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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Differential ErbB receptor dimerization modulates the ability of EGF receptor ligands to regulate metabolic flux
Jennifer Macdonald-Obermann1, Kevin Cho2, Gary J Patti2
1Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Missouri, USA.
Abstract:
The epidermal growth factor (EGF) receptor tyrosine kinase binds seven different agonist ligands. It stimulates proliferation of MCF-7 cells while epigen and EPR, stimulate differentiation. This distinction is thought to be due to the phenomenon of ligand bias in which two agonists bind to the same receptor but generate different responses. These reported differences among EGFR ligands led us to examine their effects plus those of neureglin 2ß (NRG-2ß), an ErbB3-ErbB4 ligand, on metabolism in MCF-7 cells and MDA-MB-468 cells. We followed the flux of carbons from either [1,2-13C]-glucose or [U-13C]-glutamine through the early pathways of intermediary metabolism. EGF stimulated flux through glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid cycle in both lines. However, MCF-7 cells channeled ribose from the PPP into nucleotide biosynthesis whereas MDA-MB-468 cells recycled the riboses through the nonoxidative pathway of the PPP back into glycolysis. In MDA-MB-468 cells, all EGF receptor ligands induced a similar level of metabolic flux while NRG-2ß was inactive. By contrast, in MCF-7 cells, NRG-2ß, betacellulin, EPR, and epigen were significantly more effective at stimulating metabolic flux than the other EGF receptor ligands. Thus, bias was apparent in MCF-7 cells but not in MD-MB-468 cells. As the two lines express different complements of ErbB family receptors, we speculate that the differences in response are the result of different ligands preferentially inducing specific homodimer or heterodimer pairings. Our findings highlight the need to consider the possibility of system bias in cells when interpreting data related to ligand bias.
Insights
Ligand bias in the Epidermal Growth Factor Receptor (EGFR) pathway affects cellular metabolism differently in MCF-7 and MDA-MB-468 cells. This highlights the importance of considering system bias in cancer research.
Area of Science:
- Cellular metabolism
- Receptor tyrosine kinases
- Cancer biology
Background:
- Epidermal Growth Factor Receptor (EGFR) ligands exhibit functional differences, including stimulation of proliferation or differentiation.
- Ligand bias, where agonists bind the same receptor but elicit distinct cellular responses, is a key phenomenon.
- Understanding ligand bias in EGFR signaling is crucial for cancer research.
Purpose of the Study:
- To investigate the metabolic effects of various EGFR ligands and NRG-2ß in MCF-7 and MDA-MB-468 cells.
- To determine if ligand bias influences metabolic flux pathways, including glycolysis, pentose phosphate pathway (PPP), and TCA cycle.
- To explore the role of ErbB receptor expression in differential cellular responses to ligands.
Main Methods:
- Utilized stable isotope tracing with [1,2-13C]-glucose and [U-13C]-glutamine to follow metabolic carbon flux.
- Analyzed metabolic pathways in MCF-7 and MDA-MB-468 cell lines under stimulation by EGF receptor ligands and NRG-2ß.
- Compared metabolic flux patterns and ribose utilization between the two cell lines.
Main Results:
- EGF stimulated glycolysis, PPP, and TCA cycle flux in both cell lines.
- MCF-7 cells channeled PPP-derived ribose into nucleotide biosynthesis, while MDA-MB-468 cells recycled it into glycolysis.
- Ligand bias was observed in MCF-7 cells, with NRG-2ß, BTC, EPR, and EPG being more potent metabolic stimulators, whereas MDA-MB-468 cells showed similar responses to most ligands, with NRG-2ß being inactive.
Conclusions:
- Cellular responses to EGFR ligands are dependent on the specific cell type and its complement of ErbB receptors.
- System bias, influenced by receptor dimerization (homo- or heterodimers), plays a significant role in differential ligand responses.
- Findings emphasize the need to account for cellular system bias when interpreting data on ligand bias in cancer studies.
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