Journal articles: 'Beta arrestin signaling'

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Nogueras-Ortiz, Carlos, Cristina Roman-Vendrell, Gabriel E. Mateo-Semidey, Yu-Hsien Liao, Debra A. Kendall, and Guillermo A. Yudowski. "Retromer stops beta-arrestin 1–mediated signaling from internalized cannabinoid 2 receptors." Molecular Biology of the Cell 28, no. 24 (November 15, 2017): 3554–61. http://dx.doi.org/10.1091/mbc.e17-03-0198.

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G protein–coupled receptors mediate their complex functions through activation of signaling cascades from receptors localized at the cell surface and endosomal compartments. These signaling pathways are modulated by heterotrimeric G proteins and the scaffold proteins beta-arrestin 1 and 2. However, in contrast to the events occurring at the cell surface, our knowledge of the mechanisms controlling signaling from receptors localized at intracellular compartments is still very limited. Here we sought to investigate the intracellular signaling from cannabinoid 2 receptor (CB2R). First, we show that receptor internalization is required for agonist-induced phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Then we demonstrate that ERK1/2 activation is mediated by beta-arrestin 1 from receptors localized exclusively at Rab4/5 compartments. Finally, we identify the retromer complex as a gatekeeper, terminating beta-arrestin 1–mediated ERK phosphorylation. These findings extend our understanding of the events controlling signaling from endocytosed receptors and identify the retromer as a modulator of beta-arrestin–mediated signaling from CB2R.

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Patel, Priyesh A., Douglas G. Tilley, and Howard A. Rockman. "Beta-Arrestin-Mediated Signaling in the Heart." Circulation Journal 72, no. 11 (2008): 1725–29. http://dx.doi.org/10.1253/circj.cj-08-0734.

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Ma, L., and G. Pei. "beta-arrestin signaling and regulation of transcription." Journal of Cell Science 120, no. 2 (January 15, 2007): 213–18. http://dx.doi.org/10.1242/jcs.03338.

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Laporte, S. A., and M. G. Caron. "Beta-arrestin and GPCR desensitization, internalization, and signaling." Biochemical Society Transactions 29, no. 3 (June 1, 2001): A64. http://dx.doi.org/10.1042/bst029a064.

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Lee, Claudia, Gayathri Viswanathan, Issac Choi, Chanpreet Jassal, Taylor Kohlmann, and Sudarshan Rajagopal. "Beta-Arrestins and Receptor Signaling in the Vascular Endothelium." Biomolecules 11, no. 1 (December 23, 2020): 9. http://dx.doi.org/10.3390/biom11010009.

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The vascular endothelium is the innermost layer of blood vessels and is a key regulator of vascular tone. Endothelial function is controlled by receptor signaling through G protein-coupled receptors, receptor tyrosine kinases and receptor serine-threonine kinases. The β-arrestins, multifunctional adapter proteins, have the potential to regulate all of these receptor families, although it is unclear as to whether they serve to integrate signaling across all of these different axes. Notably, the β-arrestins have been shown to regulate signaling by a number of receptors important in endothelial function, such as chemokine receptors and receptors for vasoactive substances such as angiotensin II, endothelin-1 and prostaglandins. β-arrestin-mediated signaling pathways have been shown to play central roles in pathways that control vasodilation, cell proliferation, migration, and immune function. At this time, the physiological impact of this signaling has not been studied in detail, but a deeper understanding of it could lead to the development of novel therapies for the treatment of vascular disease.

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Conley, Jason M., and Hongxia Ren. "Human GPR17 Nonsynonymous Variants Identified in Individuals with Metabolic Diseases Have Distinct Functional Signaling Profiles." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A656. http://dx.doi.org/10.1210/jendso/bvab048.1337.

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Abstract GPR17 is a G protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Our genetic knockout studies in rodents suggest that GPR17 is a potential therapeutic target for the treatment of metabolic diseases. However, the contributions of GPR17 to human metabolism and metabolic deficits are not well understood. Here, we analyzed the human GPR17 coding sequences of individuals from control and metabolic disease cohorts that were comprised of patients with clinical phenotypes including severe insulin resistance, hypercholesterolemia, and obesity. Across cohorts, 18 nonsynonymous GPR17 variants were identified, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, cellular localization, and downstream functional signaling profiles of nine human GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). We found that the protein expression levels and subcellular localization for each of the nine GPR17 variants were similar to that of the wild type GPR17. As the endogenous GPR17 ligand is still elusive, we used a synthetic GPR17 agonist to quantitatively measure the functional signaling profiles of GPR17 variants. We found some of the variants had distinctly altered signaling profiles. GPR17-G136S lost agonist-mediated cAMP, Ca2+, and beta-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT but had impaired Ca2+ and beta-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling but enhanced agonist-stimulated beta-arrestin recruitment. Also, GPR17-G354V retained cAMP and Ca2+ signaling function but had attenuated beta-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with distinct signaling profiles, including differential signaling perturbations that resulted in receptor signaling bias. These results are expected to contribute to our understanding of the molecular signaling mechanisms underlying GPR17 in metabolic regulation.

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Carneiro de Morais, Carla P., Juliano Z. Polidoro, Donna L. Ralph, Thaissa D. Pessoa, Maria Oliveira-Souza, Valério G. Barauna, Nancy A. Rebouças, Gerhard Malnic, Alicia A. McDonough, and Adriana C. C. Girardi. "Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling." American Journal of Physiology-Cell Physiology 309, no. 8 (October 15, 2015): C541—C550. http://dx.doi.org/10.1152/ajpcell.00072.2015.

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Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10−7 M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization.

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Wisler, J. W., S. M. DeWire, E. J. Whalen, J. D. Violin, M. T. Drake, S. Ahn, S. K. Shenoy, and R. J. Lefkowitz. "A unique mechanism of beta-blocker action: Carvedilol stimulates beta-arrestin signaling." Proceedings of the National Academy of Sciences 104, no. 42 (October 9, 2007): 16657–62. http://dx.doi.org/10.1073/pnas.0707936104.

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Hurst, Dow P., Diane L. Lynch, Derek M. Shore, Michael C. Pitman, and Patricia H. Reggio. "Beta-Arrestin Biased Signaling at a Class a GPCR: Modeling the ORG27569 Induced CB1/Beta-Arrestin 1 Complex." Biophysical Journal 108, no. 2 (January 2015): 97a. http://dx.doi.org/10.1016/j.bpj.2014.11.557.

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Yin, Deling, Hui Yan, Hui Li, Christopher Daniels, Krishna Singh, Balvin Chua, Charles Stuart, Yi Caudle, and Gene LeSage. "Beta-arrestin 2 plays a critical role in sepsis-induced cardiac dysfunction." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.4. http://dx.doi.org/10.4049/jimmunol.196.supp.124.4.

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Abstract Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. β-arrestin 2, a key regulator and scaffolds of various signaling, modulates cell survival and cell death in various systems. However, the effect of β-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known. Here, we show that β-arrestin 2 overexpression significantly enhances animal survival following cecal ligation and puncture (CLP)-induced sepsis. Importantly, overexpression of β-arrestin 2 in mice prevents CLP-induced cardiac dysfunction. In addition, β-arrestin 2 overexpression dramatically attenuates CLP-induced myocardial gp130 and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels following CLP. Therefore, β-arrestin 2 prevents CLP-induced cardiac dysfunction through gp130 and p38. These results suggest that modulation of β-arrestin 2 might provide a novel therapeutic approach to prevent cardiac dysfunction in patients with sepsis.

