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Constitutive phosphorylation of the epidermal growth factor receptor blocks mitogenic signal transduction
1Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester 01605.
Abstract:
The epidermal growth factor (EGF) receptor is phosphorylated by protein kinase C at Thr654. It has been proposed that the phosphorylation of this site is an important regulatory mechanism for the control of EGF receptor function. However, the physiological significance of the phosphorylation of EGF receptor Thr654 in intact cells is not understood. To address this question, the design of an experimental strategy is required that can be used to distinguish between the pleiotropic effects of kinase C activation and the specific effects of kinase C that are mediated by the phosphorylation of the EGF receptor at Thr654. The approach that we used was to examine the function of EGF receptors that are constitutively phosphorylated at residue 654. It was observed that the constitutive phosphorylation of the EGF receptor blocked mitogenic signal transduction by the receptor. These data are consistent with the hypothesis that the phosphorylation of the EGF receptor at residue 654 in intact cells inhibits EGF-stimulated cellular proliferation.
Insights
Constitutive phosphorylation of the epidermal growth factor (EGF) receptor at Thr654 blocks mitogenic signaling. This finding supports the hypothesis that EGF receptor Thr654 phosphorylation inhibits EGF-stimulated cellular proliferation in intact cells.
Area of Science:
- Cellular Biology
- Molecular Signaling
- Cancer Research
Background:
- Epidermal Growth Factor (EGF) receptor phosphorylation at Thr654 by protein kinase C is a proposed regulatory mechanism.
- The physiological role of EGF receptor Thr654 phosphorylation in intact cells remains unclear.
Purpose of the Study:
- To investigate the physiological significance of EGF receptor Thr654 phosphorylation.
- To differentiate kinase C effects from specific EGF receptor phosphorylation effects.
Main Methods:
- Examined the function of EGF receptors constitutively phosphorylated at residue 654.
- Utilized experimental strategies to isolate the effects of Thr654 phosphorylation.
Main Results:
- Constitutive phosphorylation of the EGF receptor at Thr654 was achieved.
- This constitutive phosphorylation blocked mitogenic signal transduction mediated by the EGF receptor.
Conclusions:
- Data support the hypothesis that EGF receptor Thr654 phosphorylation inhibits EGF-stimulated cellular proliferation.
- Phosphorylation at Thr654 is a key inhibitory mechanism for EGF receptor function in cellular proliferation.