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:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we showed that the human kappa-opioid receptor (hkor) stably expressed in Chinese hamster ovary (CHO) cells underwent down-regulation after prolonged U50,488H treatment. In the present study, we determined the mechanisms underlying this process. U50, 488H caused a significant down-regulation of the hkor, although etorphine did not. Neither U50,488H nor etorphine caused down-regulation of the rat kappa-opioid receptor. Thus, similar to internalization, there are agonist and species differences in down-regulation of kappa-opioid receptors. Expression of the dominant negative mutants arrestin-2(319-418) or dynamin I-K44A significantly reduced U50,488H-induced down-regulation of the hkor. Coexpression of GRK2 or GRK2 and arrestin-2 permitted etorphine to induce down-regulation of the hkor, although expression of arrestin-2 or dynamin I alone did not. Expression of the dominant negative mutants rab5A-N133I or rab7-N125I blunted U50,488H-induced down-regulation. Pretreatment with lysosomal enzyme inhibitors [(2S, 3S)trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester or chloroquine] or proteasome inhibitors (proteasome inhibitor I, MG-132, or lactacystin) decreased the extent of U50,488H-induced down-regulation. A combination of chloroquine and proteasome inhibitor I abolished U50,488H-induced down-regulation. These results indicate that U50,488H-induced down-regulation of the hkor involves GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms and receptors seem to be trafficked to lysosomes and proteasomes for degradation. Thus, U50,488H-induced internalization and down-regulation of the hkor share initial common mechanisms. To the best of our knowledge, these results represent the first report on the involvement of both rab5 and rab7 in agonist-induced down-regulation of a G protein-coupled receptor. In addition, this study is among the first to show the involvement of proteasomes in agonist-induced down-regulation of a G protein-coupled receptor.
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PMID:Mechanisms of agonist-induced down-regulation of the human kappa-opioid receptor: internalization is required for down-regulation. 1099 50

G-protein-coupled receptor kinase 2 (GRK2) plays a key role in the regulation of G-protein-coupled receptors (GPCRs). GRK2 expression is altered in several pathological conditions, but the molecular mechanisms that modulate GRK2 cellular levels are largely unknown. We recently have described that GRK2 is degraded rapidly by the proteasome pathway. This process is enhanced by GPCR stimulation and is severely impaired in a GRK2 mutant that lacks kinase activity (GRK2-K220R). In this report, we find that beta-arrestin function and Src-mediated phosphorylation of GRK2 are critically involved in GRK2 proteolysis. Overexpression of beta-arrestin triggers GRK2-K220R degradation based on its ability to recruit c-Src, since this effect is not observed with beta-arrestin mutants that display an impaired c-Src interaction. The presence of an inactive c-Src mutant or of tyrosine kinase inhibitors strongly inhibits co-transfected or endogenous GRK2 turnover, respectively, and a GRK2 mutant with impaired phosphorylation by c-Src shows a markedly retarded degradation. This pathway for the modulation of GRK2 protein stability puts forward a new feedback mechanism for regulating GRK2 levels and GPCR signaling.
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PMID:Beta-arrestin- and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. 1156 77

Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, there has been little evidence connecting ubiquitination with regulation of mammalian G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) function. Agonist stimulation of endogenous or transfected beta2-adrenergic receptors (beta2ARs) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta2AR. Receptor ubiquitination required beta-arrestin, which bound to the E3 ubiquitin ligase Mdm2. Abrogation of beta-arrestin ubiquitination, either by expression in Mdm2-null cells or by dominant-negative forms of Mdm2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta2AR mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. These findings delineate an adapter role of beta-arrestin in mediating the ubiquitination of the beta2AR and indicate that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic GPCR.
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PMID:Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. 1158 19

Mdm2 is a ubiquitin-protein ligase known to ubiquitinate p53, promoting its degradation by the ubiquitin-proteasome system. Shenoy and co-workers showed that Mdm2 can act as a key factor in the sequestration of the cell surface beta(2)-adrenergic receptor (beta-AR) through interactions with beta-arrestin. Strous and Schantl discuss how Mdm2 may be a switch connecting extracellular signals mediated through G protein-coupled receptors (GPCRs) to p53 and its functions in apoptosis and cell cycle progression.
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PMID:Beta-arrestin and Mdm2, unsuspected partners in signaling from the cell surface. 1172 70