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Petrillo, Maria G., David Diaz-Jimenez, Robert H. Oakley, and John A. Cidlowski. "Beta‐Arrestin‐1 Alters Glucocorticoid Signaling and the Glucocorticoid Receptor Transcriptome." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.03093.

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12

Hanson, Bonnie J., Justin Wetter, Mark R. Bercher, Leisha Kopp, Maya Fuerstenau-Sharp, Kevin L. Vedvik, Thomas Zielinski, Chris Doucette, Pamela J. Whitney, and Chetana Revankar. "A Homogeneous Fluorescent Live-Cell Assay for Measuring 7-Transmembrane Receptor Activity and Agonist Functional Selectivity Through Beta-Arrestin Recruitment." Journal of Biomolecular Screening 14, no. 7 (June 16, 2009): 798–810. http://dx.doi.org/10.1177/1087057109335260.

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Seven-transmembrane (7TM) receptors play an essential role in the regulation of a wide variety of physiological processes, making them one of the top target classes for pharmaceuticals. 7TM receptor function is mediated and modulated through 2 primary processes: G-protein and beta-arrestin signaling. Classically, it has been recognized that these 2 processes can interact with one another during 7TM receptor desensitization, but it has more recently been recognized that these 2 processes can also act independently of one another and can activate parallel signaling pathways. As such, the methods used to interrogate 7TM receptor signaling, both from a biological and a pharmaceutical perspective, may need to be reevaluated and the question of whether functionally selective compounds (compounds that selectively activate one pathway over another) can be rationally developed must be raised. Although numerous high-throughput screening (HTS) compatible assays exist for studying second messengers arising from G-protein signaling, far fewer HTS compatible assays exist for studying beta-arrestin recruitment. The authors report on the Tango™ 7TM receptor assay technology, a high-throughput homogeneous assay method for monitoring beta-arrestin recruitment that uses a live-cell fluorescent readout. This assay format is broadly applicable to 7TM receptors, independent of G-protein coupling and, as such, has been used to produce assays for over 70 7TM receptor targets. The authors also show how flow cytometry can be used to select clones with desired pharmacological profiles and how an inducible expression system can increase the assay window for targets with high levels of constitutive activity. Finally, they demonstrate how the Tango™ system can be used in parallel with assays aimed at second-messenger signaling to enable functional selectivity studies. ( Journal of Biomolecular Screening 2009:798-810)

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Kohout, T. A. "beta -Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking." Proceedings of the National Academy of Sciences 98, no. 4 (February 6, 2001): 1601–6. http://dx.doi.org/10.1073/pnas.041608198.

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Bryja, V., D. Gradl, A. Schambony, E. Arenas, and G. Schulte. "beta-Arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo." Proceedings of the National Academy of Sciences 104, no. 16 (April 10, 2007): 6690–95. http://dx.doi.org/10.1073/pnas.0611356104.

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Niu, Shaona, Hui Li, Wenbin Chen, Jiajun Zhao, Ling Gao, and Tao Bo. "Beta-Arrestin 1 Mediates Liver Thyrotropin Regulation of Cholesterol Conversion Metabolism via the Akt-Dependent Pathway." International Journal of Endocrinology 2018 (2018): 1–12. http://dx.doi.org/10.1155/2018/4371396.

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After activation, G protein-coupled receptors (GPCRs) are desensitized by β-arrestins (ARRBs). Moreover, ARRBs can initiate a second wave of signaling independent of G proteins. Thyroid-stimulating hormone receptor (TSHR) is one of the GPCR members. In our previous study, TSHR was identified in the liver; the major role of TSHR in cholesterol metabolism was illustrated, as TSH could regulate hepatic cholesterol metabolism via cAMP/PKA/CREB/HMGCR and SREBP2/HNF4α/CYP7A1 pathways. It has been reported that ARRB2 predominates over ARRB1 in TSHR internalization. However, the significance of ARRBs in TSH-initiated cholesterol metabolism has not been illustrated. In our study, the effects of ARRBs on TSH-regulated cholesterol metabolism are investigated. ARRB1/2 was genetically inactivated in C57BL/6 mice and HepG2 cell line, respectively. Cholesterol levels in arrestin-knockout mice and arrestin-knockdown cells were measured. Molecules participating in cholesterol metabolism were analyzed. It turned out that deficiencies in ARRB1 led to decreased cholesterol levels and decreased TSH-stimulated AKT phosphorylation. Subsequently, the inhibitory effect on CYP7A1 by SREBP2 was reduced due to lowered mature SREBP2 level. Other than the failures of TSH in ARRB-knockdown cells, the AKT activator SC79 could enhance AKT phosphorylation and mature SREBP2 level. Our results demonstrate that ARRBs, especially ARRB1, are involved in TSH-regulated cholesterol metabolism through the AKT pathway.

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Hennig, Martin Jp, Georgios Kallifatidis, Diandra K. Smith, Dailey S. Morera, Marie C. Hupe, Markus A. Kuczyk, Axel S. Merseburger, and Vinata B. Lokeshwar. "Regulation of stem cell-like phenotype and response to chemotherapy in bladder cancer by beta-arrestins." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 461. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.461.

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461 Background: Identification of molecular drivers that promote a muscle invasive phenotype and chemoresistance in bladder cancer, as well as an understanding of their mechanism of action should help in designing potential prognostic markers and effective targeted treatments for patients with advanced bladder cancer. β-arrestins (ARRBs) are classic attenuators of G-Protein coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. Methods: β-arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63; n = 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated using CRISPR-Cas9 mediated gene-knockout of ARRB1. The consequence of forced expression of ARRBs on tumor growth and response to gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. Results: ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared to normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ~ 80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity towards gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. Conclusions: β-Arrestins regulate response towards gemcitabine and are therefore potential targets and predictive markers for chemotherapy failure in bladder cancer. The present work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer.

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Wang, Wei, Tianci Han, Wei Tong, Jian Zhao, and Xueshan Qiu. "Overexpression of GPR35 confers drug resistance in NSCLC cells by β-arrestin/Akt signaling." OncoTargets and Therapy Volume 11 (September 2018): 6249–57. http://dx.doi.org/10.2147/ott.s175606.

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Nguyen, Anthony H., and Robert J. Lefkowitz. "Signaling at the endosome: cryo‐EM structure of a GPCR–G protein–beta‐arrestin megacomplex." FEBS Journal 288, no. 8 (March 8, 2021): 2562–69. http://dx.doi.org/10.1111/febs.15773.

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van Rijn, Richard M., Terrance Chiang, Rob J. Cassell, Kendall L. Mores, Mohamed S. A. El-Sayed, Mark S. Cushman, Amr H. A. Abdallah, and Markus A. Lill. "Strong beta-arrestin signaling may cause unwanted effects for drug treatments of alcohol use disorders." Alcohol 60 (May 2017): 206. http://dx.doi.org/10.1016/j.alcohol.2017.02.195.

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Taghert, Paul H. "The incidence of candidate binding sites for β-arrestin in Drosophila neuropeptide GPCRs." PLOS ONE 17, no. 11 (November 1, 2022): e0275410. http://dx.doi.org/10.1371/journal.pone.0275410.

