Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK1/2 through a mechanism involving the scaffolding protein beta arrestin. Here we report that this activating pathway is independent of G alpha s, G alpha i, G alpha q or G betagamma and that the V2R-mediated activation of G alpha s inhibits ERK1/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the beta arrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and beta arrestin prevents signal propagation to the nucleus. Beta arrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the beta arrestin-dependent activation of ERK1/2 by the V2R involves c-Src and a metalloproteinase-dependent trans-activation event. These findings demonstrate that beta arrestin is a genuine signalling initiator that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand.
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PMID:The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling. 1685 42

G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) are transmembrane receptors that initiate intracellular signaling cascades in response to a diverse array of ligands. Recent studies have shown that signal transduction initiated by GPCRs and RTKs is not organized in distinct signaling cassettes where receptor activation leads to cell division and gene transcription in a linear manner. In fact, signal integration and diversification arises from a complex network involving crosscommunication between separate signaling units. Several different styles of crosstalk between GPCR- and RTK-initiated pathways exist, with GPCRs or components of GPCR-induced pathways being either upstream or downstream of RTKs. Activation of GPCRs sometimes results in a phenomenon known as "transactivation" of RTKs, which leads to the recruitment of scaffold proteins, such as Shc, Grb2, and Sos in addition to mitogen-activated protein kinase activation. In other cases, RTKs use different components of GPCR-mediated signaling, such as beta-arrestin, G protein-receptor kinases, and regulator of G protein signaling to integrate signaling pathways. This chapter outlines some of the more common mechanisms used by both GPCRs and RTKs to initiate intracellular crosstalk, thereby creating a complex signaling network that is important to normal development.
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PMID:Crosstalk coregulation mechanisms of G protein-coupled receptors and receptor tyrosine kinases. 1687 85

The focus of our study was to determine the role of G protein-coupled receptor kinases (GRKs) and beta-arrestins in agonist-induced CB1 receptor modulation during cannabinoid tolerance and their dependence from the extracellular signal-regulated kinase (ERK) cascade. In wild-type mice, chronic Delta9-tetrahydrocannabinol (THC) exposure significantly activated specific GRK and beta- arrestin subunits in all the considered brain areas (striatum, cerebellum, hippocampus, and prefrontal cortex), suggesting their involvement in the adaptive processes underlying CB1 receptor downregulation and desensitization. These events were ERK-dependent in the striatum and cerebellum, because they were prevented in the genetic (Ras-GRF1 knockout mice) and pharmacological (SL327-pretreated mice) models of ERK activation inhibition, whereas in the hippocampus and prefrontal cortex, they appeared to be mostly ERK-independent. In the latter areas, ERK activation after chronic THC increased the transcription factors cyclic adenosine monophosphate response element-binding protein and Fos B as well as a downstream protein known as brainderived neurotrophic factor. As a whole, our data suggest that in the striatum and cerebellum, THC-induced ERK activation could represent a key signaling event to initiate homologous desensitization of CB1 receptor, accounting for the development of tolerance to THC-induced hypolocomotion. In the prefrontal cortex and hippocampus, THC-induced alteration in GRKs and beta-arrestins primarily depends on other kinases, whereas ERK activation could be part of the molecular adaptations that underlie the complex behavioral phenotype that defines the addicted state.
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PMID:Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade. 1695 96

Toll-like receptors (TLRs) are a recently described receptor class involved in the regulation of innate and adaptive immunity. Here, we demonstrate that arrestin-2 and GRK5 (G protein-coupled receptor kinase 5), proteins that regulate G protein-coupled receptor signaling, play a negative role in TLR4 signaling in Raw264.7 macrophages. We find that lipopolysaccharide (LPS)-induced ERK1/2 phosphorylation is significantly enhanced in arrestin-2 and GRK5 knockdown cells. To elucidate the mechanisms involved, we tested the effect of arrestin-2 and GRK5 knockdown on LPS-stimulated signaling components that are upstream of ERK phosphorylation. Upon LPS stimulation, IkappaB kinase promotes phosphorylation and degradation of NFkappaB1 p105 (p105), which releases TPL2 (a MAP3K), which phosphorylates MEK1/2, which in turn phosphorylates ERK1/2. We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation. GRK5 knockdown also results in enhanced IkappaB kinase-mediated p105 phosphorylation and degradation, whereas GRK2 and GRK6 knockdown have no effect on this pathway. In vitro analysis demonstrates that arrestin-2 directly binds to the COOH-terminal domain of p105, whereas GRK5 binds to and phosphorylates p105. Taken together, these results suggest that p105 phosphorylation by GRK5 and binding of arrestin-2 negatively regulates LPS-stimulated ERK activation. These results reveal that arrestin-2 and GRK5 are important negative regulatory components in TLR4 signaling.
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PMID:Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. 1698 Mar 1

