Abstract
The transcription factor Myc plays a central role in regulating cell-fate decisions, including proliferation, growth, and apoptosis. To maintain a normal cell physiology, it is critical that the control of Myc dynamics is precisely orchestrated. Recent studies suggest that such control of Myc can be achieved at the post-translational level via protein stability modulation. Myc is regulated by two Ras effector pathways: the extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) pathways. To gain quantitative insight into Myc dynamics, we have developed a mathematical model to analyze post-translational regulation of Myc via sequential phosphorylation by Erk and PI3K. Our results suggest that Myc integrates Erk and PI3K signals to result in various cellular responses by differential stability control of Myc protein isoforms. Such signal integration confers a flexible dynamic range for the system output, governed by stability change. In addition, signal integration may require saturation of the input signals, leading to sensitive signal integration to the temporal features of the input signals, insensitive response to their amplitudes, and resistance to input fluctuations. We further propose that these characteristics of the protein stability control module in Myc may be commonly utilized in various cell types and classes of proteins.
Highlights
The proto-oncogene protein Myc is a transcription factor that regulates numerous signaling pathways involved in cell-fate decisions [1,2,3,4]
We aimed to investigate how signaling patterns of extracellular signal-regulated kinase (Erk) and phosphatidylinositol 3-kinase (PI3K) regulate Myc dynamics at the post-translational level
Our model defines a unique module that connects with other models that deal with upstream signaling dynamics leading to the activation of Erk [21] or PI3K [30,31], as well as downstream dynamics leading to mammalian cell fate decisions [32,33,34] We further propose that post-translation regulation of Myc represents an example of a generic dual-kinase motif
Summary
The proto-oncogene protein Myc is a transcription factor that regulates numerous signaling pathways involved in cell-fate decisions [1,2,3,4]. We aimed to investigate how signaling patterns of Erk and PI3K regulate Myc dynamics at the post-translational level.
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