Related Experiment Videos
Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3
C Wallasch1, F U Weiss, G Niederfellner
1Department of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Abstract:
Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development of cancer in humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed in tumor-derived cell lines and that heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism for signal definition, diversification or amplification. In cells expressing HER2 and HER3, tyrosine phosphorylation of HER3 is markedly increased upon exposure to recombinant HRG. ATP binding site mutants of HER2 and HER3 demonstrate transphosphorylation of HER3 by HER2, but not vice versa. HRG-induced transphosphorylation of HER3 results in a substrate phosphorylation pattern distinct from HER2 cells and enhances association of the receptor with SHC and phosphoinositol 3-kinase in transfected 293 and mammary carcinoma-derived MCF-7 cells. The physiological relevance of HER2/HER3 heterodimerization is demonstrated by HRG-dependent transformation of NIH 3T3 cells coexpressing the two receptors. These findings demonstrate the acquisition of expanded signaling capacities for HER2 by HRG-induced heterodimerization with HER3 and provide a molecular basis for the involvement of receptor heteroactivation in the development of human malignancies.
Insights
The study reveals how HER2 and HER3 receptor tyrosine kinases form heterodimers, amplifying cancer-driving signals upon binding heregulin. This interaction provides a molecular basis for receptor heteroactivation in human malignancies.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Amplification and overexpression of HER2/neu and HER3 genes are linked to human cancer development.
- Coexpression of these receptor tyrosine kinases (RTKs) in tumor cells suggests a role in signal regulation.
- Heterodimerization of HER2 and HER3 forms high-affinity binding sites for heregulin (HRG).
Purpose of the Study:
- To investigate the mechanism of signal definition, diversification, and amplification mediated by HER2/HER3 heterodimers.
- To elucidate the role of heregulin (HRG) in activating HER2/HER3 signaling pathways.
- To establish the physiological relevance of HER2/HER3 heterodimerization in cancer development.
Main Methods:
- Utilized ATP binding site mutants of HER2 and HER3 to study transphosphorylation.
- Assessed tyrosine phosphorylation of HER3 upon exposure to recombinant HRG in cells coexpressing HER2 and HER3.
- Investigated HRG-induced association of receptors with SHC and phosphoinositol 3-kinase (PI3K) in transfected cells.
- Examined HRG-dependent transformation of NIH 3T3 cells coexpressing HER2 and HER3.
Main Results:
- Recombinant HRG markedly increased tyrosine phosphorylation of HER3 in cells expressing both HER2 and HER3.
- HER2, but not HER3, demonstrated transphosphorylation activity in ATP binding site mutants.
- HRG-induced HER3 transphosphorylation led to distinct substrate phosphorylation patterns and enhanced association with SHC and PI3K.
- Coexpression of HER2 and HER3 enabled HRG-dependent transformation of NIH 3T3 cells.
Conclusions:
- HRG-induced heterodimerization of HER2 with HER3 expands HER2 signaling capacities.
- This receptor heteroactivation provides a molecular mechanism for the involvement of HER2/HER3 in human malignancies.
- The findings highlight the significance of RTK heterodimerization in cancer progression.