  Tumor Necrosis Factor alpha (TNF) initiates a complex series of biochemical
events in the cell upon binding to its type R1 receptor (TNF-R1). Recent
experimental work has unravelled the molecular regulation of the recruitment of
initial signaling complexes that lead either to cell survival or death.
Survival signals are activated by direct binding of TNF to TNF-R1 at the cell
membrane whereas apoptotic signals by endocytosed TNF/TNF-R1 complexes. Here we
investigate these aspects by developing a quantitative mathematical model of
TNF binding, internalization and intracellular signaling. Model outputs compare
favorably with experimental data and allow to compute TNF-mediated cytotoxicity
as observed in different cell systems. We extensively study the space of
parameters to show that the model is structurally stable and robust over a
broad range of parameter values. Thus, our model is suitable for implementation
in multi-scale simulation programs that are presently under development to
study the behavior of large tumor cell populations.
