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Mechanism of activation of the human trk oncogene
F Coulier1, D Martin-Zanca, M Ernst
1Developmental Oncology Section, National Cancer Institute-Frederick Cancer Research Facility, Maryland 21701.
Abstract:
The human trk oncogene was generated by a genetic rearrangement that replaced the extracellular domain of the normal trk tyrosine kinase receptor by sequences coding for the 221 amino-terminal residues of a nonmuscle tropomyosin. Molecular dissection of a cDNA clone of the trk oncogene indicated that both the tropomyosin and tyrosine kinase domains were required for proper transforming activity. Replacement of nonmuscle tropomyosin sequences with those of other tropomyosin isoforms had no deleterious effect. However, when tropomyosin sequences were replaced with those of another cytoskeletal gene, such as beta-actin or beta-globin, transforming activity was completely abolished. These results illustrate the important role of tropomyosin sequences in endowing the trk kinase with transforming properties. Functionally unrelated subdomains of the tropomyosin molecule were equally efficient in activating the trk gene. Moreover, the transforming activity of the trk oncogene was not affected when its subcellular localization was drastically altered. Therefore, tropomyosin sequences are likely to contribute to the malignant activation of the trk oncogene not by facilitating its interaction with defined cytoskeletal structures as initially suspected, but by allowing its kinase domain to fold into a constitutively active configuration.
Insights
The tropomyosin protein sequences are crucial for the trk oncogene's transforming activity. These sequences enable the trk kinase domain to adopt a permanently active state, driving malignant transformation.
Area of Science:
- Oncogenesis
- Molecular Biology
- Cancer Research
Background:
- The trk oncogene arises from genetic rearrangement, fusing tropomyosin sequences with the trk tyrosine kinase receptor.
- Understanding the role of tropomyosin in trk oncogene activation is key to cancer research.
Purpose of the Study:
- To investigate the specific contribution of tropomyosin sequences to the transforming activity of the trk oncogene.
- To elucidate the mechanism by which tropomyosin confers transforming properties to the trk kinase.
Main Methods:
- Molecular dissection of trk oncogene cDNA clones.
- Replacement of tropomyosin sequences with those from other tropomyosin isoforms and cytoskeletal genes (beta-actin, beta-globin).
- Assessment of transforming activity and analysis of subcellular localization.
Main Results:
- Both tropomyosin and tyrosine kinase domains are essential for the trk oncogene's transforming activity.
- Replacing nonmuscle tropomyosin with other isoforms had no negative effect, but replacement with beta-actin or beta-globin abolished activity.
- Altering the subcellular localization of the trk oncogene did not impact its transforming activity.
Conclusions:
- Tropomyosin sequences are vital for the malignant activation of the trk oncogene.
- Tropomyosin likely activates the trk kinase by promoting a constitutively active conformation, rather than through interaction with cytoskeletal structures.
- These findings offer insights into oncogene activation mechanisms and potential therapeutic targets.