Molecular and biochemical characterization of the human trk proto-oncogene.
Molecular analysis of the human trk oncogene, a transforming gene isolated from a colon carcinoma biopsy, revealed the existence of a novel member of the tyrosine kinase gene family. This locus, which we now designate the trk proto-oncogene, codes for a protein of 790 amino acid residues that has several features characteristic of cell surface receptors. They include (i) a 32-amino-acid-long putative signal peptide, (ii) an amino-terminal moiety (residues 33 to 407) rich in consensus sites for N-glycosylation, (iii) a transmembrane domain, (iv) a kinase catalytic region highly related to that of other tyrosine kinases, and (v) a very short (15 residue) carboxy-terminal tail. Residues 1 to 392 were absent in the trk oncogene, as they were replaced by tropomyosin sequences. However, no other differences were found between the transforming and nontransforming trk alleles (residues 392 to 790), suggesting that no additional mutations are required to activate the transforming potential of this gene. The human trk proto-oncogene codes for a 140,000-dalton glycoprotein, designated gp140proto-trk. However, its primary translational product is a 110,000-dalton glycoprotein which becomes immediately glycosylated, presumably during its translocation into the endoplasmic reticulum. This molecule, designated gp110proto-trk, is further glycosylated to yield the mature form, gp140proto-trk. Both gp110proto-trk and gp140proto-trk proteins possess in vitro kinase activity specific for tyrosine residues. Finally, iodination of intact NIH 3T3 cells expressing trk proto-oncogene products indicated that only the mature form, gp140proto-trk, cross the plasma membrane, becoming exposed to the outside of the cell. These results indicate that the product of the human trk locus is a novel tyrosine kinase cell surface receptor for an as yet unknown ligand.
Martin-Zanca
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D
Section of Developmental Oncology, National Cancer Institute Frederick Cancer Research Facility, Maryland 21701.
Oskam
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R
Mitra
G
G
Copeland
T
T
Barbacid
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000302:isolation & purification; D004274:DNA, Recombinant / Q000032:analysis; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D008969:Molecular Sequence Data; D010957:Plasmids; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes
D004274:DNA, Recombinant; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004247:DNA; D011505:Protein-Tyrosine Kinases