An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells
| Autor: | Huaqing Cai, Sayak Bhattacharya, Huiwang Zhan, Peter N. Devreotes, Chuan Hsiang Huang, Pablo A. Iglesias |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
MAPK/ERK pathway
Carcinogenesis medicine.medical_treatment Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Line Tumor medicine Extracellular Humans Extracellular Signal-Regulated MAP Kinases Molecular Biology Actin PI3K/AKT/mTOR pathway 030304 developmental biology 0303 health sciences Kinase Growth factor Cancer Epithelial Cells Cell Biology medicine.disease Actins Cell biology Cell Transformation Neoplastic Cell culture ras Proteins Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Developmental Biology Signal Transduction |
| Zdroj: | Dev Cell |
| ISSN: | 1878-1551 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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