Transmodulation of Epidermal Growth Factor Receptor Function by Cyclic AMP-dependent Protein Kinase

Barbier, Ann; Poppleton, Helen; Yigzaw, Yinges; Mullenix, Jason B.; Wiepz, Gregory J.; Bertics, Paul J.; Patel, Tarun B.

doi:10.1074/jbc.274.20.14067

Cited by 49 publications

(47 citation statements)

References 44 publications

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“…b 2 -Agonists cause an increase in cyclic adenosine monophosphate (cAMP) with activation of cAMP-dependent protein kinase, which has been shown to catalyse phosphorylation of the EGFR on serine residues and prevent tyrosine phosphorylation [37]. The present results agree with this previous work by showing that salbutamol suppresses the immediate tyrosine phosphorylation of the EGFR induced by EGF.…”

Section: Discussionsupporting

confidence: 83%

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium

Hamilton

Puddicombe²,

Dearman³

et al. 2005

Eur Respir J

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A disease-related, corticosteroid-insensitive increase in the expression of epidermal growth factor (EGF) receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium has been shown previously by the current authors. To determine whether this is associated with enhanced intracellular signalling, the aim of this study was to evaluate epithelial tyrosine phosphorylation.Bronchial biopsies were analysed for the presence of phosphotyrosine by immunohistochemistry. Bronchial epithelial cells were exposed to EGF, hydrogen peroxide or tumour necrosis factor-a in vitro for measurement of tyrosine phosphorylated signalling intermediates and interleukin (IL)-8 release.Phosphotyrosine was increased significantly in the epithelium of severe asthmatics when compared with controls or mild asthmatics; however, in mild asthma, phosphotyrosine levels were significantly decreased when compared with controls. There was no significant difference between phosphotyrosine levels before or after 8 weeks of treatment with budesonide. Stimulation of bronchial epithelial cells resulted in tyrosine phosphorylation of several proteins, including EGFR, Shc and p42/p44 mitogen-activated protein kinase. In the presence of salbutamol, a transient partial suppression of EGFR phosphorylation occurred, whereas dexamethasone was without effect. Neither salbutamol nor dexamethasone inhibited EGFstimulated IL-8 release.These data indicate that regulation of protein tyrosine kinase activity is abnormal in severe asthma. The epidermal growth factor receptor and/or other tyrosine kinase pathways may contribute to persistent, corticosteroid-unresponsive inflammation in severe asthma.

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Section: Discussionsupporting

confidence: 83%

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium

Hamilton

Puddicombe²,

Dearman³

et al. 2005

Eur Respir J

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show abstract

“…4), implicating PP2A as a positive regulator of the PI3-kinase/Akt survival signaling cascade. Mechanistically, these results could be explained by PP2A dephosphorylating inhibitory Ser/Thr phosphorylation sites on the epidermal growth factor receptor (47)(48)(49) or its associated proteins (50,51). Intriguingly, Akt has also been shown to be a PP2A substrate (52,53), suggesting that the phosphatase can inhibit Akt signaling under certain conditions.…”

Section: Discussionmentioning

confidence: 99%

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

Strack

Cribbs

Gomez

2004

Journal of Biological Chemistry

141

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The predominant forms of protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, are dimers of catalytic (C) and scaffolding (A) subunits and trimers with an additional variable regulatory subunit. In mammals, catalytic and scaffolding subunits are encoded by two genes each (␣/␤), whereas three gene families (B, B , and B؆) with a total of 12 genes contribute PP2A regulatory subunits. We generated stable PC12 cell lines in which the major scaffolding A␣ subunit can be knocked down by inducible RNA interference (RNAi) to study its role in cell viability. A␣ RNAi decreased total PP2A activity as well as protein levels of C, B, and B but not B؆ subunits. Inhibitor experiments indicate that monomeric C and B subunits are degraded by the proteosome. Knock-down of A␣ triggered cell death by redundant apoptotic and non-apoptotic mechanisms because the inhibition of RNAi-associated caspase activation failed to stall cell death. PP2A holoenzymes positively regulate survival kinase signaling, because RNAi reduced basal and epidermal growth factor-stimulated Akt phosphorylation. RNAi-resistant A␣ cDNAs rescued RNAi-induced loss of the C subunit, and A␣ point mutants prevented regulatory subunit degradation as predicted from each mutant's binding specificity. In transient, stable, and stable-inducible rescue experiments, both wild-type A␤ and A␣ mutants capable of binding to at least one family of regulatory subunits were able to delay A␣ RNAi-induced death of PC12 cells. However, only the expression of wild-type A␣ restored viability completely. Thus, heterotrimeric PP2A holoenzymes containing the A␣ subunit and members of all three regulatory subunit families are necessary for mammalian cell viability.

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“…Data that do exist in this regard are conflicting. Although studies in COS-7 and neuronal PC12 cells indicate that cAMP-dependent agonists have the capability to induce EGFr transactivation (18 -20), agents that elevate cAMP in fibroblasts and corneal epithelium appear to inhibit signaling via the EGFr (21,22). Thus, it seems likely that heterogeneity exists in the role that EGFr-dependent signaling mechanisms play in modulating G s PCR-induced responses in different systems.…”

mentioning

confidence: 96%

Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 Cells

Bertelsen

Barrett

Keely

2004

Journal of Biological Chemistry

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We have previously shown that G q protein-coupled receptor (G q PCR) agonists stimulate epidermal growth factor receptor (EGFr) transactivation and activation of mitogen-activated protein kinases (MAPK) in colonic epithelial cells. This constitutes a mechanism by which Cl ؊ secretory responses to G q PCR agonists are limited. In the present study we examined a possible role for the EGFr in regulating Cl ؊ secretion stimulated by agonists that act through G s PCRs. All experiments were performed using monolayers of T 84 colonic epithelial cells grown on permeable supports. Protein phosphorylation and protein-protein interactions were analyzed by immunoprecipitation and Western blotting.

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Transmodulation of Epidermal Growth Factor Receptor Function by Cyclic AMP-dependent Protein Kinase

Abstract: Binding of epidermal growth factor (EGF) to its receptor (EGFR) augments

Cited by 49 publications

References 44 publications

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium

Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

Gs Protein-coupled Receptor Agonists Induce Transactivation of the Epidermal Growth Factor Receptor in T84 Cells

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