Abstract
Cells rely on input from extracellular growth factors to control their proliferation during development and adult homeostasis. Such mitogenic inputs are transmitted through multiple signaling pathways that synergize to precisely regulate cell cycle entry and progression. Although the architecture of these signaling networks has been characterized in molecular detail, their relative contribution, especially at later cell cycle stages, remains largely unexplored. By combining quantitative time-resolved measurements of fluorescent reporters in untransformed human cells with targeted pharmacological inhibitors and statistical analysis, we quantify epidermal growth factor (EGF)-induced signal processing in individual cells over time and dissect the dynamic contribution of downstream pathways. We define signaling features that encode information about extracellular ligand concentrations and critical time windows for inducing cell cycle transitions. We show that both extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) activity are necessary for initial cell cycle entry, whereas only PI3K affects the duration of S phase at later stages of mitogenic signaling.
Highlights
Mammalian cells harbor complex, interlinked signal transduction networks that relay information from the outside of the cell to the inside
We define signaling features that encode information about extracellular ligand concentrations and critical time windows for inducing cell cycle transitions. We show that both extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) activity are necessary for initial cell cycle entry, whereas only PI3K affects the duration of S phase at later stages of mitogenic signaling
We define features of ERK activity that encode information about extracellular ligand concentration and determine the time window where it is necessary for cell cycle entry. We show that both ERK and PI3K activity are necessary for initial cell cycle entry, whereas only PI3K affects the duration of S phase at later stages of the mitogenic signaling
Summary
Mammalian cells harbor complex, interlinked signal transduction networks that relay information from the outside of the cell to the inside These networks allow cells to sense fine-grained information about their environment and control cellular physiology by regulating gene expression or influencing processes like cytoskeletal organization. Target genes of FOS, such as FRA1/ FOSL1, which is stabilized by ERK phosphorylation, will be induced only by prolonged activity of ERK (Marshall, 1995) In addition to this temporal encoding, information in the MAPK pathway may be encoded by the amplitude and duration of the signal (Heinrich et al, 2002) or other features like frequency and amplitude of oscillation in the localization of ERK (Shankaran et al, 2009). Other signaling-induced processes, such as expression and stabilization of c-myc, contribute to regulating the G1 to S phase transition (Leung et al, 2008)
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