Activation of the mitogen-activated protein kinase cascade by tyrphostin (RG 50864).
Tyrphostins are synthetic compounds which have been described as in vitro inhibitors of epidermal growth factor (EGF)-receptor tyrosine kinase activity. In NIH3T3 cells, stimulation of EGF-receptor tyrosine kinase leads to an increase of intracellular protein phosphorylations, among them the phosphorylation of mitogen-activated protein (MAP) kinase and the S6 kinases p90rsk and p70S6K. Phosphorylation of these proteins, either on tyrosine or serine/threonine residues or on both residues increases their protein kinase activity. Unexpectedly, treatment of NIH3T3 cells with both tyrphostin (RG 50864) and EGF results in an increase in the level of tyrosine phosphorylation of the MAP kinase. During this treatment, we also observed an increase in MAP kinase and S6 kinase p90rsk activities. Tyrphostin treatment diminishes the level of c-fos mRNA but has no effect on c-myc mRNA expression nor on S6 kinase p70S6K activity. Mitogenic signalling induced by EGF in NIH3T3 cells was blocked by tyrphostin, suggesting that the target(s) for this event may be elements downstream from the MAP kinase or independent of this signal transduction.
Agbotounou
W K
WK
UA 0147 CNRS, Institut Gustave Roussy, Villejuif, France.
Mousset
S
S
Piperno
S
S
Pierre
M
M
Jacquemin-Sablon
A
A
Pierre
J
J
D016475:3T3 Cells; D000818:Animals; D002396:Catechols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D016259:Genes, myc; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins
D002396:Catechols; D009570:Nitriles; D012333:RNA, Messenger; D020032:Tyrphostins; C060152:tyrphostin 47; D004815:Epidermal Growth Factor; D004247:DNA; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1