Mechanism of activation of the human trk oncogene

Journal Article · Sun Jan 01 04:00:00 EST 1989 · Mol. Cell. Biol.; (United States)

DOI:https://doi.org/10.1128/MCB.9.1.15· OSTI ID:5702263

Coulier, F; Barbacid, M

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 is 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 cystoskeletal structures as initially suspected, but by allowing its kinase domain to fold into a constitutively active configuration.

• Research Organization: INSERM U199, 13009 Marseille (FR); Dept. of Molecular Biology, Squibb Institute for Medical Research, Princeton, NJ (US)
• OSTI ID: 5702263
• Journal Information: Mol. Cell. Biol.; (United States), Journal Name: Mol. Cell. Biol.; (United States) Vol. 9:1; ISSN MCEBD
• Country of Publication: United States
• Language: English

Related Subjects

550200 -- Biochemistry
550400* -- Genetics
59 BASIC BIOLOGICAL SCIENCES
ACTIN
BIOLOGICAL PATHWAYS
CELL TRANSFORMATIONS
CLONING
DNA HYBRIDIZATION
DNA SEQUENCING
DNA-CLONING
ENZYMES
GENE AMPLIFICATION
GENES
GLOBIN
HUMAN POPULATIONS
HYBRIDIZATION
MEMBRANE PROTEINS
MOLECULAR BIOLOGY
ONCOGENES
ONCOGENIC TRANSFORMATIONS
ORGANIC COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
POPULATIONS
PROTEINS
RECEPTORS
STRUCTURAL CHEMICAL ANALYSIS
TRANSFERASES
TROPOMYOSIN