Tissue-specific expression of the human tropomyosin gene involved in the generation of the trk oncogene

Abstract

The trk oncogene is a human transforming gene generated by the fusion of tropomyosin gene sequence to a truncated tyrosine kinase receptor gene. We have now characterized the normal tropomyosin gene from which the trk oncogene is derived. At least two different transcripts are expressed by this gene using a tissue-specific alternative messenger RNA splicing mechanism: a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts and a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle. The rearrangement which generates the trk oncogene preserves most of the tropomyosin-coding sequences of the normal gene, including exons alternatively spliced in muscle and non-muscle tissue. We therefore expect the trk oncogene to show a tissue-specific pattern of transforming activity. Correct expression of the trk oncogene can occur only in non-muscle tissues. In muscle tissue the oncogene would almost certainly be inactive, as splicing according to the alternative muscle pattern aborts synthesis of the tyrosine kinase domain.

Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas

“…26,140 The normally ubiquitously expressed TPM3 gene has been detected as a fusion partner with the TRK (also variously designated as TRKA or NTRK1) kinase gene in human papillary thyroid and colon carcinomas. [200][201][202] TPM3-ALK expression was restricted to the cytoplasm. It appears that the TPM3 gene contributes an active promoter for ALK expression.…”

Human hTM alpha gene: expression in muscle and nonmuscle tissue.

“…1). This protein sequence, designated skoaTM.1, is 284 amino acids long and very closely related to the 285-aminoacid a-tropomyosin sequence derived from the 1.3ATM clone from human skeletal muscle, which we have described previously (18,29). We now designate the latter sequence skaTM.2.…”

“…In particular, we have now identified three human genes, each of which encodes at least two different isoforms of tropomyosin (17)(18)(19)(20). One of these genes encodes a 285-amino-acid oatropomyosin in skeletal muscle tissue and a 248-amino-acid nonmuscle tropomyosin in cultured fibroblasts (18,29). In this paper, we identify a fourth human tropomyosin gene, the hTMa structural gene, which encodes a skeletal muscle a-tropomyosin closely related in structure to the a-tropomyosin encoded by the hTMnm structural gene.…”

“…However, tropomyosins from smooth muscle and nonmuscle tissues contain unique structural features which distinguish them from each other and from skeletal muscle tropomyosins. These tissue-specific structural domains appear to be important to the function of tropomyosin, since in the skeletal muscle isoform they correspond, in part, to the sites of binding of troponin T. Molecular cloning and DNA sequence analysis of genes and mRNAs encoding tropomyosins reveals that the structural genes encoding these proteins are expressed by using an alternative mRNA-splicing mechanism (7,9,17,(29)(30)(31). Alternative splicing of tropomyosin genes occurs principally on a tissue-specific basis and involves those exons encoding the tissue-specific structural domains of the isoforms.…”

A Highly Conserved NTRK3 C-terminal Sequence in the ETV6-NTRK3 Oncoprotein Binds the Phosphotyrosine Binding Domain of Insulin Receptor Substrate-1

“…NTRK1 (TRKA) sequences were originally isolated from a colon carcinoma biopsy as part of an oncogene encoding the N-terminal portion of tropomyosin (TPM3) fused to a truncated tyrosine kinase receptor (30). TPM3-NTRK1 fusions were subsequently detected in papillary thyroid carcinomas (31), and altered NTRK signaling has been implicated in other neoplasms (for review, see Ref.…”