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Interruption of growth signal transduction by an antiviral and antitumoral xanthate compound
K Müller-Decker1, C Doppler, E Amtmann
1Institute for Virus Research, German Cancer Research Center, Heidelberg.
Abstract:
The binding of growth factors to the cellular receptors elicits the phosphorylation of proteins which transmit growth signals to the nucleus [E. Rozengurt (1986) Science 234, 161-166]. Both the tyrosine-specific kinase (growth factor receptor) and the threonine-serine phosphorylating protein kinase C (pkC) become activated upon binding of the epidermal growth factor (EGF) to its receptor. Here we describe the selective inhibition of the pkC activation by tricyclodecane-9-yl-xanthogenate (D609) in the presence of unsuppressed receptor tyrosine autophosphorylation. As a consequence the affinity of EGF to the receptor was not down-regulated and the complex failed to be internalized.
Insights
Tricyclodecane-9-yl-xanthogenate (D609) selectively inhibits protein kinase C (pkC) activation by epidermal growth factor (EGF) receptors. This preserves EGF receptor tyrosine autophosphorylation and prevents EGF-induced receptor downregulation and internalization.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Biochemistry
Background:
- Growth factors bind cellular receptors, triggering protein phosphorylation and signal transmission to the nucleus.
- Epidermal growth factor (EGF) binding activates both receptor tyrosine kinases and protein kinase C (pkC).
Purpose of the Study:
- To investigate the selective inhibition of pkC activation by tricyclodecane-9-yl-xanthogenate (D609).
- To determine the effect of D609 on EGF receptor tyrosine autophosphorylation, affinity, and internalization.
Main Methods:
- Utilized tricyclodecane-9-yl-xanthogenate (D609) to selectively inhibit pkC activation.
- Monitored receptor tyrosine autophosphorylation in the presence of D609.
- Assessed EGF receptor affinity and internalization following D609 treatment.
Main Results:
- D609 selectively inhibited pkC activation without affecting receptor tyrosine autophosphorylation.
- EGF receptor affinity remained undiminished.
- EGF-receptor complex internalization was prevented.
Conclusions:
- D609 is a selective inhibitor of pkC activation in EGF signaling.
- Inhibition of pkC prevents EGF receptor downregulation and internalization, decoupling it from initial receptor tyrosine kinase activity.