β-Arrestin 2: A Receptor-Regulated MAPK Scaffold for the Activation of JNK3

McDonald, Patricia; Chow, Chi‐Wing; Miller, William E.; Laporte, Stéphane A.; Field, Michael E.; Lin, Fang-Tsyr; Davis, Roger J.; Lefkowitz, Robert J.

doi:10.1126/science.290.5496.1574

Cited by 777 publications

(702 citation statements)

References 23 publications

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“…A number of scaffold or anchor proteins were found to facilitate the efficiency and secure the fidelity of signaling transductions (Le Cabec et al, 1997;Schaeffer et al, 1998;Whitmarsh and Davis, 1998;McDonald et al, 2000). At the submolecular level, great advances have been made in recent years enabling the identification of domain structures for protein-protein interactions (Hunter, 2000).…”

Section: Introductionmentioning

confidence: 99%

Regulation of PRAK Subcellular Location by p38 MAP Kinases

New

Jiang

Han

2003

MBoC

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The p38 mitogen-activated protein kinase (MAPK) pathway plays an important role in cellular responses to inflammatory stimuli and environmental stress. p38 regulated/activated protein kinase (PRAK, also known as mitogen-activated protein kinase activated protein kinase 5 [MAP-KAPK5]) functions downstream of p38␣ and p38␤ in mediating the signaling of the p38 pathway. Immunostaining revealed that endogenous PRAK was predominantly localized in the cytoplasm. Interestingly, ectopically expressed PRAK was localized in the nucleus and can be redistributed by coexpression of p38␣ or p38␤ to the locations of p38␣ and p38␤. Mutations in the docking groove on p38␣/p38␤, or the p38-docking site in PRAK, disrupted the PRAK-p38 interaction and impaired the ability of p38␣ and p38␤ to redistribute ectopically expressed PRAK, indicating that the location of PRAK could be controlled by its docking interaction with p38␣ and p38␤. Although the majority of PRAK molecules were detected in the cytoplasm, PRAK is consistently shuttling between the cytoplasm and the nucleus. A sequence analysis of PRAK shows that PRAK contains both a putative nuclear export sequence (NES) and a nuclear localization sequence (NLS). The shuttling of PRAK requires NES and NLS motifs in PRAK and can be regulated through cellular activation induced by stress stimuli. The nuclear content of PRAK was reduced after stimulation, which resulted from a decrease in the nuclear import of PRAK and an increase in the nuclear export of PRAK. The nuclear import of PRAK is independent from p38 activation, but the nuclear export requires p38-mediated phosphorylation of PRAK. Thus, the subcellular distribution of PRAK is determined by multiple factors including its own NES and NLS, docking interactions between PRAK and docking proteins, phosphorylation of PRAK, and cellular activation status. The p38 MAPKs not only regulate PRAK activity and PRAK activation-related translocation, but also dock PRAK to selected subcellular locations in resting cells.

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Section: Introductionmentioning

confidence: 99%

Regulation of PRAK Subcellular Location by p38 MAP Kinases

New

Jiang

Han

2003

MBoC

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“…in addition, β-arrestin has been shown to function as a signaling intermediate and, for instance, is involved in the activation of the MApK pathway. 4,5 Historically, within the drug discovery environment, Gpcr agonists have been discovered through traditional second messenger assay formats, which measure the activation of G proteins (e.g., [ 35 s]Gtpγs binding) and subsequent signaling events (e.g., inhibition of forskolin-stimulated cAMp production). However, in recent years, pressure to develop more robust and high-throughput assays, with higher Z′ values and the discovery of non-G-protein-mediated signaling through Gpcrs, has led to the development of alternative assay formats, such as β-arrestin recruitment.…”

