Receptor chimeras indicate that the met tyrosine kinase mediates the motility and morphogenic responses of hepatocyte growth/scatter factor.
The met protooncogene is a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF is a multifunctional cytokine secreted mainly by mesenchymal cells that stimulates movement, invasion, and morphogenesis of some epithelial and endothelial cells and mitogenicity of others. Although the met receptor tyrosine kinase is a high affinity receptor for HGF/SF, it is not known whether this receptor can mediate the pleiotropic functions of HGF/SF. To investigate this in epithelial cells that normally respond to HGF/SF, we generated a chimeric receptor containing the extracellular domain from the colony stimulating factor 1 (CSF-1) receptor fused to the transmembrane and cytoplasmic domain of the met receptor. We show that the CSF-MET chimera, when expressed in Madin-Darby canine kidney (MDCK) epithelial cells, is fully functional. Treatment of MDCK cells expressing the chimera with CSF-1 leads to cell dissociation and scattering, as well as invasion and tubule formation of cells grown in collagen matrices. This effect is dependent on a functional met kinase. Stimulation of the receptor chimera with CSF-1 leads to activation of the met kinase and tyrosine phosphorylation of the chimeras in vivo, whereas a kinase inactive mutant chimera shows no biological response to CSF-1. These findings demonstrate that stimulation of the met kinase is sufficient and essential to mediate the motogenic, invasive, and morphogenic responses of MDCK cells to HGF/SF and that this is a suitable system for a detailed analysis of the molecular signaling events involved in these responses.
Zhu
H
H
Molecular Oncology Group, Royal Victoria Hospital, Montreal, Quebec, Canada.
Naujokas
M A
MA
Park
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004285:Dogs; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D007684:Kidney Tubules / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics
D011993:Recombinant Fusion Proteins; D017228:Hepatocyte Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D020794:Receptor Protein-Tyrosine Kinases