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To support studies of neuropeptide neuromodulation, I have studied beta-arrestin binding sites (BBS’s) by evaluating the incidence of BBS sequences among the C terminal tails (CTs) of each of the 49 Drosophila melanogaster neuropeptide GPCRs. BBS were identified by matches with a prediction derived from structural analysis of rhodopsin:arrestin and vasopressin receptor: arrestin complexes [1]. To increase the rigor of the identification, I determined the conservation of BBS sequences between two long-diverged species D. melanogaster and D. virilis. There is great diversity in the profile of BBS’s in this group of GPCRs. I present evidence for conserved BBS’s in a majority of the Drosophila neuropeptide GPCRs; notably some have no conserved BBS sequences. In addition, certain GPCRs display numerous conserved compound BBS’s, and many GPCRs display BBS-like sequences in their intracellular loop (ICL) domains as well. Finally, 20 of the neuropeptide GPCRs are expressed as protein isoforms that vary in their CT domains. BBS profiles are typically different across related isoforms suggesting a need to diversify and regulate the extent and nature of GPCR:arrestin interactions. This work provides the initial basis to initiate future in vivo, genetic analyses in Drosophila to evaluate the roles of arrestins in neuropeptide GPCR desensitization, trafficking and signaling.

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Pakharukova, Natalia, Ali Masoudi, Biswaranjan Pani, Dean P. Staus, and Robert J. Lefkowitz. "Allosteric activation of proto-oncogene kinase Src by GPCR–beta-arrestin complexes." Journal of Biological Chemistry 295, no. 49 (September 25, 2020): 16773–84. http://dx.doi.org/10.1074/jbc.ra120.015400.

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G protein–coupled receptors (GPCRs) initiate signaling cascades via G-proteins and beta-arrestins (βarr). βarr-dependent actions begin with recruitment of βarr to the phosphorylated receptor tail and are followed by engagement with the receptor core. βarrs are known to act as adaptor proteins binding receptors and various effectors, but it is unclear whether in addition to the scaffolding role βarrs can allosterically activate their downstream targets. Here we demonstrate the direct allosteric activation of proto-oncogene kinase Src by GPCR–βarr complexes in vitro and establish the conformational basis of the activation. Whereas free βarr1 had no effect on Src activity, βarr1 in complex with M2 muscarinic or β2-adrenergic receptors reconstituted in lipid nanodiscs activate Src by reducing the lag phase in Src autophosphorylation. Interestingly, receptor–βarr1 complexes formed with a βarr1 mutant, in which the finger-loop, required to interact with the receptor core, has been deleted, fully retain the ability to activate Src. Similarly, βarr1 in complex with only a phosphorylated C-terminal tail of the vasopressin 2 receptor activates Src as efficiently as GPCR–βarr complexes. In contrast, βarr1 and chimeric M2 receptor with nonphosphorylated C-terminal tail failed to activate Src. Taken together, these data demonstrate that the phosphorylated GPCR tail interaction with βarr1 is necessary and sufficient to empower it to allosterically activate Src. Our findings may have implications for understanding more broadly the mechanisms of allosteric activation of downstream targets by βarrs.

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Rosanò, L., R. Cianfrocca, S. Masi, F. Spinella, V. Di Castro, A. Biroccio, E. Salvati, R. Nicotra, P. G. Natali, and A. Bagnato. "168 POSTER Endothelin A receptor/beta-arrestin signaling is critical for ovarian cancer metastasis: novel molecular therapeutic applications." European Journal of Cancer Supplements 6, no. 12 (October 2008): 54. http://dx.doi.org/10.1016/s1359-6349(08)72100-1.

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Young, M., T. Dahoun, B. Sokrat, C. Arber, K. M. Chen, M. Bouvier, and P. Barth. "Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways." Proceedings of the National Academy of Sciences 115, no. 27 (June 18, 2018): 7051–56. http://dx.doi.org/10.1073/pnas.1718489115.

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Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein–coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways. Using this approach, we designed orthogonal D2–Gi complexes, which coupled with high specificity and triggered exclusively the Gi-dependent signaling pathway. We also engineered an orthogonal chimeric D2–Gs/i complex that rewired D2 signaling from a Gi-mediated inhibitory into a Gs-dependent activating pathway. Reinterpreting the evolutionary history of GPCRs in light of the designed proteins, we uncovered an unforeseen hierarchical code of GPCR–G-protein coupling selectivity determinants. The results demonstrate that membrane receptor–cytosolic protein systems can be rationally engineered to regulate mammalian cellular functions. The method should prove useful for creating orthogonal molecular switches that redirect signals at the cell surface for cell-engineering applications.

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Plisson, Fabien, Timothy A. Hill, Justin M. Mitchell, Huy N. Hoang, Aline D. de Araujo, Weijun Xu, Adam Cotterell, et al. "Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling." European Journal of Medicinal Chemistry 127 (February 2017): 703–14. http://dx.doi.org/10.1016/j.ejmech.2016.10.044.

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Persson, Mika, Evangeline Jackson, Ryan Duchatel, Liesl Bramberger, Holly McEwen, Padraic Kearney, Izac Findlay, et al. "TMIC-06. ANTAGONISM OF DRD2 USING ONC201 INCREASED EXPRESSION OF ANTIGEN PRESENTATION PATHWAY PROTEINS IN DIFFUSE MIDLINE GLIOMA, RECRUITING TUMOR INFILTRATING LYMPHOCYTES IN VIVO." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii272. http://dx.doi.org/10.1093/neuonc/noac209.1050.

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Abstract Diffuse midline glioma (DMG) is a high-grade glioma with a median overall survival of 9-11 months. Radiotherapy is the only recognized treatment. The DMG tumor microenvironment (TME) contains few, if any, tumor infiltrating lymphocytes (TILs) or inflammatory cytokines, thus is distinctive of an ‘immunologically cold’ tumor/TME.1 DMG lack the expression of immunosuppressive immune checkpoint proteins, likely explaining the failure of immune checkpoint inhibitors (ICI) tested under clinical trials for DMG patients, and suggestive of an alternative mechanism underpinning the cold TME. 1 Glioblastomas also harbor a cold TME, which can be somewhat explained by T cell lymphopenia, influenced by the sequestration of T cells in the bone marrow (through Beta-arrestin-induced internalization of Sphingosine-1-phosphate receptor 1 [S1PR1]). 2 Dopaminergic activation of Beta-arrestin and hence S1PR1 internalization, is potentially regulated through dopaminergic peripheral nerves in primary and secondary lymphoid organs, regulated by the Dopamine receptor D2 (DRD2), that is highly expressed on T cells. ONC201 is a potent DRD2 antagonist, currently in phase I-III clinical trials for DMG patients, alone and in combination with radiotherapy and the PI3K/AKT inhibitor paxalisib (NCT05009992). Proteomic profiling of DMG patient-derived cells +/-ONC201 showed increased expression of several antigen presenting pathway proteins, including Beta-2-microglobulin (B2M) and HLA class I histocompatibility antigen, A alpha chain (HLA-A). This was confirmed in vivo using SU-DIPG-VI patient-derived xenograft mouse model tissues +/-ONC201 alone, and together with paxalisib. Excitingly, this combination (given orally) promoted the recruitment of TILs to the tumor, revealing novel immunomodulatory effects. In vivo, ONC201 promoted the expression of EMILIN-3, a TGF-β antagonist that is known to inhibit HLA-A/B2M expression, possibly explaining the increased MHC-I activity. This study uncovers a novel link between treatment of DMG with ONC201 and paxalisib and the role dopaminergic peripheral nerves signaling may play on the sequestration of T cells within lymphoid organs and lymphopenia.

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Rosanò, L., R. Cianfrocca, F. Spinella, V. Di Castro, P. G. Natali, and A. Bagnato. "388 Positive inter-regulation between beta-catenin and endothelin signaling: critical role of beta-arrestin-1 in the epigenetic regulation of gene transcription in ovarian cancer cells." European Journal of Cancer Supplements 8, no. 5 (June 2010): 99. http://dx.doi.org/10.1016/s1359-6349(10)71189-7.

