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

Huiwang Zhan, Sayak Bhattacharya, Huaqing Cai, Pablo A. Iglesias, Chuan Hsiang Huang, Peter N. Devreotes

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)608-623.e5
JournalDevelopmental Cell
Volume54
Issue number5
DOIs
StatePublished - Sep 14 2020

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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