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confidence: 99%

Understanding the Effect of Different Assay Formats on Agonist Parameters: A Study Using the µ-Opioid Receptor

et al. 2011

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IntroductIonG -protein-coupled receptors (Gpcrs) are the largest superfamily of cell surface signal transduction molecules. they are important targets in drug discovery, with an estimated 25% of prescription drugs exerting their effects through them. 1 Gpcrs exert many of their effects by activation of heterotrimeric G proteins (Gi, Gs, Gq). Following activation, G proteins divide into respective α and βγ subunits, both of which have the ability to activate or inhibit effector molecules, such as adenylate cyclase and phospholipase c. the receptor then becomes phosphorylated on intracellular serine and threonine residues by Gpcr kinases (GrKs). 2,3 the phosphorylated receptor is then bound by β-arrestin, which sterically prevents further G-protein interaction and recruits other proteins such as clathrin, which are involved in receptor internalization. in addition, β-arrestin has been shown to function as a signaling intermediate and, for instance, is involved in the activation of the MApK pathway. 4,5 Historically, within the drug discovery environment, Gpcr agonists have been discovered through traditional second messenger assay formats, which measure the activation of G proteins (e.g., [ 35 s]Gtpγs binding) and subsequent signaling events (e.g., inhibition of forskolin-stimulated cAMp production). However, in recent years, pressure to develop more robust and high-throughput assays, with higher Z′ values and the discovery of non-G-protein-mediated signaling through Gpcrs, has led to the development of alternative assay formats, such as β-arrestin recruitment. in particular, the discoverx pathHunter assay technology used in this report uses an enzyme complementation system to detect the interaction between a tagged Gpcr and tagged β-arrestin. 6,7 Although this assay is being used with increasing frequency, the pharmacologic values generated have not been thoroughly investigated and put into context with traditional pharmacological models.Agonists have two properties: affinity (K A ), which is a purely drug-dependent parameter and determines how well the agonist binds to the receptor (and therefore should be equivalent for all functional endpoints), and efficacy (tau), which measures the efficiency of the transduction of binding into a response and is dependent on the ligand and the tissue/signaling pathway involved (and therefore is likely to differ for different functional endpoints). the translation of occupancy into effect is what is measured in the form of an agonist-concentration/effect ([A]/e) curve. the ability to discriminate between agonists with different efficacies is of critical importance in drug discovery. However, overexpressing recombinant systems can lead to the overestimation of the potency and efficacy of compounds, and in particular, 1 discovery Biology, pfizer inc., Kent, uK. the correct interpretation of data is fundamental to the study of G-protein-coupled receptor pharmacology. often, new assay technologies are assimilated into the drug discovery environment without full consideration of t...

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“…b-Arrestins 1 and 2 are associated with ND D Sun et al roles in the opioid receptor and MAPK signaling transduction processes [24][25][26]46 and the extensive evidence that opioid receptors and MAPK cascades are involved in drug addiction, [18][19][20][21][22][27][28][29][30] ARRB1 and ARRB2 were considered plausible candidates for ND.…”

Section: Discussionmentioning

confidence: 99%

β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

Sun

Payne

et al. 2007

Mol Psychiatry

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On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the b-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample. Molecular Psychiatry (2008) 13, 398-406; doi:10.1038/sj.mp.4002036; published online 19 June 2007Keywords: haplotype; SNP; ARRB1; ARRB2; association analysis; nicotine dependence Introduction Tobacco use is a leading preventable cause of death in the United States, with one in every five deaths attributable to smoking. 1 Nicotine is believed to be the primary addictive component of cigarette smoke. Nicotine dependence (ND) is a complex quantitative trait that is influenced by both genetic and environmental factors. 2 A number of linkage and association studies have identified susceptibility genes for ND; 3,4 however, few association studies of candidate genes and/or linkage analyses for susceptibility loci have been replicated in independent samples. 3,5 Previously, we identified several chromosomal regions that are likely to harbor susceptibility loci for ND in the Framingham Heart Study (FSH) and Mid-South Tobacco Family (MSTF) samples, including one region on chromosome 11q13 and one on chromosome 17p13, 3,[6][7][8] where the two genes of interest, b-arrestins 1 and 2 (ARRB1 and ARRB2), are located, 9,10 respectively. b-arrestins are key negative regulators and scaffolds for G-protein-coupled receptor (GPCR) signaling, one of the most fundamental cellular signal ...

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β-Arrestin 2: A Receptor-Regulated MAPK Scaffold for the Activation of JNK3

Cited by 777 publications

References 23 publications

Regulation of PRAK Subcellular Location by p38 MAP Kinases

Regulation of PRAK Subcellular Location by p38 MAP Kinases

Understanding the Effect of Different Assay Formats on Agonist Parameters: A Study Using the µ-Opioid Receptor

β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

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