ERK phosphorylation in intact, adult brain by α2-adrenergic transactivation of EGF receptors

Du, Ting; Liu, Shufang; Zang, Ping; Prévot, Vincent; Hertz, Leif; Peng, Liang

doi:10.1016/j.neuint.2009.05.016

Cited by 30 publications

(25 citation statements)

References 59 publications

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“…It has been shown that MMPs are involved in GPCR-mediated transactivation of EGFR in different cell types [42, 43]. Activation of MMPs can release heparin binding-EGF (HB-EGF) by cleaving membrane bound pro-HB-EGF.…”

Section: Resultsmentioning

confidence: 99%

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

et al. 2016

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Injury to the eye or retina triggers Müller cells, the major glia cell of the retina, to dedifferentiate and proliferate. In some species they attain retinal progenitor properties and have the capacity to generate new neurons. The epidermal growth factor receptor (EGFR) system and extracellular signal-regulated kinase (ERK) signaling are key regulators of these processes in Müller cells. The extracellular signals that modulate and control these processes are not fully understood. In this work we studied whether endothelin receptor signaling can activate EGFR and ERK signaling in Müller cells. Endothelin expression is robustly upregulated at retinal injury and endothelin receptors have been shown to transactivate EGFRs in other cell types. We analyzed the endothelin signaling system in chicken retina and cultured primary chicken Müller cells as well as the human Müller cell line MIO-M1. The Müller cells were stimulated with receptor agonists and treated with specific blockers to key enzymes in the signaling pathway or with siRNAs. We focused on endothelin receptor mediated transactivation of EGFRs by using western blot analysis, quantitative reverse transcriptase PCR and immunocytochemistry. The results showed that chicken Müller cells and the human Müller cell line MIO-M1 express endothelin receptor B. Stimulation by the endothelin receptor B agonist IRL1620 triggered phosphorylation of ERK1/2 and autophosphorylation of (Y1173) EGFR. The effects could be blocked by Src-kinase inhibitors (PP1, PP2), EGFR-inhibitor (AG1478), EGFR-siRNA and by inhibitors to extracellular matrix metalloproteinases (GM6001), consistent with a Src-kinase mediated endothelin receptor response that engage ligand-dependent and ligand-independent EGFR activation. Our data suggest a mechanism for how injury-induced endothelins, produced in the retina, may modulate the Müller cell responses by Src-mediated transactivation of EGFRs. The data give support to a view in which endothelins among several other functions, serve as an injury-signal that regulate the gliotic response of Müller cells.

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Section: Resultsmentioning

confidence: 99%

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

et al. 2016

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“…The membranes were incubated with the first antibody, specific to one of the phosphorylation sites, or rabbit anti‐EGFR antibody at 1 × 1000 dilution for 2 h at 25°C as previously described (Li et al. 2008a; Du et al. 2009).…”

Section: Methodsmentioning

confidence: 99%

“…The supernatant was collected and the entire immunoprecipitates were subjected to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The membranes were incubated with the first antibody, specific to one of the phosphorylation sites, or rabbit anti-EGFR antibody at 1 · 1000 dilution for 2 h at 25°C as previously described (Li et al 2008a;Du et al 2009). The second antibody goat antirabbit IgG HRP conjugate at 1 · 1000 dilution was also used for 2 h at 25°C.…”

Section: Cell Culturesmentioning

confidence: 99%

Signaling pathways of isoproterenol‐induced ERK_1/2 phosphorylation in primary cultures of astrocytes are concentration‐dependent

Du¹,

et al. 2010

Journal of Neurochemistry

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J. Neurochem. (2010) 115, 1007–1023. Abstract Stimulation of β‐adrenoceptors activates the canonical adenylate cyclase pathway (via Gs protein) but can also evoke phosphorylation of extracellular‐regulated kinases 1 and 2 (ERK1/2) via Gs/Gi switching or β‐arrestin‐mediated recruitment of Src. In primary cultures of mouse astrocytes, activation of the former of these pathways required micromolar concentrations of the β1/β2‐adrenergic agonist isoproterenol, that acted on β1‐adrenoceptors, whereas the latter was activated already by nanomolar concentrations, acting on β2 receptors. Protein kinase A activity was required for Gs/Gi switching, which was followed by Ca2+ release from intracellular stores and Giα‐ and metalloproteinase‐dependent transactivation of the epidermal growth factor receptor (EGFR; at its Y1173 phophorylation site), via its receptor‐tyrosine kinase, β‐arrestin 1/2 recruitment, and MAPK/ERK kinase‐dependent ERK1/2 phosphorylation. ERK1/2 phosphorylation by Src activation depended on β‐arrestin 2, but not β‐arrestin 1, was accompanied by Src/EGFR co‐precipitation and phosphorylation of the EGFR at the Src‐phosphorylated Y845 site and the Y1045 autophosphorylation site; it was independent of transactivation but dependent on MAPK/ERK kinase activity, suggesting EGFR phosphorylation independently of the receptor‐tyrosine kinase or activation of Ras or Raf directly from Src. Most astrocytic consequences of activating either pathway (or both) are unknown, but morphological differentiation and increase in glial fibrillary acidic protein in response to dibutyryl cAMP‐mediated increase in cAMP depend on Gs/Gi switching and transactivation.

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“…The observation that imidazoline I 2 receptors are involved in the DEX-mediated long-term potentiation reduction provides novel information on the basic actions of DEX in the CNS (28). Epidermal growth factor receptor transactivation in astrocytes in the mature brain in vivo represents an important process in response to α 2 -AR stimulation, and it may lead to ERK1/2 phosphorylation in astrocytes and adjacent neurons (29). The α 2 -ARs also activate the mitogen-activated protein kinase pathway and thus facilitate the proliferation of cells derived from human intestinal epithelium, as well as the proximal tubule of rats and pigs (30,31).…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

Cai

Jia

et al. 2014

Molecular Medicine Reports

116

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Abstract. Dexmedetomidine (DEX), a highly specific α 2 -adrenergic agonist, which exhibits anaesthetic-sparing, analgesia and sympatholytic properties. DEX modulates gene expression, channel activation, transmitter release, inflammatory processes and apoptotic and necrotic cell death. It has also been demonstrated to have protective effects in a variety of animal models of ischemia/reperfusion (I/R) injury, including the intestine, myocardial, renal, lung, cerebral and liver. The broad spectrum of biological activities associated with DEX continues to expand, and its diverse effects suggest that it may offer a novel therapeutic approach for the treatment of human diseases with I/R involvement.

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ERK phosphorylation in intact, adult brain by α2-adrenergic transactivation of EGF receptors

Cited by 30 publications

References 59 publications

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Signaling pathways of isoproterenol‐induced ERK_1/2 phosphorylation in primary cultures of astrocytes are concentration‐dependent

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

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ERK phosphorylation in intact, adult brain by α2-adrenergic transactivation of EGF receptors

Cited by 30 publications

References 59 publications

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Endothelin B Receptors on Primary Chicken Müller Cells and the Human MIO-M1 Müller Cell Line Activate ERK Signaling via Transactivation of Epidermal Growth Factor Receptors

Signaling pathways of isoproterenol‐induced ERK1/2 phosphorylation in primary cultures of astrocytes are concentration‐dependent

Molecular targets and mechanism of action of dexmedetomidine in treatment of ischemia/reperfusion injury (Review)

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Signaling pathways of isoproterenol‐induced ERK_1/2 phosphorylation in primary cultures of astrocytes are concentration‐dependent