Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase.
Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.
Rodrigues
G A
GA
Molecular Oncology Laboratory, Royal Victoria Hospital, Montreal, Canada.
Park
M
M
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002878:Chromosomes, Human, Pair 1; D017931:DNA Primers; D015723:Gene Library; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D016350:Leucine Zippers / Q000502:physiology*; D046911:Macromolecular Substances; D051379:Mice; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins; D009857:Oncogenes; D012516:Osteosarcoma / Q000235:genetics; D010957:Plasmids; D016133:Polymerase Chain Reaction; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D017931:DNA Primers; D046911:Macromolecular Substances; D028861:Nuclear Pore Complex Proteins; D011518:Proto-Oncogene Proteins; C073597:TPR protein, human; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases