Cell cycle effects by C-FADD depend on its C-terminal phosphorylation site

Expression of a truncated form of the death receptor adaptor FADD (C-FADD) as a transgene in mice blocks T cell proliferation. Here we provide evidence that the C-terminal phosphorylation site Ser(19)4 in C-FADD affects the cell cycle in nonlymphoid cells as well. High expression of wild type C-FADD but not C-FADD with a S194A point mutation arrested the nontumor cell line MCF10A in G(2)/M but not the tumor cell line MCF7. BJAB as well as MCF10A cells expressing moderate levels of C-FADD with a S194E mutation mimicking phosphorylated C-FADD were more susceptible to a Taxol(R)-induced G(2)/M arrest than cells expressing C-FADD S194A suggesting that C-FADD S194E lowers the threshold for G(2)/M arrest. Our data suggest that C-FADD may affect apoptosis sensitivity of cells by interfering with cell cycle progression and not only by binding to death receptors.