Constitutive phosphorylation mutation in Fas-associated death domain (FADD) results in early cell cycle defects.

Fas-associated death domain (FADD) is an adaptor molecule for the death receptor subfamily of the tumor necrosis factor receptor superfamily, but it is also required for cell proliferation. Cell cycle-specific regulation of FADD phosphorylation plays an important role in FADD proliferative function since mice with a mutant form of FADD mimicking constitutive phosphorylation at serine 191 (FADD-D) exhibit defective T cell proliferation. Here we characterized these mice in detail and found that T cell development in 2-4-week-old mice is relatively normal, although mature FADD-D T cells manifest defective G(0) and G(1) to S transition with abnormalities in regulation of p130, p27 degradation, retinoblastoma protein phosphorylation, and CDK2 kinase activity. These downstream defects are further associated with the failure to up-regulate the forkhead box M1 cell cycle transcription factor, FoxM1. FADD-D protein is also mislocalized during cell cycle progression. Thus, regulation of FADD phosphorylation is crucial for proper cell cycle entry.