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.

Details

Title
Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation
Author
Jr-Ming, Yang 1 ; Bhattacharya, Sayak 2   VIAFID ORCID Logo  ; West-Foyle, Hoku 3 ; Chien-Fu, Hung 4   VIAFID ORCID Logo  ; T-C, Wu 5   VIAFID ORCID Logo  ; Iglesias, Pablo A 6   VIAFID ORCID Logo  ; Huang, Chuan-Hsiang 1   VIAFID ORCID Logo 

1  Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA 
2  Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA 
3  Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD, USA 
4  Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA 
5  Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA 
6  Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD, USA 
Pages
1-13
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07150-9
ProQuest document ID
2130793189
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.