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Published on: September 19, 2018
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Quantitative analysis of receptor tyrosine kinase-effector coupling at functionally relevant stimulus levels
Simin Li1, Devayani Bhave1, Jennifer M Chow1
1From the Department of Chemistry, Boston University, Boston, Massachusetts 02215.
The Journal of Biological Chemistry
|January 31, 2015
Summary
Low concentrations of artemin (ART) optimize RET receptor tyrosine kinase signaling to ERK and Akt pathways, crucial for cell growth. High growth factor levels can distort understanding of these vital cellular communication processes.
Area of Science:
- Cellular signaling
- Receptor tyrosine kinases
- Neurotrophin signaling
Background:
- Understanding receptor tyrosine kinase (RTK) activation and downstream signaling is key to cell function.
- Quantitative analysis of receptor-effector coupling is needed for a complete picture of cellular responses.
Purpose of the Study:
- To quantitatively measure the coupling efficiency between RET receptor tyrosine kinase activation and downstream signaling pathways (ERK, Akt).
- To investigate the impact of artemin (ART) concentration on RET signaling dynamics and pathway discrimination.
Main Methods:
- Utilized mouse neuroblastoma cells expressing the RET receptor tyrosine kinase.
- Measured RET activation and downstream effector phosphorylation (pERK, pAkt) at varying ART concentrations using quantitative methods.
- Performed kinetic experiments to analyze signaling dynamics and pathway response times.
Main Results:
- RET coupling efficiency to ERK and Akt is highest at low ART concentrations (~100 pM), coinciding with optimal neurite outgrowth.
- Quantitative discrimination between ERK and Akt signaling is also maximal at low ART levels.
- Super-physiological ART concentrations yielded misleading quantitative signaling data.
- Signaling pathways exhibit distinct lag times, leading to dynamic shifts in signal flux over time.
Conclusions:
- Low physiological concentrations of growth factors are critical for accurate quantitative assessment of receptor signaling.
- Receptor-effector coupling efficiency modulates signal amplification and sensitization, influencing cellular outcomes.
- A quantitative model of receptor-effector coupling provides insights into signal decoding for functional cellular responses.
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