Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors

  title={Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors},
  author={Pnina Yaish and Aviv Gazit and Chaim Gilon and Alexander Levitzki},
  pages={933 - 935}
A systematic series of low molecular weight protein tyrosine kinase inhibitors were synthesized; they had progressively increasing affinity over a 2500-fold range toward the substrate site of epidermal growth factor (EGF) receptor kinase domain. These compounds inhibited EGF receptor kinase activity up to three orders of magnitude more than they inhibited insulin receptor kinase, and they also effectively inhibited the EGF-dependent autophosphorylation of the receptor. The most potent compounds… 
Specific Inhibition of Insulin-Like Growth Factor-1 and Insulin Receptor Tyrosine Kinase Activity and Biological Function by Tyrphostins.
A series of the synthetic protein tyrosine kinase inhibitors known as tyrphostins were studied for their effect on insulin-like growth factor-1 and insulin-stimulated cellular proliferation on
Dimerization Activates the Epidermal Growth Factor Receptor Tyrosine Kinase
Using EGF-R mutants, the protein tyrosine kinase activity was shown to be essential for mitogenic signaling (Schlessinger, 1988a).
The inhibition of EGF-dependent proliferation of keratinocytes by tyrphostin tyrosine kinase blockers
Protein tyrosine kinase blockers of the tyrphostin family inhibited the EGF-dependent proliferation of human and guinea pig keratinocytes grown in culture and induced their growth arrest, and are suggested as agents to treat hyperproliferative conditions of human skin.
Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins.
The results suggest that, in spite of the high homology of the kinase regions of both receptors, it could be possible to design and synthesize small molecules capable of discriminating between them.
Effect of tyrphostin on cell growth and tyrosine kinase activity of epidermal growth factor receptor in human gliomas.
It might be suggested that tyrphostin inhibits EGF- Stimulated cell growth by a specific suppression of EGF receptor tyrosine kinase activity, and at higher concentrations there appears to be some degree of either nonspecific inhibition or inhibition of serum-stimulated protein tyrosinase activity to induce the cell growth inhibition of gliomas.
Protein binding modulates inhibition of the epidermal growth factor receptor kinase and DNA synthesis by tyrphostins
It is demonstrated that protein binding accounts for the apparent selectivity of some highly protein-bound tyrphostins for TGFα-stimulated DNA synthesis of L23/P cells.
The EGF receptor system as a target for antitumor therapy.
In those malignancies in which growth control resides in the EGF-receptor system, antitumor therapy using monoclonal anti-EGF receptor antibodies and tyrosine kinase inhibitors is a possibility worth pursuing.
Inhibition of pancreatic cancer cell growth in vitro by the tyrphostin group of tyrosine kinase inhibitors.
AG17 was found to be the most potent of these agents and caused a dose-dependent but reversible inhibition of cell growth, and Tyrosine kinase inhibitors may prove to be useful agents for the treatment of pancreatic cancer.


Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor
It is concluded that the tyrosine kinase activity of the EGF receptor is essential for the diverse biochemical effects of EGF, including rapid alterations in intracellular calcium, activation of gene transcription, receptor down-regulation and the ultimate stimulatory effects on cell proliferation.
Genistein, a specific inhibitor of tyrosine-specific protein kinases.
Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor
The present report demonstrates that PDGF binding to cellular receptors might similarly stimulate kinase activity, and induces the phosphorylation of tyrosine residues of membrane proteins with apparent molecular weights of 175,000 and 130,000 when incubated with plasma membranes from human fibroblasts or glial cells.
A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis
EGF was unable to stimulate the stimulation of various responses, including enhanced expression of proto-oncogenes c-fos and c-myc, morphological changes, and stimulation of DNA synthesis, suggesting that the tyrosine kinase activity is essential for EGF receptor signal transduction.
Self-phosphorylation of epidermal growth factor receptor: evidence for a model of intermolecular allosteric activation.
An allosteric aggregation model is formulated for the activation of the cytoplasmic kinase function of the receptor by EGF because this model may be relevant to the mechanism by which the mitogenic signal of EGF is transferred across the membrane.
A chimaeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor
It is shown here that the EGF receptor kinase domain of the chimaeric protein, expressed transiently in simian cells, is activated by insulin binding, which strongly suggests that insulin and EGF receptors employ closely related or identical mechanisms for signal transduction across the plasma membrane.
A nonmitogenic analogue of epidermal growth factor induces early responses mediated by epidermal growth factor
The results are consistent with the notion that EGF-induced phosphorylation could act as a "second messenger" for the action of various E GF-induced responses such as activation of Na+-K+-ATPase, changes in the cytoskeleton and cell morphology, and the activation of the enzyme ornithine decarboxylase.
After insulin binds.
Three recent advances pertinent to the mechanism of insulin action include (i) the discovery that the insulin receptor is an insulin-dependent protein tyrosine kinase, functionally related to certain
Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor.
Phosphorylation was specifically stimulated by insulin in a dose-dependent fashion after 1 and 15 minutes of hormone treatment, whereas human growth hormone was without effect, suggesting this phosphorylation may be a very early event in insulin action.