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The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin
R Pinkas-Kramarski1, A E Lenferink, S S Bacus
1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Abstract:
The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor alpha (TGFalpha). The functional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFalpha, we identified the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.
Insights
Epidermal growth factor (EGF) can trigger cell growth via the ErbB-3/ErbB-2 receptor complex, independent of ErbB-1. This finding reveals a novel signaling pathway for EGF and betacellulin, with implications for cancer development.
Area of Science:
- Cellular biology
- Molecular oncology
- Signal transduction
Background:
- The ErbB receptor family plays crucial roles in cell growth and differentiation.
- ErbB-2 is known to partner with other ErbB receptors, but its specific role with ligand-bound complexes was unclear.
- Epidermal growth factor (EGF) typically signals through ErbB-1.
Purpose of the Study:
- To investigate novel signaling pathways for epidermal growth factor (EGF).
- To identify the specific ErbB receptor complex mediating EGF and betacellulin activity.
- To understand the mechanism of EGF-induced cell growth and differentiation independent of ErbB-1.
Main Methods:
- Co-expression of ErbB-3 and ErbB-2 receptors.
- Site-specific antibody blocking experiments.
- Analysis of chimeric growth factor constructs (EGF and TGFalpha).
Main Results:
- EGF and betacellulin induce cell growth and differentiation through an ErbB-3/ErbB-2 heterodimer, even without ErbB-1.
- Neither ErbB-3 nor ErbB-2 alone can mediate EGF signaling; strict cooperativity is required.
- The middle portion (loop B) of EGF is critical for activating the ErbB-2/ErbB-3 complex.
Conclusions:
- The ErbB-2/ErbB-3 heterodimer mediates EGF and betacellulin signaling, expanding known ErbB receptor functions.
- This cooperative signaling mechanism highlights the potential involvement of the ErbB-2/ErbB-3 complex in cancer development.
- The findings offer insights into receptor dimerization mechanisms and ligand-receptor interactions.