Abstract
The Ras-ERK signaling pathway regulates diverse cellular processes in response to environmental stimuli and contains important therapeutic targets for cancer. Recent single cell studies revealed stochastic pulses of ERK activation, the frequency of which determines functional outcomes such as cell proliferation. Here we show that ERK pulses are initiated by localized protrusive activities. Chemically and optogenetically induced protrusions trigger ERK activation through various entry points into the feedback loop involving Ras, PI3K, the cytoskeleton, and cellular adhesion. The excitability of the protrusive signaling network drives stochastic ERK activation in unstimulated cells and oscillations upon growth factor stimulation. Importantly, protrusions allow cells to sense combined signals from substrate stiffness and the growth factor. Thus, by uncovering the basis of ERK pulse generation we demonstrate how signals involved in cell growth and differentiation are regulated by dynamic protrusions that integrate chemical and mechanical inputs from the environment.
Highlights
The cellular responses to complex environmental stimuli are governed by the spatiotemporal dynamics of signaling networks[4]
To detect Ras and PI3K activation, we used fluorescent protein (FP)-tagged RBD (Ras-binding domain) and PH-AKT (PH domain from AKT), which are recruited to the membrane upon Ras and PI3K activation, respectively
Total internal reflection fluorescence (TIRF) images revealed that RBD and PH-AKT signals, normalized to that of a membrane marker Lyn, were elevated in large protrusions (Supplementary Figure 1c-d, Supplementary Movie 1, 2)
Summary
The cellular responses to complex environmental stimuli are governed by the spatiotemporal dynamics of signaling networks[4]. Ras-PI3K signaling activities propagate as traveling waves on the membrane to drive the actin-based cytoskeleton during protrusion formation[13,14,15,16,17,18,19,20]. These waves reflect an underlying excitability of the Ras-PI3K signaling network, which is characterized by all-or-none activation and the existence of a refractory period upon repeated stimulation. The protrusions allow cells to integrate chemical and mechanical stimuli from the environment in the regulation of ERK signaling
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