Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation

Jr-Ming Yang, Sayak Bhattacharya, Hoku West-Foyle, Chien-Fu Hung, T.-C. Wu, Pablo A. Iglesias and Chuan-Hsiang Huang ()
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Jr-Ming Yang: Johns Hopkins Medical Institutions
Sayak Bhattacharya: Whiting School of Engineering, Johns Hopkins University
Hoku West-Foyle: Johns Hopkins School of Medicine
Chien-Fu Hung: Johns Hopkins Medical Institutions
T.-C. Wu: Johns Hopkins Medical Institutions
Pablo A. Iglesias: Whiting School of Engineering, Johns Hopkins University
Chuan-Hsiang Huang: Johns Hopkins Medical Institutions

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07150-9

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