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Wisniewski, Szymon, Paulina Dragan, Anna Makal, and Dorota Latek. "Helix 8 in chemotactic receptors of the complement system." PLOS Computational Biology 18, no. 7 (July 21, 2022): e1009994. http://dx.doi.org/10.1371/journal.pcbi.1009994.

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Host response to infection involves the activation of the complement system leading to the production of anaphylatoxins C3a and C5a. Complement factor C5a exerts its effect through the activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. An analysis of mutual interactions of subunits in the C5aR1—G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparing two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular level. By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway but instead recruits beta-arrestin. A comparison of microsecond MD trajectories started from active and inactive C5aR1 receptor conformations has provided insights into details of local and global changes in the transmembrane domain induced by interactions with the Gα subunit and explained the impact of inverted H8 on the C5aR1 activation.

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Ahn, Seungkirl, Alem W. Kahsai, Biswaranjan Pani, Qin-Ting Wang, Shuai Zhao, Alissa L. Wall, Ryan T. Strachan, et al. "Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library." Proceedings of the National Academy of Sciences 114, no. 7 (January 27, 2017): 1708–13. http://dx.doi.org/10.1073/pnas.1620645114.

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The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein–coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β2AR. In cell-signaling studies, 15 inhibits cAMP production through the β2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β2AR. This study presents an allosteric small-molecule ligand for the β2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

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Yan, Cheng, Yan Yang, Yunxiang Tang, Xiaojing Zheng, and Bin Xu. "The Critical Gene Screening to Prevent Chromophobe Cell Renal Carcinoma Metastasis through TCGA and WGCNA." Journal of Oncology 2022 (October 15, 2022): 1–14. http://dx.doi.org/10.1155/2022/2909095.

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Common chromophobe renal cell carcinoma (chRCC) has a good prognosis when cured by surgery. However, clinical practice shows that a small number of patients with chRCC will produce metastasis, and the prognosis after metastasis is poor. In this regard, we try to find potential biological targets to prevent CRCC metastasis. In this experiment, we analyzed the clinical traits and gene expression data of chRCC samples which were provided by the TCGA database by the WGCNA method. On this basis, we selected MEtan, a module with a significant positive correlation with the M phase of chRCC, for subsequent analysis. The MEtan module genes in the biological process of chRCC were mainly related to steroid metabolic process, cholesterol metabolic process and STEM cell differentiation. KEGG analysis showed that these genes were mainly enriched in cancer-related signaling pathways, such as Neuroactive Ligand−receptor interaction, cAMP signaling pathway, and Wnt signaling pathway. Subsequently, we mapped the PPI interaction network and screened the key gene beta-arrestin 2 (ARRB2). Expression analysis showed that there was a significantly increased expression of ARRB2 in chRCC patients in comparison to the normal group. Expression survival analysis indicated that ARRB2 was inversely associated with overall survival. We firmly believe that the key genes identified in this study would be able to provide new clues and research basis for the treatment of chRCC.

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Wu, Na, Agnieszka M. Olechwier, Cyrill Brunner, Patricia C. Edwards, Ching-Ju Tsai, Christopher G. Tate, Gebhard F. X. Schertler, et al. "High-mass MALDI-MS unravels ligand-mediated G protein–coupling selectivity to GPCRs." Proceedings of the National Academy of Sciences 118, no. 31 (July 29, 2021): e2024146118. http://dx.doi.org/10.1073/pnas.2024146118.

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G protein–coupled receptors (GPCRs) are important pharmaceutical targets for the treatment of a broad spectrum of diseases. Although there are structures of GPCRs in their active conformation with bound ligands and G proteins, the detailed molecular interplay between the receptors and their signaling partners remains challenging to decipher. To address this, we developed a high-sensitivity, high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) method to interrogate the first stage of signal transduction. GPCR–G protein complex formation is detected as a proxy for the effect of ligands on GPCR conformation and on coupling selectivity. Over 70 ligand–GPCR–partner protein combinations were studied using as little as 1.25 pmol protein per sample. We determined the selectivity profile and binding affinities of three GPCRs (rhodopsin, beta-1 adrenergic receptor [β1AR], and angiotensin II type 1 receptor) to engineered Gα-proteins (mGs, mGo, mGi, and mGq) and nanobody 80 (Nb80). We found that GPCRs in the absence of ligand can bind mGo, and that the role of the G protein C terminus in GPCR recognition is receptor-specific. We exemplified our quantification method using β1AR and demonstrated the allosteric effect of Nb80 binding in assisting displacement of nadolol to isoprenaline. We also quantified complex formation with wild-type heterotrimeric Gαiβγ and β-arrestin-1 and showed that carvedilol induces an increase in coupling of β-arrestin-1 and Gαiβγ to β1AR. A normalization strategy allows us to quantitatively measure the binding affinities of GPCRs to partner proteins. We anticipate that this methodology will find broad use in screening and characterization of GPCR-targeting drugs.

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Buechler, Christa, Susanne Feder, Elisabeth Haberl, and Charalampos Aslanidis. "Chemerin Isoforms and Activity in Obesity." International Journal of Molecular Sciences 20, no. 5 (March 5, 2019): 1128. http://dx.doi.org/10.3390/ijms20051128.

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Overweight and adiposity are risk factors for several diseases, like type 2 diabetes and cancer. White adipose tissue is a major source for adipokines, comprising a diverse group of proteins exerting various functions. Chemerin is one of these proteins whose systemic levels are increased in obesity. Chemerin is involved in different physiological and pathophysiological processes and it regulates adipogenesis, insulin sensitivity, and immune response, suggesting a vital role in metabolic health. The majority of serum chemerin is biologically inert. Different proteases are involved in the C-terminal processing of chemerin and generate diverse isoforms that vary in their activity. Distribution of chemerin variants was analyzed in adipose tissues and plasma of lean and obese humans and mice. The Tango bioassay, which is suitable to monitor the activation of the beta-arrestin 2 pathway, was used to determine the ex-vivo activation of chemerin receptors by systemic chemerin. Further, the expression of the chemerin receptors was analyzed in adipose tissue, liver, and skeletal muscle. Present investigations assume that increased systemic chemerin in human obesity is not accompanied by higher biologic activity. More research is needed to fully understand the pathways that control chemerin processing and chemerin signaling.

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Pavlova, Olga, Alexander Shirokov, Alexander Fomin, Nikita Navolokin, Andrey Terskov, Alexander Khorovodov, Anton Namykin, Alexey Pavlov, Valery Tuchin, and Oxana Semyachkina-Glushkovskaya. "Opticalin vivoandex vivoimaging of glioma cells migration via the cerebral vessels: Prospective clinical application of the beta2-adrenoreceptors blockade for glioma treatment." Journal of Innovative Optical Health Sciences 11, no. 04 (July 2018): 1850025. http://dx.doi.org/10.1142/s1793545818500256.

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Malignant gliomas are highly invasive tumors that use the cerebral vessels for invasion due to high vascular fragility of the blood–brain barrier (BBB). On one hand, glioma is characterized by the BBB disruption, on the other hand, drug brain delivery via the BBB is a big challenge in glioma therapy. The limited information about vascular changes associated with glioma growth is a reason of slow progress in prevention of glioma development.Here, we present in vivo and ex vivo study of the BBB disruption and glioma cells (GCs) migration in rats using fluorescence and confocal microscopy. We uncovered a local breach in the BBB in the main tumor mass but not within the border of normal and malignant cells, where the BBB was impermeable for high weight molecules. The migration of GCs were observed via the cerebral vessels with the intact BBB that was associated with macrophages infiltration.The mechanisms underlying glioma progression remain unknown but there is an evidence that the sympathetic nervous system (SNS) via activation of vascular beta2-adrenoreceptors (B2-ADRs) can play an important role in tumor metastasis. Our results clearly show an increase in the expression of vascular B2-ADRs and production of the beta-arrestin-1 — co-factor of B2-ADRs signaling pathway in rats with glioma. Pharmacological blockade of B2-ADRs reduces the BBB disruption, macrophages infiltration, GCs migration and increases survival rate.These data suggest that the blockade of B2-ADRs may be a novel adjuvant therapeutic strategy to reduce glioma progression and prevent metastasis.

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Lee, Hsiang-Ying, Yi-Jen Chen, Wei-An Chang, Wei-Ming Li, Hung-Lung Ke, Wen-Jeng Wu, and Po-Lin Kuo. "Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches." Medicina 55, no. 12 (December 1, 2019): 768. http://dx.doi.org/10.3390/medicina55120768.

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Background and objectives: Bladder urothelial carcinoma is the most common type of genitourinary cancer. Patients with bladder cancer may have limited treatment efficacy related to drug toxicity, resistance or adverse effects, and novel therapeutic strategies to enhance treatment efficacy or increase sensitivity to drugs are of high clinical importance. Epigallocatechin gallate (EGCG) is a polyphenolic compound found in green tea leaves, and a potential anti-cancer agent in various cancer types through modulating and regulating multiple signaling pathways. The current study aimed to explore the role and novel therapeutic targets of EGCG on bladder urothelial carcinoma. Materials and Methods: The BFTC-905 cells, human urinary bladder transitional cell carcinoma (TCC) cell line, were treated with EGCG or water for 24 hours, and the expression profiles of mRNAs and microRNAs were analyzed using next generation sequencing (NGS). The enriched biological functions were determined using different bioinformatics databases. Results: A total of 108 differentially expressed genes in EGCG-treated bladder TCC cells were identified, which were mainly involved in nicotinamide adenine dinucleotide (NAD) biogenesis, inflammatory response and oxidation-reduction metabolism. Moreover, several microRNA-mRNA interactions that potentially participated in the response of bladder TCC to EGCG treatment, including miR-185-3p- ARRB1 (arrestin beta 1), miR-3116- MGAT5B (alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase B), miR-31-5p-TNS1 (tensin 1), miR-642a-5p-TNS1, miR-1226-3p- DLG2 (discs large homolog 2), miR-484-DLG2, and miR-22-3p- PPM1K (protein phosphatase 1K). Conclusions: The current findings provide insights into novel therapeutic targets and underlying mechanisms of action of EGCG treatment in bladder cancer.

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Abubaker, Mohammed, and George I. Fantus. "ODP251 Thioredoxin-Interacting Protein (Txnip) And Cellular Senescence: Potential Adverse Effects of Txnip Deficiency." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A336—A337. http://dx.doi.org/10.1210/jendso/bvac150.699.

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Abstract Thioredoxin-interacting protein (TXNIP) is a ubiquitously expressed protein that belongs to the α-arrestin family of proteins but is unique in that it interacts with and inhibits the function of the endogenous antioxidant, Thioredoxin (Trx). TXNIP is strongly upregulated by hyperglycemia and is associated with increased oxidative stress and promotes pancreatic beta cell apoptosis accelerating the progression of diabetes. Age-dependent dysregulation of the Trx/TXNIP redox system has been implicated in cellular senescence and aging. However, the mechanisms are not fully understood. While Trx overexpression has been reported to protect against aging and age-related diseases, and we found that TXNIP-/- (KO) mice were protected from Diabetic kidney disease, paradoxically, others reported TXNIP KO mice had reduced survival in response to paraquat mediated oxidative stress. To investigate the potential effects of TXNIP in cellular senescence we used primary mouse renal glomerular mesangial cells (MC) from WT and TXNIP KO mice. Passaging of cells leads to replicative senescence. In WT MC this was associated with a significant reduction in TXNIP expression in late passage (LP-passage 25) compared to early passage (EP-passage 5-7) (p<0. 05), and this was accompanied by appearance of the senescence phenotype determined by significant increases in expression of the cellular senescence markers, p53, p16, p21, phosphorylation of histone H2AX (p<0. 05) and senescence associated beta-galactosidase staining (13-fold increase) (p<0. 01). To determine whether TXNIP downregulation played a causal role, primary MC from TXNIP KO were compared to WT at EP 5. TXNIP KO showed significantly higher expression of senescence markers P53 and P16 (p<0. 05), and beta-galactosidase staining (15-fold). AKT activation has been implicated in replicative senescence. Here, increased phosphorylation of AKT and its substrate FOXO were found in LP versus EP WT, and EP KO versus WT MC (p<0. 05). These studies indicate that TXNIP downregulation is a mediator of replicative senescence associated with increased AKT signaling. Thus, while beneficial for diabetes, targeting TXNIP may have long term untoward effects on aging. Presentation: No date and time listed

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Gritsina, Galina, Zhuoyuan Lin, Ka Wing Fong, Xiaodong Lu, Changsheng Zhao, and Jindan Yu. "Abstract LB032: CXCR7 drives prostate cancer growth through AURKA activation." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB032. http://dx.doi.org/10.1158/1538-7445.am2022-lb032.

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Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer among males in the United States. The mainstay treatment for metastatic PCa patients is androgen-deprivation therapies, including high-affinity androgen receptor antagonists, such as enzalutamide. Unfortunately, most patients develop resistance and relapse with castration-resistant PCa (CRPC). We have previously reported up-regulation of CXCR7, an atypical chemokine receptor, in CRPC. CXCR7 interacts with beta-arrestin (ARRB2), a cytoplasmic scaffold protein, and translocates to the cytoplasm to induce signal transduction and PCa progression. However, much remains to be known regarding CXCR7-driven downstream signaling and its therapeutic targeting in advanced PCa. To unveil CXCR7-downstream signaling, we utilized RNA-seq to profile gene expression. Gene ontology analyses revealed remarkable enrichment of CXCR7-regulated genes in G2/M cell cycle progression. Comprehensive phospho-proteomics analysis of CXCR7-knockdown PCa cells showed markedly reduced phosphorylation of AURKA substrates. AURKA, a serine/threonine-protein kinase, is a key regulator of mitosis and G2/M progression and is frequently upregulated in CRPC and the late-stage neuroendocrine PCa (NEPC). Activated AURKA experiences autophosphorylation and phosphorylates downstream substrates, e.g., TACC3, that mediate proper cell division. Immunoblotting confirmed that CXCR7 depletion reduces phosphorylation of AURKA and TACC3. Co-immunoprecipitation revealed protein-protein interaction between CXCR7 and AURKA, which is mediated by ARRB2. Accordingly, ARRB2-knockdown similarly inhibits AURKA phosphorylation and arrests cell proliferation. Immunofluorescence coupled with confocal imaging demonstrated that CXCR7 is packed into clathrin-coated vesicles and locates in the plasma membrane, cytoplasm, and perinuclear Golgi complex, which surrounds the centrosomal AURKA and ARRB2. We found that CXCR7 translocates to the Golgi complex along microtubule-dependent trafficking. Finally, we found that pharmacological inhibitors of AURKA abolish CXCR7-driven PCa cell proliferation in vitro and tumor growth in vivo. Conclusions: Our results describe for the first time that the CXCR7-ARRB2 complex interacts with AURKA and promotes its activation. Our data suggest that AURKA-targeting is a promising therapeutic strategy for CRPC and NEPC with CXCR7 up-regulation. Citation Format: Galina Gritsina, Zhuoyuan Lin, Ka Wing Fong, Xiaodong Lu, Changsheng Zhao, Jindan Yu. CXCR7 drives prostate cancer growth through AURKA activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB032.

