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A Systems Model of Signaling Identifies a Molecular Basis Set for Cytokine-Induced Apoptosis
Kevin A. Janes,1,2*John G. Albeck,2,3*Suzanne Gaudet,2,3Peter K. Sorger,1,2,3Douglas A. Lauffenburger,1,2,3Michael B. Yaffe1,2,3
Signal transduction pathways control cellular responses to stimuli,but it is unclear how molecular information is processed asa network. We constructed a systems model of 7980 intracellularsignaling events that directly links measurements to 1440 responseoutputs associated with apoptosis. The model accurately predictedmultiple time-dependent apoptotic responses induced by a combinationof the death-inducing cytokine tumor necrosis factor with theprosurvival factors epidermal growth factor and insulin. Bycapturing the role of unsuspected autocrine circuits activatedby transforming growth factor– and interleukin-1, themodel revealed new molecular mechanisms connecting signalingto apoptosis. The model derived two groupings of intracellularsignals that constitute fundamental dimensions (molecular "basisaxes") within the apoptotic signaling network. Projection alongthese axes captures the entire measured apoptotic network, suggestingthat cell survival is determined by signaling through this canonicalbasis set.
1 Biological Engineering Division, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 2 Center for Cell Decision Processes, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 3 Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: myaffe{at}mit.edu
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and interleukin-1
To whom correspondence should be addressed. E-mail: 