In this study we investigated the mechanisms responsible for MAP kinase ERK1/2 activation following agonist activation of endogenous mu opioid receptors (MOR) normally expressed in cultured striatal neurons. Treatment with the MOR agonist fentanyl caused significant activation of ERK1/2 in neurons derived from wild type mice. Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock-out (-/-) mice. In contrast, ERK1/2 activation by fentanyl was not evident in neurons from GRK3-/- mice or neurons pretreated with small inhibitory RNA for arrestin3. Consistent with this observation, treatment with the opiate morphine (which is less able to activate arrestin) did not elicit ERK1/2 activation in wild type neurons; however, transfection of arrestin3-(R170E) (a dominant positive form of arrestin that does not require receptor phosphorylation for activation) enabled morphine activation of ERK1/2. In addition, activation of ERK1/2 by fentanyl and morphine was rescued in GRK3-/- neurons following transfection with dominant positive arrestin3-(R170E). The activation of ERK1/2 appeared to be selective as p38 MAP kinase activation was not increased by either fentanyl or morphine treatment in neurons from wild type, MOR-/-, or GRK3-/- mice. In addition, U0126 (a selective inhibitor of MEK kinase responsible for ERK phosphorylation) blocked ERK1/2 activation by fentanyl. These results support the hypothesis that MOR activation of ERK1/2 requires opioid receptor phosphorylation by GRK3 and association of arrestin3 to initiate the cascade resulting in ERK1/2 phosphorylation in striatal neurons.
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PMID:Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons. 1698 18

Parathyroid hormone (PTH) stimulates ERK1/2 through both G-protein signaling and beta-arrestin2-mediated internalization. Beta-arrestin may serve as a scaffold for c-Src. However, the molecular mechanisms for ERK1/2 activation by PTH remain unclear. By using a targeted mutagenesis approach, we investigated the PTH/PTH-related protein receptor (PTH1R) structural determinants for ERK1/2 activation and transcriptional activity in HEK-293 cells. First, ERK1/2 activation was inhibited by PTH1R mutations that specifically abrogate G(q)-protein kinase C signaling without a decrease in cAMP-protein kinase A. Second, PTH1R C-terminal mutations and/or deletions that prevent interaction with beta-arrestin inhibited ERK1/2 activation. Similar results were obtained in HEK-293 cells co-expressing wild-type PTH1R and a dominant-negative beta-arrestin2. Third, the c-Src inhibitor PP2 and a kinase-dead c-SrcK295M mutant co-expressed with wild-type PTH1R both inhibited ERK1/2 activation. Furthermore, c-Src co-precipitated with both PTH1R and beta-arrestin2 in response to PTH. Deleting the PTH1R-proximal C terminus abolished these interactions. However, the need for receptor interaction with beta-arrestin to co-precipitate Src and activate ERK1/2 was obviated by expressing a constitutively active c-SrcY527A mutant, suggesting direct binding of activated Src to PTH1R. Subsequently, we identified and mutated to alanine four proline-rich motifs in the PTH1R distal C terminus, which resulted in loss of both c-Src and arrestin co-precipitation and significantly decreased ERK1/2 activation. These data delineate the multiple PTH1R structural determinants for ERK1/2 activation and newly identify a unique mechanism involving proline-rich motifs in the receptor C terminus for reciprocal scaffolding of c-Src and beta-arrestin2 with a class II G-protein-coupled receptor.
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PMID:Proline-rich motifs in the parathyroid hormone (PTH)/PTH-related protein receptor C terminus mediate scaffolding of c-Src with beta-arrestin2 for ERK1/2 activation. 1703 11

Signal transduction networks allow cells to recognize and respond to changes in the extracellular environment. All eukaryotic cells have MAPK (mitogen-activated protein kinase) pathways that participate in diverse cellular functions, including differentiation, survival, transformation and movement. Five distinct groups of MAPKs have been characterized in mammals, the most extensively studied of which is the Ras/Raf/MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]/ERK cascade. Numerous stimuli, including growth factors and phorbol esters, activate MEK/ERK signalling. How disparate extracellular signals are translated by MEK/ERK into different cellular functions remains obscure. Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1. Scaffolds organize multiprotein signalling complexes. This targets MEK/ERK to specific substrates and facilitates communication with other pathways, thereby mediating diverse functions. The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.
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PMID:The role of scaffold proteins in MEK/ERK signalling. 1705 9

