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

• Published in: Developmental cell 2020-09, Vol.54 (5), p.608-623.e5
• Main Authors: Zhan, Huiwang, Bhattacharya, Sayak, Cai, Huaqing, Iglesias, Pablo A., Huang, Chuan-Hsiang, Devreotes, Peter N.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Epithelial Cells - metabolism; ERK; excitability; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; oncogenic transformation; Phosphatidylinositol 3-Kinases - metabolism; PI(3,4)P2; PI(4,5)P2; PI3K; Proto-Oncogene Proteins c-akt - metabolism; Ras; ras Proteins - metabolism; Signal Transduction - genetics; Signal Transduction - physiology; threshold; wave
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.08.001

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. [Display omitted] •The Ras/PI3K/ERK network displays features of excitable systems in epithelial cells•Network perturbations can increase the wave activity and the frequency of ERK pulses•Wave activity is increased in transformed cells and increasingly metastatic cancer cells•Cancer progression is a shift to a lower threshold of the excitable signaling network Zhan et al., investigate the excitability of the Ras/PI3K/ERK signaling network. They demonstrate that activities propagate as coordinated waves on the cell cortex and delineate the molecular feedbacks that cause excitability. Transformed cells display more waves suggesting that cancer can be viewed as a low-threshold state of the network.