Mutational removal of the major site of serine phosphorylation of the epidermal growth factor receptor causes potentiation of signal transduction: role of receptor down-regulation.

Abstract

The major site of epidermal growth factor receptor (EGF-R) serine phosphorylation is located within the COOH-terminal domain of the receptor at Ser1046/7. We have previously demonstrated that this phosphorylation site accounts for the acute desensitization of the EGF-R observed in EGF-treated cells. Here we show that the mutational removal of this negative regulatory phosphorylation site causes potentiation of signal transduction by the EGF-R. This potentiation can be accounted for in part by a block in the EGF-stimulated down-regulation of the EGF-R. These data indicate that the SER1046/7 phosphorylation site may have a regulatory role during long term incubation of cells with mitogenic concentrations of EGF.

Functional Regions of the Mouse Interleukin-10 Receptor Cytoplasmic Domain

“…Finally, we defined a third membraneproximal domain, elimination of which resulted in a superactivating IL-10R; cells expressing these mutant IL-10R were 30-to 100-fold more sensitive to IL-10 than cells with wild-type receptor. This property of superactivation was not associated with dramatically altered ligand affinity or IL-10R number, or with detectably impaired ability to internalize ligand (in contrast to epidermal growth factor receptor [38]). We therefore suggest that this region may interact with an intracellular protein(s) which negatively regulates IL-10R activation.…”

Epidermal Growth Factor Receptor (EGFR) Phosphorylation, Signaling and Trafficking in Prostate Cancer

“…Besides the tyrosine phosphorylation events, EGFR can be phosphorylated at several serine and threonine residues (Bao et al, 2000;Countaway et al, 1990;Theroux et al, 1992a), which may influence the EGFR kinase activity (Countaway et al, 1992;Theroux et al, 1992b). We have recently uncovered a previously unappreciated type of EGFR phosphorylation induced by EGF stimulation in several cell types.…”

“…Early studies of EGFR phosphorylation at serine and threonine sites, including serine-1046, serine 1047, and threonine-654, revealed that mutations at these sites can modulate EGFR signaling and downregulation (Bao et al, 2000;Countaway et al, 1990;Countaway et al, 1992;Theroux et al, 1992a). When examining the impact of ERK-mediated EGFR phosphorylation at threonine-669 on EGFR signaling, we found that in the CHO cell reconstitution system, the mutant EGFR-T669A exhibits enhanced tyrosine phosphorylation (reflecting EGFR kinase activation) compared to wild-type EGFR upon EGF stimulation (Li et al, 2008).…”

HSP90 inhibitors induce desensitization of EGF receptor via p38 MAPK-mediated phosphorylation at Ser1046/1047 in human pancreatic cancer cells

“…One is the phosphorylation at Tyr1045, which provides a docking site for the ubiquitin ligase c-Cbl resulting in ubiquitination of the EGFR (18) and the others are the phosphorylation at serine or threonine residues, which are thought to represent a mechanism for attenuation of the receptor kinase activity (19,20). Among the major sites of serine and threonine phosphorylation of the EGFR, it has previously been shown that the serine 1046/1047 (Ser1046/7) phosphorylation sites are required for EGFR desensitization in EGF-treated cells (21). Moreover, mutations of Ser1046/7 are reported to cause a marked inhibition of the EGFstimulated endocytosis and desensitization of cell surface receptors (20).…”