of this PTPase. (iv) biochemical studies of ceramide production through the sphingomyelinase (SMase) pathways to determine where FAP-1 modulates this Fas-induced event associated with apoptosis-induction; and (v) production of FAP-1 knock-out mice to examine FAP-1 function in vivo. Taken together, these investigations of FAP-1 will improve understanding of the signal transduction pathways through which Fas controls apoptosis and could ultimately provide insights leading to improved treatments for cancer and autoimmune diseases.
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