UV activation of receptor tyrosine kinase activity.
The exposure of mammalian cells to ultraviolet radiation (UV) may lead to DNA damage resulting in mutation and thus possibly cancer, while irradiation can further act as a potent tumor promoter. In addition UV induces p21ras-mediated signalling leading to activation of transcription factors such as AP-1 and NF-kappa B, as well as activation of the Src tyrosine kinase. This 'UV-response' has been well studied in mammalian cells and furthermore is conserved in yeast, however the most upstream components of this signal transduction pathway have remained elusive. Here we show that UV rapidly activates both the EGF receptor and insulin receptor, as shown by tyrosine phosphorylation of these receptors. We demonstrate that this activation is due to autophosphorylation as it only occurs in cells containing receptors with a functional kinase domain. We have further analysed the propagation of the UV-induced signal to downstream events such as, IRS-1 and Shc tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, leukotriene synthesis, MAP kinase activation and gene induction all of which are activated by UV irradiation. Importantly, we demonstrate that in cells expressing a 'kinase-dead' receptor mutant the UV-response is inhibited, blocking leukotriene synthesis, MAP kinase activation and transcriptional induction. Furthermore, prior-stimulation of cells with UV appears to reduce further responsiveness to addition of growth factor suggesting a common signaling pathway. These data demonstrate a critical role for receptor-mediated events in regulating the response mammalian cells to UV exposure.
Coffer
P J
PJ
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
Burgering
B M
BM
Peppelenbosch
M P
MP
Bos
J L
JL
Kruijer
W
W
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism / Q000528:radiation effects*; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D011972:Receptor, Insulin / Q000378:metabolism / Q000528:radiation effects*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000528:radiation effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1