HER/ErbB receptor interactions and signaling patterns in human mammary epithelial cells
Yi Zhang,Yi Zhang,Lee K. Opresko,Harish Shankaran,William B. Chrisler,H. Steven Wiley,Haluk Resat +6 more
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TLDR
The 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, and shows that clone cell libraries can be a powerful resource in systems biology research.Abstract:
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. 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. 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.read more
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Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.
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TL;DR: In this article, the authors investigated the genomic and transcriptomic landscapes of 36 brain metastases from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome-and RNA-sequencing.
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erbB3 Is an Active Tyrosine Kinase Capable of Homo- and Heterointeractions
Mara P. Steinkamp,Shalini T. Low-Nam,Shujie Yang,Keith A. Lidke,Diane S. Lidke,Bridget S. Wilson +5 more
TL;DR: Heregulin stimulation is shown to markedly upregulate kinase activity in erbB3 immunoprecipitates, and a model in which transient erBB3/erbB2 heterointeractions set the stage for erb B3 homodimers to be signaling competent is tested.
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Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines
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TL;DR: Mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment are suggested.
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