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Samarel, A. M., and G. L. Engelmann. "Contractile activity modulates myosin heavy chain-beta expression in neonatal rat heart cells." American Journal of Physiology-Heart and Circulatory Physiology 261, no. 4 (October 1, 1991): H1067—H1077. http://dx.doi.org/10.1152/ajpheart.1991.261.4.h1067.

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To determine whether spontaneous contractile activity affected the expression of myosin heavy chain isoenzymes in cultured neonatal rat heart cells, ventricular myocytes were isolated from 2-day-old rat pups by collagenase digestion and cultured for 24-96 h in the presence and absence of verapamil (10 microM), KCl (50 mM), or dihydropyridine receptor antagonists that produced contractile arrest. Inhibition of spontaneous contractile activity was associated with significant reductions in total myosin heavy chain (MHC) content and synthetic rates. Electrophoretic analysis of MHC isoenzymes indicated that MHC-beta protein rapidly disappeared from arrested cells, whereas MHC-alpha isoenzyme levels were less affected. In association with these protein changes, mRNA transcript levels for MHC-beta were markedly reduced in quiescent cells, whereas mRNA transcript levels for several other contractile protein genes were relatively less affected. Inhibition of contractile activity and MHC-beta expression were reversible upon removal of the arresting agents. Furthermore, the decrease in MHC-beta mRNA levels in arrested myocytes could be prevented by direct activation of protein kinase C with phorbol 12-myristate 13-acetate (without restoration of contractile activity). Conversely, MHC-beta mRNA levels in beating cells were reduced by treatment with staurosporine (a selective protein kinase C inhibitor). Thus contractile arrest (produced by either L-channel blockade or membrane depolarization) inhibited the accumulation of MHC-beta in cultured neonatal rat heart cells via a pretranslational mechanism. These effects may occur in response to the modulation of signaling system(s) involving mechanical “stretch” transduced via protein kinase C.

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Iacovelli, L., L. Capobianco, GM D'Ancona, A. Picascia, and A. De Blasi. "Regulation of lysophosphatidic acid receptor-stimulated response by G-protein-coupled receptor kinase-2 and beta-arrestin1 in FRTL-5 rat thyroid cells." Journal of Endocrinology 174, no. 1 (July 1, 2002): 103–10. http://dx.doi.org/10.1677/joe.0.1740103.

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Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that activates a variety of biological activities including cell proliferation. Three mammalian LPA receptor (LPAr) subtypes have been identified by molecular cloning, named lp(A1), lp(A2) and lp(A3), that are coupled to heterotrimeric G-proteins for signal transduction. The LPAr are endogenously expressed in the rat thyroid cell line FRTL-5 and we used the FRTL-5 cells permanently transfected to obtain moderate overexpression of G-protein-coupled receptor kinase-2 (GRK2) or beta-arrestin1 to study whether GRK2 and beta-arrestin1 desensitise LPAr-mediated signalling and regulate LPA-stimulated functional effects. Using RT-PCR we documented that lp(A1), lp(A2) and lp(A3) receptors are all expressed in FRTL-5 cells. We then analysed the signal transduction of the LPAr in FRTL-5 cells. Exposure to LPA did not stimulate inositol phosphate formation nor cAMP accumulation but reduced forskolin-stimulated cAMP. LPA was also able to stimulate MAP kinase activation and this effect was abolished by pertussis toxin pretreatment. These results suggest that LPAr are mainly coupled to a pertussis toxin-sensitive G-protein in FRTL-5 cells. In order to investigate whether GRKs and arrestins are involved in the regulation of LPAr-mediated signalling, we used the FRTL-5 cell line permanently transfected to overexpress GRK2 (named L5GRK2 cells) or beta-arrestin1 (L5betaarr1 cells). The ability of LPA to inhibit forskolin-stimulated cAMP accumulation was blunted in L5GRK2 and more markedly in L5betaarr1. The MAP kinase activation was also blunted in L5GRK2 and in L5betaarr1B cells. Exposure to 20 microM LPA increased the phosphorylation of extracellular signal-regulated kinases ERK1/2 by approximately 3-fold in L5pBJI cells (FRTL-5 cells transfected with the empty vector pBJI) while it induced a modest increase in L5betaarr1 and was ineffective in L5GRK2. We measured [3H]thymidine uptake in L5betaarr1B and in L5 GRK2 cells to test whether GRK2 and beta-arrestin1 could have a role in the regulation of LPAr-mediated cell proliferation. The mitogenic response induced by 35 microM LPA was substantially blunted in L5betaarr1 (-69+/-6%) and in L5GRK2 (-69.8+/-4.5%) cells as compared with L5pBJI. Our findings document that the receptor-mediated responses elicited by LPA are regulated by GRK2 and beta-arrestin1 in FRTL-5 cells and indicate that this mechanism is potentially important for the control of the LPA-stimulated proliferative response.

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McArdle, CA, J. Franklin, L. Green, and JN Hislop. "Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors." Journal of Endocrinology 173, no. 1 (April 1, 2002): 1–11. http://dx.doi.org/10.1677/joe.0.1730001.

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Sustained stimulation of G-protein-coupled receptors (GPCRs) typically causes receptor desensitisation, which is mediated by phosphorylation, often within the C-terminal tail of the receptor. The consequent binding of beta-arrestin not only prevents the receptor from activating its G protein (causing desensitisation), but can also target it for internalisation via clathrin-coated vesicles and can mediate signalling to proteins regulating endocytosis and mitogen-activated protein kinase (MAPK) cascades. GnRH acts via phospholipase C (PLC)-coupled GPCRs on pituitary gonadotrophs to stimulate a Ca(2+)-mediated increase in gonadotrophin secretion. The type I GnRH receptors (GnRH-Rs), found only in mammals, are unique in that they lack C-terminal tails and apparently do not undergo agonist-induced phosphorylation or bind beta-arrestin; they are therefore resistant to receptor desensitisation and internalise slowly. In contrast, the type II GnRH-Rs, found in numerous vertebrates, possess such tails and show rapid desensitisation and internalisation, with concomitant receptor phosphorylation (within the C-terminal tails) or binding of beta-arrestin, or both. The association with beta-arrestin may also be important for regulation of dynamin, a GTPase that controls separation of endosomes from the plasma membrane. Using recombinant adenovirus to express GnRH-Rs in Hela cells conditionally expressing a dominant negative mutant of dynamin (K44A), we have found that blockade of dynamin-dependent endocytosis inhibits internalisation of type II (xenopus) GnRH-Rs but not type I (human) GnRH-Rs. In these cells, blockade of dynamin-dependent internalisation also inhibited GnRH-R-mediated MAPK activation, but this effect was not receptor specific and therefore not dependent upon dynamin-regulated GnRH-R internalisation. Although type I GnRH-Rs do not desensitise, sustained activation of GnRH-Rs causes desensitisation of gonadotrophin secretion, and we have found that GnRH can cause down-regulation of inositol (1,4,5) trisphosphate receptors and desensitisation of Ca(2+) mobilisation in pituitary cells. The atypical resistance of the GnRH-R to desensitisation may underlie its atypical efficiency at provoking this downstream adaptive response. GnRH-Rs are also expressed in several extrapituitary sites, and these may mediate direct inhibition of proliferation of hormone-dependent cancer cells. Infection with type I GnRH-R-expressing adenovirus facilitated expression of high-affinity, PLC-coupled GnRH-R in mammary and prostate cancer cells, and these mediated pronounced antiproliferative effects of receptor agonists. No such effect was seen in cells transfected with a type II GnRH-R, implying that it is mediated most efficiently by a non-desensitising receptor. Thus it appears that the mammalian GnRH-Rs have undergone a period of rapidly accelerated molecular evolution that is of functional relevance to GnRH-Rs in pituitary and extrapituitary sites.

