Activation of Raf by ionizing radiation.
The critical pathways through which ionizing radiation induces malignant transformation and cell death are not well defined. Raf-1, a cytoplasmic serine-threonine protein kinase, mediates the transmission of mitogenic signals initiated at the cell membrane to the nucleus, resulting in the activation of transcription factors that regulate cell growth and proliferation. Moreover, Raf-1 overexpression and activation increases the survival response of mammalian cells to the toxic effects of ionizing radiation by an as-yet unknown mechanism (refs 3, 4 and V. Soldatenkov et al.; manuscript submitted). Somewhat analogous to mitogen-induced signalling, radiation stimulates protein-tyrosine kinase(s) and transcription factors. No direct biochemical link has been established, however, between radiation-stimulated protein tyrosine phosphorylation and downstream signals. Here we report a series of radiation-responsive events in which protein-tyrosine phosphorylation is followed by membrane recruitment, then tyrosine phosphorylation and activation of Raf-1 in vivo. Our results show that radiation-stimulated protein-tyrosine kinase(s) modify Raf-1, and implicate Raf-1 in the ionizing-radiation signal-transduction pathway.
Kasid
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U
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University, Washington DC 20007, USA.
Suy
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S
Dent
P
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Ray
S
S
Whiteside
T L
TL
Sturgill
T W
TW
D001692:Biological Transport; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000528:radiation effects*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000528:radiation effects*; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases