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Human trk oncogenes activated by point mutation, in-frame deletion, and duplication of the tyrosine kinase domain
1BRI-Basic Research Program, National Cancer Institute-Frederick Cancer Research Facility, Maryland 21701.
Abstract:
Malignant activation of the human trk proto-oncogene, a member of the tyrosine protein kinase receptor family, has been implicated in the development of certain human cancers, including colon and thyroid papillary carcinomas. trk oncogenes have also been identified in cultured cells transfected with various DNAs. In this study, we report the characterization of three in vitro-generated trk oncogenes, trk2, trk4, and trk5 (R. Oskam, F. Coulier, M. Ernst, D. Martin-Zanca, and M. Barbacid, Proc. Natl. Acad. Sci. USA 85:2964-2968, 1988), in an effort to understand the spectrum of mutational events that can activate the human trk gene. Nucleotide sequence analysis of cDNA clones of trk2 and trk4 revealed that these oncogenes were generated by a head-to-tail arrangement of two trk tyrosine protein kinase domains connected by a purine-rich region. These oncogenes code for cytoplasmic molecules of 67,000 (p67trk2) and 69,000 (p69trk4) daltons. In contrast, the product of the trk5 oncogene, gp95trk5, is a cell surface glycoprotein of 95,000 daltons. This oncogene was generated by a 153-base-pair in-frame deletion within sequences coding for the extracellular domain of the trk receptor. This activating deletion encompasses a triplet coding for one of the nine cysteine residues that the trk receptor shares with the product of the highly related trkB tyrosine protein kinase gene. Introduction of a single point mutation (TGT----AGT) in this codon resulted in a novel trk oncogene whose product, gp140S345, differs from the nontransforming trk proto-oncogene receptor in a single amino acid residue, Ser-345 instead of Cys-345. These results illustrate that multiple molecular mechanisms, including point mutation, internal deletion, and kinase domain duplication, can result in the malignant activation of the human trk proto-oncogene.
Insights
Malignant activation of the human trk proto-oncogene can occur through various molecular mechanisms, including point mutations, deletions, and duplications, leading to cancer development. Understanding these events is crucial for cancer research.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The human trk proto-oncogene, a tyrosine protein kinase receptor, is implicated in cancers like colon and thyroid carcinomas.
- trk oncogenes have been observed in cells transfected with various DNAs.
Purpose of the Study:
- To characterize three in vitro-generated trk oncogenes (trk2, trk4, trk5).
- To understand the spectrum of mutational events activating the human trk gene.
Main Methods:
- Nucleotide sequence analysis of cDNA clones.
- Characterization of oncogene products' molecular weight and localization.
Main Results:
- trk2 and trk4 oncogenes result from kinase domain duplication, producing cytoplasmic molecules p67trk2 and p69trk4.
- trk5 oncogene arises from an in-frame deletion in the extracellular domain, yielding cell surface glycoprotein gp95trk5.
- A single point mutation (Ser-345 instead of Cys-345) in trk5 creates a novel oncogene product, gp140S345.
Conclusions:
- Multiple molecular mechanisms, including point mutation, internal deletion, and kinase domain duplication, can activate the human trk proto-oncogene.
- These findings provide insight into the oncogenic potential of trk gene alterations.