A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis.
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-alpha and interleukin-1alpha, 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.
Janes
Kevin A
KA
Biological Engineering Division, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Albeck
John G
JG
Gaudet
Suzanne
S
Sorger
Peter K
PK
Lauffenburger
Douglas A
DA
Yaffe
Michael B
MB
D017209:Apoptosis; D019898:Autocrine Communication; D002470:Cell Survival; D016207:Cytokines / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016018:Least-Squares Analysis; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction; D049490:Systems Biology; D013598:Systems Theory; D016211:Transforming Growth Factor alpha / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases