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Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation
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Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation
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Journal Article
Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation
2018
Overview
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.
Cellular ERK activation occurs as discrete pulses but their relationship to upstream Ras signaling is still under debate. Here, the authors show that Ras signaling associated with cellular protrusions triggers pulsed ERK activation, thereby enabling cells to integrate chemical and mechanical stimuli.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
1-Phosphatidylinositol 3-kinase
/ 14/10
/ 14/19
/ 14/33
/ 14/35
/ 14/63
/ 96/1
/ 96/109
/ 96/63
/ 96/95
/ Cancer
/ Cell Surface Extensions - metabolism
/ Extracellular signal-regulated kinase
/ Extracellular Signal-Regulated MAP Kinases - metabolism
/ Humanities and Social Sciences
/ Humans
/ Mechanotransduction, Cellular
/ Science
