Differential ErbB receptor dimerization modulates the ability of EGF receptor ligands to regulate metabolic flux

Abstract The EGF receptor tyrosine kinase binds seven different agonist ligands. EGF stimulates proliferation of MCF-7 cells while EPG 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 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 TCA 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 non-oxidative 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, BTC, EPR, and EPG 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.