Portal de Periódicos da CAPES

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

2018; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41467-018-07150-9

2041-1723

Jr-Ming Yang, Sayak Bhattacharya, Hoku West‐Foyle, Chien‐Fu Hung, T.‐C. Wu, Pablo A. Iglesias, Chuan‐Hsiang Huang,

thermodynamics and calorimetric analyses

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.