An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2020 Sep 3

PMID 32877650

Citations 36

Authors

Huiwang Zhan

Sayak Bhattacharya

Huaqing Cai

Pablo A Iglesias

Chuan-Hsiang Huang

Peter N Devreotes

Affiliations

Soon will be listed here.

Abstract

The Ras/PI3K/extracellular signal-regulated kinases (ERK) signaling network plays fundamental roles in cell growth, survival, and migration and is frequently activated in cancer. Here, we show that the activities of the signaling network propagate as coordinated waves, biased by growth factor, which drive actin-based protrusions in human epithelial cells. The network exhibits hallmarks of biochemical excitability: the annihilation of oppositely directed waves, all-or-none responsiveness, and refractoriness. Abrupt perturbations to Ras, PI(4,5)P2, PI(3,4)P2, ERK, and TORC2 alter the threshold, observations that define positive and negative feedback loops within the network. Oncogenic transformation dramatically increases the wave activity, the frequency of ERK pulses, and the sensitivity to EGF stimuli. Wave activity was progressively enhanced across a series of increasingly metastatic breast cancer cell lines. The view that oncogenic transformation is a shift to a lower threshold of excitable Ras/PI3K/ERK network, caused by various combinations of genetic insults, can facilitate the assessment of cancer severity and effectiveness of interventions.

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Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration.

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Editorial: Self-organizing and excitable signaling networks in cell biology.

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