A specific combination of substrates is involved in signal transduction by the kit-encoded receptor.
The kit protooncogene encodes a transmembrane tyrosine kinase related to the receptors for the platelet derived growth factor (PDGF-R) and the macrophage growth factor (CSF1-R), and was very recently shown to bind a stem cell factor. To compare signal transduction by the kit kinase with signaling by homologous receptors we constructed a chimeric protein composed of the extracellular domain of the epidermal growth factor receptor (EGF-R) and the transmembrane and cytoplasmic domains of kit. We have previously shown that the chimeric receptor transmits potent mitogenic and transforming signals in response to the heterologous ligand. Here we demonstrate that upon ligand binding, the ligand-receptor complex undergoes endocytosis and degradation and induces short- and long-term cellular effects. Examination of the signal transduction pathway revealed that the activated kit kinase strongly associates with phosphatidylinositol 3'-kinase activity and a phosphoprotein of 85 kd. In addition, the ligand-stimulated kit kinase is coupled to modifications of phospholipase C gamma and the Raf1 protein kinase. However, it does not lead to a significant change in the production of inositol phosphate. Comparison of our results with the known signaling pathways of PDGF-R and CSF1-R suggests that each receptor is coupled to a specific combination of signal transducers.
Lev
S
S
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Givol
D
D
Yarden
Y
Y
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002678:Chimera; D003847:Deoxyglucose / Q000378:metabolism; D004705:Endocytosis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor; D015398:Signal Transduction
D008024:Ligands; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D003847:Deoxyglucose; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor