A Systems Model of Signaling Identifies a Molecular Basis Set for Cytokine-Induced Apoptosis

TLDR

Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7,980 intracellular signaling events that directly links measurements to 1,440 response outputs associated with apoptosis. The model accurately predicted time‑dependent apoptotic responses to TNF combined with EGF and insulin, revealed unsuspected autocrine circuits involving TGF‑α and IL‑1α, and identified two fundamental molecular basis axes that capture the entire apoptotic network, indicating that cell survival is governed by signaling through this canonical basis set.

Abstract

Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7980 intracellular signaling events that directly links measurements to 1440 response outputs associated with apoptosis. The model accurately predicted multiple time-dependent apoptotic responses induced by a combination of the death-inducing cytokine tumor necrosis factor with the prosurvival factors epidermal growth factor and insulin. By capturing the role of unsuspected autocrine circuits activated by transforming growth factor–α and interleukin-1α, the model revealed new molecular mechanisms connecting signaling to apoptosis. The model derived two groupings of intracellular signals that constitute fundamental dimensions (molecular “basis axes”) within the apoptotic signaling network. Projection along these axes captures the entire measured apoptotic network, suggesting that cell survival is determined by signaling through this canonical basis set.