G protein-coupled receptor kinase 2 (GRK2) is a key modulator of G protein-coupled receptors (GPCR). Altered expression of GRK2 has been described to occur during pathological conditions characterized by impaired GPCR signaling. We have reported recently that GRK2 is rapidly degraded by the proteasome pathway and that beta-arrestin function and Src-mediated phosphorylation are involved in targeting GRK2 for proteolysis. In this report, we show that phosphorylation of GRK2 by MAPK also triggers GRK2 turnover by the proteasome pathway. Modulation of MAPK activation alters the degradation of transfected or endogenous GRK2, and a GRK2 mutant that mimics phosphorylation by MAPK shows an enhanced degradation rate, thus indicating a direct effect of MAPK on GRK2 turnover. Interestingly, MAPK-mediated modulation of wild-type GRK2 stability requires beta-arrestin function and is facilitated by previous phosphorylation of GRK2 on tyrosine residues by c-Src. Consistent with an important physiological role, interfering with this GRK2 degradation process results in altered GPCR responsiveness. Our data suggest that both c-Src and MAPK-mediated phosphorylation would contribute to modulate GRK2 degradation, and put forward the existence of new feedback mechanisms connecting MAPK cascades and GPCR signaling.
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PMID:MAPK-dependent degradation of G protein-coupled receptor kinase 2. 1273 76

Several years ago ubiquitin immunocytochemistry first demonstrated that ubiquitin protein conjugates are present in intraneuronal inclusions in all the major human chronic neurodegenerative diseases, as well as in inclusions in cerebellar astrocytomas and in hepatocytes in alcoholic liver disease. Unexpectedly, further studies showed that Lewy bodies are present in the cortex. Lewy bodies were originally described in the brain stem and are pathogonomic in the neuropathological diagnosis of Parkinson's disease. A balanced interpretation of further elegant experimental approaches, including transgenesis, suggests that the formation of intraneuronal inclusions is cytoprotective. Putative oligomeric proaggregates (prefibrillar entities) of cellular proteins inhibit the 26S proteasome and promote apoptosis. In the last few years a clutch of distinct experimental approaches have focused on the roles of ubiquitin-related processes in the development of the nervous system and neurohomeostasis. It is now clear that the ubiquitin/proteasome system (UPP) has a pivotal role in synaptogenesis, the formation of neuromuscular junctions and neurotransmitter receptor function. The inhibitory GABA(A) receptor, alpha1 glycine receptor, beta(2)-adrenergic receptor and arrestin, opiate receptors and the excitatory metabotropic glutamate receptor (mGluR1alpha) are regulated by the UPP. It is also increasingly clear that the regulation of long-term synaptic plasticity, and therefore memory, is dependent on both protein synthesis and protein degradation. Therefore, for the first time we have the opportunity to dissect the substrate of memory and the basis of cognitive decline in aging and in chronic neurodegenerative disease. Clearly, further understanding will provide a platform for novel drug development to treat chronic neurodegenerative diseases, including Alzheimer- and Parkinson-related conditions, and possibly psychiatric disorders.
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PMID:From neurodegeneration to neurohomeostasis: the role of ubiquitin. 1279 71

G protein-coupled receptor kinases (GRKs) are key modulators of G protein-coupled receptor signalling. Increasing evidence points to the occurrence of complex mechanisms able to modulate the subcellular localization, activity and expression levels of GRKs, revealing new functional interactions of these kinases with different cellular proteins and transduction cascades. GRK activity and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins, caveolin and calcium-sensing proteins. In addition, GRK phosphorylation by several other kinases has recently been shown to modulate its functionality, thus putting forward new feedback mechanisms connecting different signalling pathways to G protein-coupled receptors (GPCR) regulation. On the other hand, the mechanisms governing GRK expression at both transcriptional and protein stability levels are just beginning to be unveiled. Namely, GRK2 has been shown to be rapidly degraded by the proteasome pathway in a process dependent on beta-arrestin and c-Src function, and also to be proteolyzed by m-calpain. A better knowledge of GRK regulatory mechanisms would contribute to greater understanding of GRK physiological function and also its reported alterations in different pathological situations, such as congestive heart failure, hypertension or inflammation.
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PMID:Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. 1449 40

