Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration

Jagadeesha, Dammanahalli K.; Takapoo, Maysam; Bánfi, Botond; Bhalla, Ramesh C.; Miller, Francis J.

doi:10.1093/cvr/cvr308

Cited by 63 publications

(54 citation statements)

References 41 publications

(59 reference statements)

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“…Therefore, the diverse roles of NOX isoforms in this complex signaling pathway likely depend on the stage of EGFR activation or on OCTOBER 28, 2016 • VOLUME 291 • NUMBER 44 specific subcellular events after EGFR/Src internalization or trafficking localization. Moreover, the relative role(s) of DUOX1 or other NOX isoforms may also depend on the cell type, highlighted by previous studies showing a role for NOX1 in Src-dependent transactivation of EGFR in vascular smooth muscle cells (25). Nevertheless, our findings indicate that EGFR activation in airway epithelial cells is associated with combined oxidative mechanisms initiated by activation of both DUOX1 and NOX2, which both contribute to cysteine oxidation within EGFR and Src.…”

Section: Discussionmentioning

confidence: 53%

“…Indeed, recent studies from our group revealed that EGFR transactivation in airway epithelial cells by initial activation with ATP of purinergic GPCRs, due to epithelial injury or exposure to environmental allergens, is associated with enhanced cysteine oxidation within Src as well as EGFR, depending on activation of the NADPH oxidase homolog dual oxidase 1 (DUOX1) (22)(23)(24). Other studies indicate a comparable role for NOX1 in EGFR transactivation in vascular smooth muscle cells in response to thrombin (25). Alternatively, recent studies by Carroll and co-workers (16) indicated that EGF-dependent activation of EGFR in epidermoid carcinoma A431 cells involves cysteine oxidation within the EGFR kinase domain mediated by ROS generated from the NADPH oxidase NOX2.…”

Section: From the Department Of Pathology And Laboratory Medicine Unmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 53%

Section: From the Department Of Pathology And Laboratory Medicine Unmentioning

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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“…Moreover, it has been reported that endogenous hydrogen peroxide (H 2 O 2 ), produced as a consequence of EGF binding to EGFR, can be utilized by the cells as a secondary messenger to regulate physiological signal transduction (17,18).…”

Section: Introductionmentioning

confidence: 99%

Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells

D’Anneo¹,

Carlisi²,

Emanuele³

et al. 2013

International Journal of Oncology

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Abstract. The sesquiterpene lactone parthenolide (PN) has recently attracted considerable attention because of its antimicrobial, anti-inflammatory and anticancer effects. However, the mechanism of its cytotoxic action on tumor cells remains scarcely defined. We recently provided evidence that the effect exerted by PN in MDA-MB-231 breast cancer cells was mediated by the production of reactive oxygen species (ROS). The present study shows that PN promoted the phosphorylation of EGF receptor (phospho-EGFR) at Tyr1173, an event which was observed already at 1 h of incubation with 25 µM PN and reached a peak at 8-16 h. This effect seemed to be a consequence of ROS production, because N-acetylcysteine (NAC), a powerful ROS scavenger, prevented the increment of phospho-EGFR levels. In addition fluorescence analyses performed using dihydroethidium demonstrated that PN stimulated the production of superoxide anion already at 2-3 h of incubation and the effect further increased prolonging the time of treatment, reaching a peak at 8-16 h. Superoxide anion production was markedly hampered by apocynin, a well known NADPH oxidase (NOX) inhibitor, suggesting that the effect was dependent on NOX activity. The finding that AG1478, an EGFR kinase inhibitor, substantially blocked both EGFR phosphorylation and superoxide anion production strongly suggested that phosphorylation of EGFR can be responsible for the activation of NOX with the consequent production of superoxide anion. Therefore, EGFR phosphorylation can exert a key role in the production of superoxide anion and ROS induced by PN in MDA-MB-231 cells.

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“…It not only plays an important physiological role in processes such as cellular migration and apoptosis, but also its deregulation can cause pathological states such as cancer. Transactivation of various growth factor receptors, including epidermal growth factor receptor (EGFR), by GPCRs has been documented in multiple cellular model systems, hence demonstrating the potential role of GPCRs in tumor tropism via receptor transactivation ( Jagadeesha, Takapoo, Banfi, Bhalla, & Miller, 2012;Maretzky et al, 2011;Yahata et al, 2006). A commonly reported mechanism of receptor transactivation involves the activation of membrane-tethered growth factors, such as EGFR, through direct interaction with GPCRs, such as CXCR4 (Porcile et al, 2005).…”

Section: Stem Cell Homing and Migrationmentioning

confidence: 99%

Stem Cell-Based Therapies for Cancer

Bhere

Shah

2015

Advances in Cancer Research

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Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration

Abstract: The Nox1 NADPH oxidase signals through EGFR to activate MMP-9 and promote the shedding of N-cadherin, thereby contributing to SMC migration.

Cited by 63 publications

References 41 publications

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

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

Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells

Stem Cell-Based Therapies for Cancer

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