Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.
Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.
Mahdavi
Alborz
A
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.
Davey
Ryan E
RE
Bhola
Patrick
P
Yin
Ting
T
Zandstra
Peter W
PW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003198:Computer Simulation; D050822:Cytokine Receptor gp130; D016207:Cytokines; D004789:Enzyme Activation / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000502:physiology; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*; D013997:Time Factors
D016207:Cytokines; D008024:Ligands; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130