![]() Dong et al., “ Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor,” Cell Biol. Hiratsuka, “ Propagating wave of ERK activation orients collective cell migration article propagating wave of ERK activation orients collective cell migration,” Dev. Lauffenburger, “ Receptor-mediated effects on ligand availability influence relative mitbgenic potencies of epidermal growth factor and transforming growth factor a,” J. Kreeger, “ Analysis of the quantitative balance between insulin-like growth factor (IGF)−1 ligand, receptor, and binding protein levels to predict cell sensitivity and therapeutic efficacy,” BMC Syst. Voldman, “ Microfluidic perfusion for regulating diffusible signaling in stem cells,” PLoS One 6, e22892 (2011). Wang et al., “ Shear stress regulation of endothelial glycocalyx structure is determined by glucobiosynthesis,” Arterioscler. Abràmoff, “ Image processing with ImageJ,” Biophotonics Int. Werb, “ Lentiviral transduction of mammary stem cells for analysis of gene function during development and cancer,” Cell Stem Cell 2, 90– 102 (2008). Kreeger, “ Design and implementation of a microfluidic device capable of temporal growth factor delivery reveal filtering capabilities of the EGFR/ERK pathway,” APL Bioeng. Davies et al., “ Systems-level properties of EGFR-RAS-ERK signaling amplify local signals to generate dynamic gene expression heterogeneity,” Cell Syst. Brugge, “ Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals,” Mol. Ryu et al., “ Frequency modulation of ERK activation dynamics rewires cell fate,” Mol. Clark, and Regot, “ MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression,” eLife 9, e60541 (2020). Harvey et al., “ A genetically encoded fluorescent sensor of ERK activity,” Proc. Covert, “ High-sensitivity measurements of multiple kinase activities in live single cells,” Cell 157, 1724– 1734 (2015). Griffith, “ Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells,” J. Masters, “ Immobilized epidermal growth factor stimulates persistent, directed keratinocyte migration via activation of PLCγ1,” FASEB J. Lauffenburger, “ RAS mutations impact TNF-induced apoptosis in colon carcinoma cells via ERK-modulatory negative and positive feedback circuits along with non-ERK pathway effects,” Cancer Res. Shi et al., “ Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway,” Sci. Wolf-Yadlin et al., “ Effects of HER 2 overexpression on cell signaling networks governing proliferation and migration,” Mol. Muta et al., “ Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine,” Nat. Rodland et al., “ Multiple mechanisms are responsible for transactivation of the epidermal growth factor receptor in mammary epithelial cells,” J. Keyes et al., “ Signaling diversity enabled by Rap1-regulated plasma membrane ERK with distinct temporal dynamics,” eLife 9, e57410 (2020). Wan, “ EGF-induced cell migration is mediated by ERK and PI 3K/AKT pathways in cultured human lens epithelial cells,” J. Lauffenburger, “ Parsing ERK activation reveals quantitatively equivalent HER 2 in human mammary epithelial cells,” J. Our results demonstrate that context impacts ERK dynamics and that comparison of distinct contexts can be used to elucidate new aspects of the cell signaling network. Through experimental analysis we identified growth differentiation factor-15 as a candidate factor that led to extended ERK activation through a protein kinase C-α/β dependent pathway. The activity in microfluidic culture resembled that of the control condition, suggesting that shear stress led to the early activity and a loss of autocrine factors dampened extended signaling. ![]() ![]() Using a single-cell ERK kinase translocation reporter, we observed extended ERK activation in well culture and only transient activity in microfluidic culture. Here, we compared extracellular-regulated kinase (ERK) signaling in response to epidermal growth factor treatment of human mammary epithelial cells cultures in either well culture or a microfluidic device. These signaling patterns are also impacted by the larger context that the cell experiences (i.e., stimuli such as media formulation or substrate stiffness that are constant in an experiment exploring a particular variable but may differ between independent experiments which explore that variable) although the reason for different dynamics is not always obvious. Cellular signaling dynamics are sensitive to differences in ligand identity, levels, and temporal patterns. ![]()
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