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Published on: June 15, 2017
Multiple ErbB-2/Neu Phosphorylation Sites Mediate Transformation through Distinct Effector Proteins.
D Dankort1, N Jeyabalan, N Jones
1Institute for Molecular Biology and Biotechnology, Departments of Biology and Pathology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
The Journal of Biological Chemistry
|August 14, 2001
Summary
Amplification of human epidermal growth factor receptor 2 (HER2/Neu) drives cancer. Specific autophosphorylation sites on HER2/Neu mediate transforming signals through distinct protein interactions, revealing new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Amplification of ErbB-2 (HER2/Neu) occurs in 20-30% of breast cancers, associated with poor prognosis.
- Previous studies identified four key autophosphorylation sites on HER2/Neu that independently mediate transforming signals.
- The transforming potential of these sites is linked to their association with adapter proteins like Grb2 and Shc.
Purpose of the Study:
- To confirm the specificity of interactions between HER2/Neu autophosphorylation sites and downstream signaling proteins.
- To elucidate the distinct effector pathways through which HER2/Neu mediates transformation.
Main Methods:
- Creation of second-site mutants in specific HER2/Neu autophosphorylation sites.
- Analysis of Grb2 and Shc adapter protein recruitment to mutated sites.
- Investigation of interactions with protein tyrosine-binding domain-containing proteins, including DOK-R.
Main Results:
- Grb2 recruitment to Tyr(1144) is essential for transformation mediated by this site.
- Shc-mediated transformation requires the NPXY motif encompassing Tyr(1227).
- DOK-R and other proteins interact with HER2/Neu at Tyr(1253), with p34 association correlating with transformation.
Conclusions:
- HER2/Neu mediates transformation through multiple, distinct effector pathways.
- Specific autophosphorylation sites on HER2/Neu engage different signaling molecules to drive cancer progression.
- Understanding these distinct pathways offers potential for targeted cancer therapies.
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