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Related Experiment Video

Updated: Jul 25, 2026

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

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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.

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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.