The authors of the cover article for the August 2014 issue of Integrative Biology explore how extracellular signals are transmitted into the cells for the epidermal growth factor (EGF) pathway. In addition to shedding light on the complex nature of the EGFR pathway, this work provides insights that could be used to further understand mutations that cause cancerous cells to form. Signalling pathways, especially those involving growth factors, are often causes of the excessive growth and division rates of cancer cells
Extracellular signalling pathways are important for cell growth, division and death (apoptosis), but are difficult to study due to their transient nature and the presence of feedback loops. The epidermal growth factor (EGF) pathway also feeds into the MAPK signal cascade, so the quantitative responses of the cell to the initial signal is difficult to determine experimentally. Once the extracellular signal molecule (here EGF) binds to its receptor (EGFR), the cell acts on the signal, and then the original ligand is degraded. Further, the receptors themselves can be made and recycled during this process, adding another layer of complexity.
The researchers investigated the activation of the EGF receptor itself both experimentally and using a mathematical model (outlined in the paper). Using their mathematical model they predicted that the activation of EGFR (by phosphorylation) should be linearly related to the concentration of ligand EGF which binds to the cell. They then took serum starved cells, added varying concentrations of EGF and determined the amount of phosphorylated EGFR by high-throughput imaging of the immunofluorescence level. They determined that the activation level of the ligand was directly proportional to the ligand concentration, in agreement with the mathematical model.
The study also showed that the activation of EGFR does not depend on the receptor turnover rate, the ligand binding affinity or the number of receptors available. The methods reported here could be used to describe other extracellular signalling pathways in future, leading to a greater understanding of these complicated and crucial systems.
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Diego A. Oyarzun, Jo L. Bramhall, Fernando Lopez-Caamal, Frances M. Richards, Duncan I Jodrell, and Ben-Fillippo Krippendorff
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