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Del’ Guidice, Thomas, and Jean-Martin Beaulieu. "Selective disruption of dopamine D2-receptors/beta-arrestin2 signaling by mood stabilizers." Journal of Receptors and Signal Transduction 35, no. 3 (May 4, 2015): 224–32. http://dx.doi.org/10.3109/10799893.2015.1072976.

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Browning, J. L., K. Miatkowski, I. Sizing, D. Griffiths, M. Zafari, C. D. Benjamin, W. Meier, and F. Mackay. "Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines." Journal of Experimental Medicine 183, no. 3 (March 1, 1996): 867–78. http://dx.doi.org/10.1084/jem.183.3.867.

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Surface lymphotoxin (LT) is a heteromeric complex of LT-alpha and LT-beta chains that binds to the LT-beta receptor (LT-beta-R), a member of the tumor necrosis factor (TNF) family of receptors. The biological function of this receptor-ligand system is poorly characterized. Since signaling through other members of this receptor family can induce cell death, e.g., the TNF and Fas receptors, it is important to determine if similar signaling events can be communicated via the LT-beta-R. A soluble form of the surface complex was produced by coexpression of LT-alpha and a converted form of LT-beta wherein the normally type II LT-beta membrane protein was changed to a type I secreted form. Recombinant LT-alpha 1/beta 2 was cytotoxic to the human adenocarcinoma cell lines HT-29, WiDr, MDA-MB-468, and HT-3 when added with the synergizing agent interferon (IFN) gamma. When immobilized on a plastic surface, anti-LT-beta-R monoclonal antibodies (mAbs) induced the death of these cells, demonstrating direct signaling via the LT-beta-R. Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution. The human WiDr adenocarcinoma line forms solid tumors in immunocompromised mice, and treatment with an anti-LT-beta-R antibody combined with human IFN-gamma arrested tumor growth. The delineation of a biological signaling event mediated by the LT-beta-R opens a window for further studies on its immunological role, and furthermore, activation of the LT-beta-R may have an application in tumor therapy.

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Daneshyar, Saeed, Mehdi Bahmani, and Yazdan Fourotan. "The effect of aerobic exercise training on gene expression of beta3-adrenergic receptor and beta-arrestin2 in inguinal white adipose tissue of mice fed with a high fat diet." Journal of Shahrekord University of Medical Sciences 23, no. 3 (September 29, 2021): 124–30. http://dx.doi.org/10.34172/jsums.2021.21.

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Background and aims: Beta-adrenergic signaling deficiency has been established to be related to obesity and related diseases. Beta3- adrenergic receptor (Adrb3) and beta-arrestin2 (Barr2) are pivotal agents in the beta-adrenergic-signaling pathway. This study aimed to investigate the preventive effect of aerobic training on dysregulation of Adrb3 and Barr2 gene expression that was induced by high-fat diet (HFD) in inguinal white adipose tissue of mice. Materials and Methods: Twenty-one C57BL/6 mice were assigned to three groups as follows: 1) control group (n=7), 2) high-fat diet-induced overweight (HFD-OW) (n=7), and 3) high-fat diet with aerobic training (HFD-AT) (n=7). The HFD-OW group were fed with a HFD for 12 weeks. The HFD-AT group had aerobic training for six weeks on a treadmill in addition to feeding with the HFD. The real-time polymerase chain reaction (PCR) method was used to measure the gene expression of Adrb3 and Barr2 in inguinal white adipose tissue. Results: The gene expression of Adrb3 did not significantly change between groups (P>0.05). However, the expression of Barr2 in HFD-OW group was significantly increased as compared to the control group (1.5-fold: P=0.001). Interestingly, the Barr2 expression in HFD-AT group was significantly lower compared with HFD-OW group (P=0.045). Conclusion: The results indicated that aerobic training could inhibit the upregulation of Barr2 induced by HFD. It seems that a portion of the preventive effect of aerobic training on the development of obesity may be mediated by inhibiting the Barr2 expression in adipose tissue.

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Ramachandran, R. K., A. H. Wikramanayake, J. A. Uzman, V. Govindarajan, and C. R. Tomlinson. "Disruption of gastrulation and oral-aboral ectoderm differentiation in the Lytechinus pictus embryo by a dominant/negative PDGF receptor." Development 124, no. 12 (June 15, 1997): 2355–64. http://dx.doi.org/10.1242/dev.124.12.2355.

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Little is known about the cell signaling involved in forming the body plan of the sea urchin embryo. Previous work suggested that PDGF-like and EGF-like receptor-mediated signaling pathways are involved in gastrulation and spiculogenesis in the Lytechinus pictus embryo. Here we show that expression of the human PDGF receptor-beta lacking the cytoplasmic domain disrupted development in a manner consistent with a dominant/negative mechanism. The truncated PDGF receptor-beta inhibited gut and spicule formation and differentiation along the oral-aboral axis. The most severely affected embryos arrested at a developmental stage resembling mesenchyme blastula. Coinjection into eggs of RNA encoding the entire human PDGF receptor-beta rescued development. The truncated PDGF receptor-beta caused the aboral ectoderm-specific genes LpS1 and LpC2 to be repressed while an oral ectoderm-specific gene, Ecto-V, was expressed in all ectoderm cells. The results support the hypothesis that a PDGF-like signaling pathway plays a key role in the intercellular communication required for gastrulation and spiculogenesis, and in cell commitment and differentiation along the oral-aboral axis.

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Fuentes, Nathalie, Morgan McCullough, Reynold A. Panettieri, and Kirk M. Druey. "RGS proteins, GRKs, and beta-arrestins modulate G protein-mediated signaling pathways in asthma." Pharmacology & Therapeutics 223 (July 2021): 107818. http://dx.doi.org/10.1016/j.pharmthera.2021.107818.

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Moonen, Lies, Patrick D’Haese, and Benjamin Vervaet. "Epithelial Cell Cycle Behaviour in the Injured Kidney." International Journal of Molecular Sciences 19, no. 7 (July 13, 2018): 2038. http://dx.doi.org/10.3390/ijms19072038.

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Acute kidney injury (AKI), commonly caused by ischemia-reperfusion injury, has far-reaching health consequences. Despite the significant regenerative capacity of proximal tubular epithelium cells (PTCs), repair frequently fails, leading to the development of chronic kidney disease (CKD). In the last decade, it has been repeatedly demonstrated that dysregulation of the cell cycle can cause injured kidneys to progress to CKD. More precisely, severe AKI causes PTCs to arrest in the G1/S or G2/M phase of the cell cycle, leading to maladaptive repair and a fibrotic outcome. The mechanisms causing these arrests are far from known. The arrest might, at least partially, be attributed to DNA damage since activation of the DNA-damage response pathway leads to cell cycle arrest. Alternatively, cytokine signalling via nuclear factor kappa beta (NF-κβ) and p38-mitogen-activated protein kinase (p38-MAPK) pathways, and reactive oxygen species (ROS) can play a role independent of DNA damage. In addition, only a handful of cell cycle regulators (e.g., p53, p21) have been thoroughly studied during renal repair. Still, why and how PTCs decide to arrest their cell cycle and how this arrest can efficiently be overcome remain open and challenging questions. In this review we will discuss the evidence for cell cycle involvement during AKI and development of CKD together with putative therapeutic approaches.

