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

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

  • Dev Cell. 2020 Sep 14;54(5):608-623.e5. doi: 10.1016/j.devcel.2020.08.001.
Huiwang Zhan 1,  Sayak Bhattacharya 2,  Huaqing Cai 3,  Pablo A Iglesias 4,  Chuan-Hsiang Huang 5,  Peter N Devreotes 6
Affiliations

Affiliations

  • 1 Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  • 2 Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 3 National Laboratory of Biomacromolecules, Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 5 Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: [email protected].
  • 6 Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: [email protected].
PMID: 32877650 DOI: 10.1016/j.devcel.2020.08.001
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.

Keywords

ERK; PI(3,4)P2; PI(4,5)P2; PI3K; Ras; excitability; oncogenic transformation; threshold; wave.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15816
    99.95%, ERK1/2 Inhibitor
    ERK