ET-1 stimulates ERK signaling pathway through sequential  activation of PKC and Src in rat myometrial cells

Robin, Philippe; Boulven, Isaline; Desmyter, Christine; Harbon, Simone; Leiber, Denis

doi:10.1152/ajpcell.00601.2001

Cited by 68 publications

(69 citation statements)

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“…ET A receptors are functionally coupled to Gq/11 protein to activate PLC, and to Gi protein to inhibit adenylyl cyclase (128). Binding of ET-1 to the ET A receptor induces a conformational change in the receptor that allows guanosine triphosphate (GTP) binding to the ␣-subunit of the receptor associatedtrimeric Gq/11 protein.…”

Section: Et Systemmentioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Glycosylation with Olinked ␤-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET A and ETB receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed. endothelin receptor; vascular signaling; O-GlcNAc modification GLYCOSYLATION IS THE SITE-specific enzymatic addition of saccharides to proteins and lipids. There are many types of glycosylation, but great interest has been directed to O-GlcNAcylation, or glycosylation with O-linked ␤-N-acetylglucosamine or ␤-Olinked 2-acetamido-2-deoxy-D-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [␤-N-acetylglucosamine (O-GlcNAc)] is added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169).Considering that almost every functional class of proteins is subject to O-GlcNAcylation (55, 177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets for O-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca 2ϩ )-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (...

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Section: Et Systemmentioning

confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…3). ET A receptors are functionally coupled to G q/11 protein to activate phospholiphase C-β (PLC-β), and to G i protein to inhibit adenylyl cyclase [54]. ET A receptormediated activation of G q/11 protein and PLC-β result in the breakdown of phosphatidylinositol 4,5-bisphosphate, and the generation of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol.…”

Section: Et Receptor-mediated Signaling Pathwaysmentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

107

105

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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“…PLCB3 may be targeted by both contractant and relaxant signaling pathways in the human myometrium and play a critical role in the balance between them (Zhong et al 2005). Both DAG-sensitive PKC, activated by PLCB products, and diacylglycerol (DAG)-insensitive PKC, possibly activated by PI3K-dependent process are involved in ERK activation to modulate rat uterine functions (Robin et al 2002). In addition, protein tyrosine kinase/phosphatase activities may control both phosphorylation and activation of PLCG1 and contribute to the modulation of the generation of inositol phosphates and uterine tension.…”

Section: Phosphatidyl Inositol Signaling Pathwaymentioning

confidence: 99%

“…ET-1 was first described as a potent modulator of uterine contractionsfor a review see Hertelendy & Zakar (2004) -but also has mitogenic properties in humans (Breuiller-Fouche et al 1998) and rat myometrial cells (Robin et al 2002). ET-1 transcript is up-regulated in the pregnant myometrium (Rehman et al 2003).…”

Section: Neuroactive-ligands and Parturitionmentioning

confidence: 99%

Gene and protein expression in the myometrium in pregnancy and labor

Breuiller-Fouché¹,

Germain²

2006

Reproduction

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Microarray technologies widen our comprehension of the major structural and metabolic transformations which affect the myometrium from the very beginning of pregnancy until parturition. The results are coherent with the mass of information which was accumulated previously, primarily on the basis of studies of selected critical factors. They highlight the activation of precise signaling pathways, some of which may have been previously under evaluated. The remodelling and maturation processes that the myometrium undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. Comparatively, the onset of labor is perhaps the phenomenon which remains the least well described by these methods of analysis. Nevertheless, genomic studies constitute a necessary first step of orientation and help establishing new links between the generic signaling pathways that are activated during the normal or pathological gestation. These studies also represent an indicative step that will have to be paralleled, in the future, with the results of the systematic proteomic analysis of the myometrium.

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ET-1 stimulates ERK signaling pathway through sequential activation of PKC and Src in rat myometrial cells

Cited by 68 publications

References 48 publications

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Gene and protein expression in the myometrium in pregnancy and labor

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