In addition to regulating growth hormone release from the pituitary, ghrelin receptors also influence cell proliferation and apoptosis. By studying mitogen-activated protein kinase activity in human embryonic kidney 293 cells over-expressing ghrelin receptors, we aimed to identify the specific cell signalling pathways used by ghrelin receptors, and to determine if the truncated ghrelin receptor polypeptide had any influence on the functional activity of ghrelin receptors. We found that ghrelin activated extracellular signal-regulated kinases 1/2 with an EC50 value of 10 nM, and that this response was inhibited by the ghrelin receptor antagonists D-Lys3-GHRP-6 and [D-Arg1,D-Phe5,D-Trp(7,9),Leu11]-substance P. Ghrelin had little or no effect on the activity of c-Jun N-terminal kinase, p38 kinase or Akt. Ghrelin appeared to activate extracellular signal-regulated kinases 1/2 through a calcium-independent novel protein kinase C isoform which may utilize diacylglycerol derived from hydrolysis of phosphatidylcholine rather than from phosphatidylinositol. Ghrelin-stimulated extracellular signal-regulated kinases 1/2 activity was independent of transactivation of epidermal growth factor receptors, and even when ghrelin receptor internalization was blocked by concanavalin A or a beta-arrestin mutant, there was no decrease in phosphorylated extracellular signal-regulated kinases 1/2, suggesting this is a G protein-dependent process. The truncated ghrelin receptor polypeptide had no effect on ghrelin receptor signalling to extracellular signal-regulated kinases 1/2, but decreased the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors. In conclusion, our results suggest that any up-regulation of the truncated ghrelin receptor polypeptide might preferentially attenuate functional activity dependent on the constitutive activation of ghrelin receptors, while leaving ghrelin-dependent signalling unaffected.
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PMID:Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity. 1716

Beta-arrestin 1 and beta-arrestin 2 are well-known negative regulators of G-protein-coupled receptor (GPCR) signaling. Upon GPCR activation, beta-arrestins translocate to the cell membrane and bind to the agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, thus causing desensitization. However, accumulating evidence indicates that beta-arrestins also function as scaffold proteins that interact with several cytoplasmic proteins and link GPCRs to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that, in response to activation of certain GPCRs, beta-arrestins translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and cAMP-response element-binding protein (CREB) at the promoters of target genes to promote transcription. They also interact with regulators of transcription factors, such as IkappaBalpha and MDM2, in the cytoplasm and regulate transcription indirectly. This beta-arrestin-mediated regulation of transcription appears to play important roles in cell growth, apoptosis and modulation of immune functions.
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PMID:Beta-arrestin signaling and regulation of transcription. 1721 50

The concept of pharmacological efficacy has been much discussed recently with significant interest both in inverse agonists and in protean agonists (i.e., compounds with functional selectivity for different effector responses). Although first proposed in the mid-1990s, the pharmacological and therapeutic importance of these concepts is now receiving wider support. Two articles in recent issues of Molecular Pharmacology, Lane et al. (p. 1349, current issue) and Galandrin and Bouvier (Mol Pharmacol 70:1575-1584, 2006), provide new mechanistic information on functionally selective ligands at the pharmacologically important D2 dopamine receptor and the beta(1) and beta(2) adrenergic receptors. Each article bridges a gap between recent biophysical studies showing distinct receptor conformations produced by different ligands and the increasing number of reports of discordant outputs by a single ligand to two effector readouts. The Lane et al. study clearly demonstrates G protein-specific actions of D(2) dopamine receptor ligands. These range from equivalent responses for Galpha(o) and Galpha(i) activation by norapomorphine and 7-hydroxy-2-dipropylaminotetralin to S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine, which is an agonist for Galpha(o) activation and an inverse agonist at Galpha(i1) and Galpha(i2). Likewise, Galandrin and Bouvier describe a two-dimensional Cartesian efficacy approach in which propranolol is an agonist for extracellular signal-regulated kinase activation, probably through beta-arrestin, while functioning as an inverse agonist for adenylyl cyclase activation. Thus, these two important articles further solidify the concepts of functional selectivity and protean agonism and begin to define the first postreceptor step in actions of protean agonist ligands.
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PMID:Missing links: mechanisms of protean agonism. 1728 1


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