HER/ErbB receptor interactions and signaling patterns in human mammary epithelial cells
Open Access
- 31 October 2009
- journal article
- Published by Springer Science and Business Media LLC in BMC Cell Biology
- Vol. 10 (1), 78
- https://doi.org/10.1186/1471-2121-10-78
Abstract
Background: Knowledge about signaling pathways is typically compiled based on data gathered using different cell lines. This approach implicitly assumes that the cell line dependence is not important. However, different cell lines do not always respond to a particular stimulus in the same way, and lack of coherent data collected from closely related cellular systems can be detrimental to the efforts to understand the regulation of biological processes. To address this issue, we created a clone library of human mammary epithelial (HME) cells that expresses different levels of HER2 and HER3 receptors in combination with endogenous EGFR/HER1. Using our clone library, we have quantified the receptor activation patterns and systematically tested the validity of the existing hypotheses about the interaction patterns between HER1-3 receptors.Results: Our study identified HER2 as the dominant dimerization partner for both EGFR and HER3. Contrary to earlier suggestions, we find that lateral interactions with HER2 do not lead to strong transactivation between EGFR and HER3, i.e., EGFR activation and HER3 activation are only weakly linked in HME cells. We also find that observed weak transactivation is uni-directional where stimulation of EGFR leads to HER3 activation whereas HER3 stimulation does not activate the EGFR. Repeating our experiments at lower cell confluency established that cell confluency is not a major factor in the observed interaction patterns. We have also quantified the dependence of the kinetics of Erk and Akt activation on different HER receptors. We found that HER3 signaling makes the strongest contribution to Akt activation and that, stimulation of either EGFR or HER3 leads to significant Erk activation.Conclusion: Our study shows that clone cell libraries can be a powerful resource in systems biology research by making it possible to differentiate between various hypotheses in a consistent cellular background. Using our constructed clone library we profiled the cell signaling patterns to establish the role of HER2 in the crosstalk between EGFR and HER3 receptors in HME cells. Our results for HME cells show that the weak linkage between EGFR and HER3 pathways can lead to distinct downstream cellular signaling patterns in response to the ligands of these two receptors.Keywords
This publication has 64 references indexed in Scilit:
- Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic dataMolecular Systems Biology, 2009
- Quantifying the effects of co-expressing EGFR and HER2 on HER activation and traffickingBiochemical and Biophysical Research Communications, 2008
- Differential binding patterns of monoclonal antibody 2C4 to the ErbB3–p185her2/neu and the EGFR–p185her2/neu complexesOncogene, 2008
- Differential regulation and properties of MAPKsOncogene, 2007
- Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3Nature, 2007
- Ligand‐dependent responses of the ErbB signaling network: experimental and modeling analysesMolecular Systems Biology, 2007
- Phosphotyrosine interactome of the ErbB‐receptor kinase familyMolecular Systems Biology, 2005
- Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complexCancer Cell, 2004
- Expression of the HER1–4 family of receptor tyrosine kinases in breast cancerThe Journal of Pathology, 2003
- The ErbB receptors and their role in cancer progressionExperimental Cell Research, 2003