Capturing cell-fate decisions from the molecular signatures of a receptor-dependent signaling response

Abstract

We examined responses of the B-cell antigen receptor-dependent intracellular signaling network to targeted perturbations induced through siRNA-mediated depletion of select signaling intermediates. The constituent nodes displayed graded sensitivities, which resulted from the differential effects of perturbations on the kinetic and quantitative aspects of phosphorylation at each node. By taking the rate of initial phosphorylation, rate of subsequent dephosphorylation, and the total intensity of phosphorylation at each node as separate signaling parameters, we generated data-driven models that accurately predicted the cellular responses of apoptosis, proliferation, and cytokine secretion. Importantly, the effects of perturbation on the primary target alone did not yield successful models. Rather, it also required incorporation of secondary effects on many other nodes. A significant feature of these models was that the three signaling parameters derived from each node functioned largely as independent entities, making distinctive contributions to the cellular response. Thus, the kinetic and quantitative features of phosphorylation at a node appear to play discrete roles during signal processing.