The effect of exercise on beta-adrenergic receptor (beta-AR) trafficking was investigated in rat adipocytes. The binding sites of a hydrophilic ligand, [(3)H]CGP12177, increased immediately (0 h) and at 3 h after exercise (3 h) but decreased at 24 h after exercise (24 h). The data of immunoblotting revealed that the alterations in the binding sites mainly paralleled the alterations in the beta2-AR proteins in membrane fractions. The protein expressions of both G-protein-coupled receptor kinase (GRK)-2 and beta-arrestin-2 were reduced, with a decline in beta2-AR ubiquitination at 0 h and 3 h. The protein expressions of beta2-AR, GRK-2, beta-arrestin-2, the beta2-AR/beta-arrestin-2 complex, and beta2-AR ubiquitination returned to their respective control levels at 24 h, whereas the beta2-AR mRNA level was reduced. Administration of either lactacystin or propranolol did not alter GRK-2 and beta2-AR protein expressions after exercise. Thus, the mechanism underlying the increased density of beta2-AR up to at least 3 h may involve alterations in a multistep event involving the coordinate interaction among proteins mediating beta2-AR trafficking, in which both the receptor-agonist interactions and ubiquitin-proteasome pathway have a key role. However, the decreased protein expression of beta2-AR at 24 h might be due to some change occurring at the translational levels.
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PMID:Beta-adrenergic receptor trafficking by exercise in rat adipocytes: roles of G-protein-coupled receptor kinase-2, beta-arrestin-2, and the ubiquitin-proteasome pathway. 1636 19

Amphetamine derivatives are the most commonly abused drugs. These compounds have been known for many years to induce neurotoxicity. However, recent findings have highlighted novel alterations produced by amphetamines in the central nervous system consisting of neuronal inclusions and the involvement of proteins belonging to a multi-enzymatic complex known as the ubiquitin-proteasome system. These ultrastructural and molecular changes are similar to those that occur during degenerative processes that affect the basal ganglia, and in particular Parkinson's disease, which is characterized by ubiquitin-containing neuronal inclusions in the subtantia nigra. This is recently confirmed by the occurrence of ubiquitin immunoreactive structures in the substantia nigra of humans abusing methamphetamines. In this article, we propose that the neurotoxicity of amphetamines and degenerative disorders share a number of steps in their mechanism of action involving the ubiquitin-proteasome system. The fine tuning of this ubiquitous proteolytic pathway is now being elucidated because G-protein-coupled receptors and signaling proteins such as beta-arrestin regulate access to this catalytic machinery. The identification of the ubiquitin-proteasome pathway and beta-arrestin as molecular targets of neurotoxicity is expected to provide novel therapeutic strategies both for the treatment of drug addiction and the treatment of neurodegenerative disorders.
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PMID:The neurotoxicity of amphetamines: bridging drugs of abuse and neurodegenerative disorders. 1667 60

Beta-arrestin1, which regulates many aspects of seven transmembrane receptor (7TMR) biology, has also been shown to serve as an adaptor, which brings Mdm2, an E3 ubiquitin ligase to the insulin-like growth factor-1 receptor (IGF-1R), leading to its proteasome-dependent destruction. Here we demonstrate that IGF-1R stimulation also leads to ubiquitination of beta-arrestin1, which regulates vesicular trafficking and activation of ERK1/2. This beta-arrestin1-dependent ERK activity can occur even when the classical tyrosine kinase signaling is impaired. siRNA-mediated suppression of beta-arrestin1 in human melanoma cells ablates IGF-1-stimulated ERK and prolongs the G1 phase of the cell cycle. These data suggest that beta-arrestin-dependent ERK signaling by the IGF-1R regulates cell cycle progression and may thus be an important regulator of the growth of normal and malignant cells.
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PMID:Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. 1730 58


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