EGF receptor activation by GPCRs: An universal pathway reveals different versions

Liebmann, Claus

doi:10.1016/j.mce.2010.04.008

Cited by 134 publications

(122 citation statements)

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“…Src, Pyk) that regulate EGFR activation by direct phosphorylation of its kinase domain (e.g. Tyr-845) (3)(4)(5). The relative involvement of ligand-dependent and -independent mechanisms in GPCRmediated EGFR transactivation is highly cell and context-dependent, and these various activation modes variably affect EGFR phosphorylation profiles, thereby promoting diverse EGFR-dependent signaling processes (4,6).…”

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: From the Department Of Pathology And Laboratory Medicine Unmentioning

confidence: 99%

“…Ligand-dependent and -independent EGFR activation mechanisms are thought to differentially stimulate downstream signaling pathways (4,5). Therefore, we investigated the impact of DUOX1 or NOX2 on activation of two downstream effector targets of EGFR activation, ERK1/2 and STAT3, in response to either ATP or EGF.…”

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 GPCR and EGF transactivation pathways are cell specific and depend on various parameters such as the G protein type, receptor type and cellular network (Liebmann 2011). In VSMCs, the activation of ERK1/2 by Ang II via AT I is partially dependent on the transactivation of EGFR (Eguchi et al 1998 …”

Section: Apj Signalling To Erk1/2mentioning

confidence: 99%

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

O’Carroll

Lolait

Harris

et al. 2013

Journal of Endocrinology

292

216

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The apelin receptor (APJ; gene symbol APLNR) is a member of the G protein-coupled receptor gene family. Neural gene expression patterns of APJ, and its cognate ligand apelin, in the brain implicate the apelinergic system in the regulation of a number of physiological processes. APJ and apelin are highly expressed in the hypothalamo-neurohypophysial system, which regulates fluid homeostasis, in the hypothalamic-pituitary-adrenal axis, which controls the neuroendocrine response to stress, and in the forebrain and lower brainstem regions, which are involved in cardiovascular function. Recently, apelin, synthesised and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is growing awareness of a potential role for apelin and APJ in glucose and energy metabolism. In this review we provide a comprehensive overview of the structure, expression pattern and regulation of apelin and its receptor, as well as the main second messengers and signalling proteins activated by apelin. We also highlight the physiological and pathological roles that support this system as a novel therapeutic target for pharmacological intervention in treating conditions related to altered water balance, stress-induced disorders such as anxiety and depression, and cardiovascular and metabolic disorders.

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“…Activation of the small GTPase Rac also promotes membrane recruitment of NADPH oxidase complex components (Gregg et al, 2003), while the p47phox subunit (necessary for oxidase activation) is phospho-regulated by both PKC (Fontayne et al, 2002) and the PI3K/Akt pathways (Hoyal et al, 2003). Generation of ROS plays a key role in MMP activation (Wetzker and Bohmer, 2003), increases PTK activity and EGFR phosphorylation via inhibitory oxidation of tyrosine phosphatases targeting Src kinase and EGFR (Salmeen et al, 2003;Chen et al, 2006), and may enhance proteolysis of proteins that repress PTK activity (Liebmann, 2011;George et al, 2013a). These important functions may, in turn, render EGFR transactivation sensitive to age-and disease-dependent perturbations in myocardial ROS and phosphatases.…”

Section: Mechanisms Of Egfr Transactivationmentioning

confidence: 99%

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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EGF receptor activation by GPCRs: An universal pathway reveals different versions

Cited by 134 publications

References 78 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

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

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