Mechanism of desensitization of the epidermal growth factor receptor protein-tyrosine kinase

The intrinsic protein-tyrosine kinase activity of the epidermal growth factor (EGF) receptor is required for signal transduction. Increased protein-tyrosine kinase activity is observed following the binding of EGF to the receptor. However, signaling is rapidly desensitized during EGF treatment. We r...

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Bibliographic Details
Published in:The Journal of biological chemistry 1992-01, Vol.267 (2), p.1129-1140
Main Authors: Countaway, J L, Nairn, A C, Davis, R J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Calcium-Calmodulin-Dependent Protein Kinases
Down-Regulation
Endocytosis
Epidermal Growth Factor - metabolism
Epidermal Growth Factor - pharmacology
ErbB Receptors - metabolism
Molecular Sequence Data
Mutation
Phosphorylation
Protein Kinases - metabolism
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Rabbits
Rats
Serine - metabolism
Signal Transduction
Threonine - metabolism
Tyrosine - metabolism
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Summary:The intrinsic protein-tyrosine kinase activity of the epidermal growth factor (EGF) receptor is required for signal transduction. Increased protein-tyrosine kinase activity is observed following the binding of EGF to the receptor. However, signaling is rapidly desensitized during EGF treatment. We report that EGF receptors isolated from desensitized cells exhibit a lower protein-tyrosine kinase activity than EGF receptors isolated from control cells. The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity. Furthermore, this mutation causes a marked inhibition of the EGF-stimulated endocytosis and down-regulation of cell surface receptors. Thus, the phosphorylation site Ser1046/7 is required for EGF receptor desensitization in EGF-treated cells. This regulatory phosphorylation site is located at the carboxyl terminus of the EGF receptor within the subdomain that binds src homology 2 regions of signaling molecules.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)48406-2