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The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. liyarden@wiccmail.weizmann.ac.il
Abstract:
Extensive clinical and biochemical evidence implicates ErbB-2, a transmembrane tyrosine kinase related to growth factor receptors, in the development, metastasis, and resistance to therapy of multiple, common human carcinomas. Previous attempts to uncover an ErbB-2-specific ligand led to isolation of the neuregulin (NRG) family, but these ligands, like all other growth factors with an EGF-like motif, only indirectly active ErbB-2. On the other hand, biochemical and genetic evidence suggest a non-autonomous function of ErbB-2 in an interactive ErbB signaling network. Accordingly, the oncoprotein acts as a shared signaling subunit of primary growth factor receptors. By stabilizing heterodimers with other ErbB proteins, ErbB-2 prolongs and enhances signal transduction by a large group of stroma-derived growth factors. Furthermore, we have proposed a model in which all ErbB-2 ligands are bivalent and bind to ErbB-2 with low affinity, following high affinity binding to a primary receptor with which ErbB-2 is heterodimerized. Thus the presence of ErbB-2 in relevant ErbB heterodimeric structures on the surfaces of certain epithelial tumor cells can amplify signals arising from the binding of stromal ErbB ligands. This effect, in turn, may promote the growth of carcinoma cells.
Insights
ErbB-2, a key protein in carcinomas, amplifies growth signals by partnering with other receptors. This interaction, mediated by stromal ligands, promotes tumor cell growth and may drive cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- ErbB-2, a tyrosine kinase, is implicated in human carcinoma development, metastasis, and therapy resistance.
- Previous research identified neuregulin (NRG) as an ErbB-2 ligand, but it indirectly activates ErbB-2.
- ErbB-2 functions non-autonomously within a complex ErbB signaling network.
Purpose of the Study:
- To elucidate the non-autonomous role of ErbB-2 in carcinoma signaling.
- To propose a model for ErbB-2 ligand binding and signal amplification.
Main Methods:
- Biochemical and genetic evidence analysis.
- Review of existing clinical and biochemical data on ErbB-2 function.
- Development of a theoretical model for ErbB-2 ligand interactions.
Main Results:
- ErbB-2 acts as a shared signaling subunit, stabilizing heterodimers with other ErbB proteins.
- ErbB-2 prolongs and enhances signal transduction from stroma-derived growth factors.
- A model is proposed where bivalent ErbB-2 ligands bind with low affinity to ErbB-2 after high-affinity binding to a primary receptor.
Conclusions:
- ErbB-2 amplifies signals from stromal ligands by forming heterodimers on tumor cells.
- This signal amplification mediated by ErbB-2 may promote carcinoma cell growth.