Redox-dependent regulation of epidermal growth factor receptor signaling

Heppner, David E.; Vliet, Albert van der

doi:10.1016/j.redox.2015.12.002

Cited by 66 publications

(62 citation statements)

References 19 publications

(21 reference statements)

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“…Our work and that of others has shown that moderate exogenous or endogenous H 2 O 2 elevation can lead to a net increase of EGFR autophosphorylation in cells [reviewed in (Corcoran and Cotter, 2013; Heppner and van der Vliet, 2015; Truong and Carroll, 2012)]. Using recombinant GST-tagged EGFR kinase domain with a peptide-based assay, we have demonstrated that sulfenylation of C797 enhances the intrinsic tyrosine kinase activity (Paulsen, et al, 2012).…”

Section: Resultsmentioning

confidence: 62%

“…These kinases include members of the Erb family (Her2, Her4), the Tec family (BMX, BTK, ITK, TEC, and TXK), one Src member (BLK), MKKa7 and JAK3. Proximity to the catalytic pocket and selective oxidation strongly support an important regulatory function for sulfenylation of C797 (Heppner and van der Vliet, 2015; Truong and Carroll, 2013); however, the precise molecular mechanism for redox-based activation of EGFR remains entirely unknown. This question is critical to address both from a fundamental perspective and owing to implications for related kinases.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Truong

Ung

Palde

et al. 2016

Cell Chemical Biology

113

127

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SUMMARY EGFR is a target of signal-derived H2O2 and oxidation of active site cysteine 797 to sulfenic acid enhances kinase activity. Although a major class of covalent drugs targets C797, nothing is known about its catalytic importance or how S-sulfenylation leads to activation. Here, we report the first detailed functional analysis of C797. In contrast to prior assumptions, mutation of C797 diminishes catalytic efficiency in vitro and cells. The experimentally determined pKa and reactivity of C797 towards H2O2 correspondingly distinguish this residue from the bulk of the cysteinome. Molecular dynamic simulation of reduced versus oxidized EGFR, reinforced by experimental testing, indicates that sulfenylation of C797 allows new electrostatic interactions to be formed with the catalytic loop. Finally, we show that chronic oxidative stress yields an EGFR subpopulation that is refractory to the FDA-approved drug, afatinib. Collectively, our data highlight the significance of redox biology to understanding kinase regulation and drug pharmacology.

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Section: Resultsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Truong

Ung

Palde

et al. 2016

Cell Chemical Biology

113

127

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“…Moreover, abnormalities in EGFR activation in the context of chronic diseases such as cancer or IBD may not only simply be due to altered expression of EGFR or its ligands but also be related to altered expression or activation of NOX enzymes that regulate this signaling pathway [41]. Also exogenous ROS stimulates the induction of VEGF expression in endothelial cells, smooth muscle cells, and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

Kuznietsova

Yena

Kotlyar

et al. 2016

The Scientific World Journal

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In our previous studies we showed antitumor and anti-inflammatory activities of protein kinases inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1H-pyrrol-2,5-dione (MI-1) on rat colon cancer model. Therefore anti-inflammatory effect of MI-1 on rat acetic acid induced ulcerative colitis (UC) model was aimed to be discovered. The anti-inflammatory effects of MI-1 (2.7 mg/kg daily) compared to reference drug Prednisolone (0.7 mg/kg daily) after 14-day usage were evaluated on macro- and light microscopy levels and expressed in 21-grade scale. Redox status of bowel mucosa was also estimated. It was shown that in UC group the grade of total injury (GTI) was equal to 9.6 (GTIcontrol = 0). Increase of malonic dialdehyde (MDA) by 89% and protein carbonyl groups (PCG) by 60% and decrease of superoxide dismutase (SOD) by 40% were also observed. Prednisolone decreased GTI to 3 and leveled SOD activity, but MDA and PCG remained higher than control ones by 52% and 42%, respectively. MI-1 restored colon mucosa integrity and decreased mucosa inflammation down to GTI = 0.5 and leveled PCG and SOD. Thus, MI-1 possessed anti-inflammatory properties, which were more expressed that Prednisolone ones, as well as normalized mucosa redox balance, and so has a prospect for correction of inflammatory processes.