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Grishin, A. V., J. L. Weiner, and K. J. Blumer. "Control of adaptation to mating pheromone by G protein beta subunits of Saccharomyces cerevisiae." Genetics 138, no. 4 (December 1, 1994): 1081–92. http://dx.doi.org/10.1093/genetics/138.4.1081.

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Abstract The STE4 gene of the yeast Saccharomyces cerevisiae encodes the beta subunit of a heterotrimeric G protein that mediates response to mating pheromones and influences recovery from pheromone-induced growth arrest. To explore how G beta subunits regulate response and recovery (adaptation), we isolated and characterized signaling-defective STE4 alleles (STE4sd). STE4sd mutations resulted in amino acid substitutions in the N-terminal region of Ste4p, proximal to the first of seven repeat units conserved in G protein beta subunits. Genetic tests indicated that STE4sd mutations disrupted functions of Ste4p required for inducing pheromone responses. Wild-type cells that overexpressed STE4sd alleles displayed apparently normal initial responses to pheromone as judged by quantitative mating, G1 arrest and transcriptional assays. However, after undergoing initial G1 arrest, wild-type cells overexpressing STE4sd alleles recovered more quickly from division arrest, suggestive of a hyperadaptive phenotype. Because hyperadaptation occurred when STE4sd alleles were overexpressed in cells lacking Sst1p (Bar1p), Sst2p or the C-terminal domain of the alpha-factor receptor, this phenotype did not involve three principal modes of adaptation in yeast. However, hyperadaptation was abolished when STE4sd mutations were combined in cis with a deletion that removes a segment of Ste4p (residues 310-346) previously implicated in adaptation to pheromone. These results indicate that G beta subunits possess two independent activities, one required for triggering pheromone response and another that promotes adaptation. Potential models for G beta subunit-mediated adaptation are discussed.

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Rajagopal, Sudarshan, Jeff Kovacs, Cristian Badea, G. Allan Johnson, Howard A. Rockman, Claude A. Piantadosi, and Robert J. Lefkowitz. "BETA-ARRESTINS REGULATE SIGNALING BY BONE MORPHOGENETIC PROTEIN TYPE II RECEPTOR IN PULMONARY ARTERIAL HYPERTENSION." Journal of the American College of Cardiology 57, no. 14 (April 2011): E2046. http://dx.doi.org/10.1016/s0735-1097(11)62046-9.

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Zhang, Rui-Gang, Ya Niu, Ke-Wu Pan, Hao Pang, Chun-Ling Chen, Chung-Yin Yip, and Wing-Hung Ko. "β2-Adrenoceptor Activation Stimulates IL-6 Production via PKA, ERK1/2, Src, and Beta-Arrestin2 Signaling Pathways in Human Bronchial Epithelia." Lung 199, no. 6 (November 1, 2021): 619–27. http://dx.doi.org/10.1007/s00408-021-00484-0.

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Abstract Objective β2-Adrenoceptor agonists are widely used to treat asthma because of their bronchial-dilation effects. We previously reported that isoprenaline, via the apical and basolateral β2-adrenoceptor, induced Cl− secretion by activating cyclic AMP (cAMP)-dependent pathways in human bronchial epithelia. Despite these results, whether and how the β2-adrenoceptor-mediated cAMP-dependent pathway contributes to pro-inflammatory cytokine release in human bronchial epithelia remains poorly understood. Methods We investigated β2-adrenoceptor-mediated signaling pathways involved in the production of two pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, in 16HBE14o- human bronchial epithelia. The effects of isoprenaline or formoterol were assessed in the presence of protein kinase A (PKA), exchange protein directly activated by cAMP (EPAC), Src, and extracellular signal-regulated protein kinase (ERK)1/2 inhibitors. The involvement of β-arrestin2 was examined using siRNA knockdown. Results Isoprenaline and formoterol (both β2 agonists) induced IL-6, but not IL-8, release, which could be inhibited by ICI 118,551 (β2 antagonist). The PKA-specific inhibitor, H89, partially inhibited IL-6 release. Another intracellular cAMP receptor, EPAC, was not involved in IL-6 release. Isoprenaline-mediated IL-6 secretion was attenuated by dasatinib, a Src inhibitor, and PD98059, an ERK1/2 inhibitor. Isoprenaline treatment also led to ERK1/2 phosphorylation. In addition, knockdown of β-arrestin2 by siRNA specifically suppressed cytokine release when a high concentration of isoprenaline (1 mM) was used. Conclusion Our results suggest that activation of the β2-adrenoceptor in 16HBE14o- cells stimulated the PKA/Src/ERK1/2 and/or β-arrestin2 signaling pathways, leading to IL-6 release. Therefore, our data reveal that β2-adrenoceptor signaling plays a role in the immune regulation of human airway epithelia.

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Varner, J. A., D. A. Emerson, and R. L. Juliano. "Integrin alpha 5 beta 1 expression negatively regulates cell growth: reversal by attachment to fibronectin." Molecular Biology of the Cell 6, no. 6 (June 1995): 725–40. http://dx.doi.org/10.1091/mbc.6.6.725.

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Cells selected for overexpression of the integrin alpha 5 beta 1 show decreased proliferation and loss of the transformed phenotype. We provide evidence that de novo expression of the integrin alpha 5 beta 1 in HT29 colon carcinoma cells results in the growth arrest of these cells as characterized by reduced DNA synthesis and cellular proliferation in vitro. In fact, expression of integrin alpha 5 beta 1 on these cells induces the transcription of growth arrest specific gene 1 (gas-1), a gene product known to induce cellular quiescence, but blocks transcription of the immediate early genes c-fos, c-jun, and jun B. In vivo, the alpha 5 beta 1 transfectants display dramatically reduced tumorigenicity as well as a highly differentiated phenotype when compared with their pSVneo-transfected counterparts. Surprisingly, ligation of alpha 5 beta 1 on these cells by cell attachment to a fibronectin substrate not only reverses the growth inhibition and gas-1 gene induction but activates immediate early gene transcription. These findings demonstrate that integrin alpha 5 beta 1 expression in the absence of attachment to fibronectin activates a signaling pathway leading to decreased cellular proliferation and that ligation of this receptor with fibronectin reverses this signal, thereby contributing to the proliferation of transformed cells.

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Maguire, JJ, RE Kuc, VR Pell, and AP Davenport. "12 Pharmacology of Human ETA and ETB Receptor Signalling VIA G-Protein and Beta-Arrestin Pathways." Heart 98, Suppl 3 (November 2012): A4.2—A4. http://dx.doi.org/10.1136/heartjnl-2012-302951.012.

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Bright, J. J., L. D. Kerr, and S. Sriram. "TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes." Journal of Immunology 159, no. 1 (July 1, 1997): 175–83. http://dx.doi.org/10.4049/jimmunol.159.1.175.

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Abstract Signaling through IL-2R, IL-2 induces tyrosine phosphorylation and activation of Jak-1 and Jak-3 kinases and Stat 3 and Stat 5 transcription factors leading to cell cycle progression of activated T cells from G1 to S phase. TGF-beta is an immunosuppressive cytokine, which inhibits T cell proliferation at G1 to S phase transition. We examined the effect of TGF-beta on IL-2R signal transduction pathway in activated T cells. We show here that treatment of activated T cells with TGF-beta inhibited IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 but not Jak-3 and Stat 3. TGF-beta also inhibited IL-2-induced expression of alpha- and beta-chains of IL-2R and induced apoptotic cell death in T cells. These results suggest that TGF-beta-induced growth arrest and apoptosis are associated with the modulation of IL-2-induced activation of Jak-Stat pathway in T cells.

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Journal articles on the topic 'Beta arrestin signaling'

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