A neuroprotective compound, aurin tricarboxylic acid, stimulates the tyrosine phosphorylation cascade in PC12 cells.
Aurin tricarboxylic acid (ATA), a general nuclease inhibitor, was reported to prevent PC12 cells from cell death caused by serum starvation (1). In our study, ATA also protected PC12 cells, but not NIH3T3 cells, from serum-starved cell death. When we investigated the mechanism of action of ATA on these cells, ATA was found to increase tyrosine phosphorylation in PC12 cells, but not in NIH3T3 cells. Further investigation on tyrosine-phosphorylated proteins revealed that ATA, similar to nerve growth factor and epidermal growth factor, induced tyrosine phosphorylation of mitogen-activated protein kinases. Since the tyrosine phosphorylation of mitogen-activated protein kinases is thought to play an important role inn growth factor-dependent signal pathways, this finding suggests that the action of ATA on PC12 cells is mediated by tyrosine phosphorylation cascade, similar to growth factor signaling. In addition, we found that Shc proteins, phosphatidylinositol 3-kinase, and phospholipase C-gamma were also phosphorylated in ATA-treated PC12 cells. These key proteins in signal transduction pathways are known to associate with ligand-activated growth factor receptors and are phosphorylated on tyrosine. Thus, the phosphorylation of these three proteins by ATA stimulation supports the speculation that ATA activates a certain receptor tyrosine kinase.
Okada
N
N
Bio-Organic Research Department, International Research Laboratories, Ciba-Geigy Japan Limited, Takarazuka.
Koizumi
S
S
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D003851:Deoxyribonucleases / Q000037:antagonists & inhibitors; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D012260:Ribonucleases / Q000037:antagonists & inhibitors; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016895:Culture Media, Serum-Free; D007527:Isoenzymes; D009414:Nerve Growth Factors; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D001312:Aurintricarboxylic Acid; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003851:Deoxyribonucleases; D012260:Ribonucleases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma