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Oncogenic activation of the neu-encoded receptor protein by point mutation and deletion
1Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 01242.
Abstract:
The rat neu gene, which encodes a receptor-like protein homologous to the epidermal growth factor receptor, is frequently activated by a point mutation altering a valine residue to a glutamic acid residue in its predicted transmembrane domain. Additional point mutations have been constructed in a normal neu cDNA at and around amino acid position 664, the site of the naturally arising mutation. A mutation which causes a substitution of a glutamine residue for the normal valine at residue 664 leads to full oncogenic activation of the neu gene, but five other substitutions do not. Substituted glutamic acid residues at amino acid positions 663 or 665 do not activate the neu gene. Thus only a few specific residues at amino acid residue 664 can activate the oncogenic potential of the neu gene. Deletion of sequences of the transforming neu gene demonstrates that no more than 420 amino acids of the 1260 encoded by the gene are required for full transforming function. Mutagenesis of the transforming clone demonstrates a correlation between transforming activity and tyrosine kinase activity. These data indicate that the activating point mutation induces transformation through (or together with) the activities of the tyrosine kinase.
Insights
Specific mutations in the rat neu gene can activate its oncogenic potential. These activating mutations correlate with tyrosine kinase activity, suggesting a key role in cell transformation.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- The rat neu gene encodes a receptor-like protein similar to the epidermal growth factor receptor.
- This gene is often activated by a point mutation in its transmembrane domain, changing valine to glutamic acid.
Purpose of the Study:
- To investigate the specific amino acid residues and sequences required for neu gene oncogenic activation.
- To determine the relationship between neu gene transforming activity and its tyrosine kinase function.
Main Methods:
- Site-directed mutagenesis was used to create point mutations in the normal neu cDNA around amino acid position 664.
- Deletion analysis was performed on the transforming neu gene to identify essential functional domains.
- Mutagenesis of a transforming clone was conducted to assess the correlation between transforming activity and tyrosine kinase activity.
Main Results:
- A mutation substituting glutamine for valine at residue 664 resulted in full oncogenic activation of the neu gene.
- Mutations at positions 663 or 665 did not activate the neu gene, indicating specificity at residue 664.
- Only a small portion (420 out of 1260 amino acids) of the neu gene is required for full transforming function.
- A strong correlation was observed between the transforming activity and tyrosine kinase activity of the mutated neu gene.
Conclusions:
- The activating point mutation in the neu gene specifically requires certain residues at amino acid position 664 to confer oncogenic potential.
- The oncogenic transformation induced by the neu gene mutation is mediated through, or in conjunction with, its tyrosine kinase activity.
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