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“…Stepwise Protein Oxidation to Sulfenic Acids and S-Glutathionylation-Several reports indicate that EGFR and Src are subject to redox regulation by cysteine oxidation within these kinases (8,9,28,29), but the nature of the oxidative cysteine modification responsible for activating these kinases is unknown. Extending our recent observations of ATP-stimulated redox-dependent activation of EGFR and Src within the airway epithelium (22,24), we assessed the relationship between cysteine oxidation and activation of Src and EGFR by determining the temporal association between phosphorylation of EGFR (at Tyr-845 and Tyr-1068) and Src (at Tyr-416) and cysteine oxidation within these proteins to either sulfenic acids (-SOH) or S-glutathionylation (-SSG).…”

Section: Duox1-dependent Egfr Activation Involvesmentioning

confidence: 99%

The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling

Heppner

Hristova

Dustin

et al. 2016

Journal of Biological Chemistry

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The epidermal growth factor receptor (EGFR) plays a critical role in regulating airway epithelial homeostasis and responses to injury. Activation of EGFR is regulated by redox-dependent processes involving reversible cysteine oxidation by reactive oxygen species (ROS) and involves both ligand-dependent and -independent mechanisms, but the precise source(s) of ROS and the molecular mechanisms that control tyrosine kinase activity are incompletely understood. Here, we demonstrate that stimulation of EGFR activation by ATP in airway epithelial cells is closely associated with dynamic reversible oxidation of cysteine residues via sequential sulfenylation and S-glutathionylation within EGFR and the non-receptor-tyrosine kinase Src. Moreover, the intrinsic kinase activity of recombinant Src or EGFR was in both cases enhanced by H 2 O 2 but not by GSSG, indicating that the intermediate sulfenylation is the activating modification. H 2 O 2 -induced increase in EGFR tyrosine kinase activity was not observed with the C797S variant, confirming Cys-797 as the redox-sensitive cysteine residue that regulates kinase activity. Redox-dependent regulation of EGFR activation in airway epithelial cells was found to strongly depend on activation of either the NADPH oxidase DUOX1 or the homolog NOX2, depending on the activation mechanism. Whereas DUOX1 and Src play a primary role in EGFR transactivation by wound-derived signals such as ATP, direct ligand-dependent EGFR activation primarily involves NOX2 with a secondary role for DUOX1 and Src. Collectively, our findings establish that redoxdependent EGFR kinase activation involves a dynamic and reversible cysteine oxidation mechanism and that this activation mechanism variably involves DUOX1 and NOX2.The epidermal growth factor receptor (EGFR 2 ; HER1; ErbB1) is the principal member of the human ErbB receptortyrosine kinase family that facilitates diverse signal transduction pathways to regulate imperative cellular functions including growth, development, differentiation, and migration (1). A transmembrane protein expressed on the cell membrane, EGFR consists of an extracellular ligand binding domain, a single transmembrane-spanning sequence, and an intracellular kinase domain containing a C-terminal peptide tail with several tyrosine residues targeted for autophosphorylation or phosphorylation by related tyrosine kinases (2). Activation of EGFR is enabled though binding of one of seven ligands to its extracellular domain, thereby promoting receptor homo-or heterodimerization and autophosphorylation of several C-terminal tail tyrosines (e.g. Tyr-1068) and activation of downstream signals. In addition, it has become apparent that EGFR can also be activated in response to stimulation of a large class of G-protein coupled receptors (GPCRs), which involves activation of membrane-associated EGFR ligands by matrix metalloproteases or ADAM (a disintegrin and metalloprotease)-family sheddases, a process known as "triple-membrane-passing-signaling," as well as ligand-independent mechanisms me...

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Redox-dependent regulation of epidermal growth factor receptor signaling

Cited by 66 publications

References 19 publications

Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate

The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling

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