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Robert J Lefkowitz - One of the best experts on this subject based on the ideXlab platform.
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Molecular Mechanism of β-Arrestin-Biased Agonism at Seven-Transmembrane Receptors
Annual review of pharmacology and toxicology, 2011Co-Authors: Eric Reiter, Seungkirl Ahn, Arun K Shukla, Robert J LefkowitzAbstract:The concept of biased agonism has recently come to the fore with the realization that seven-Transmembrane Receptors (7TMRs, also known as G protein-coupled Receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the "efficacy" of Receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural "unbiased" ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction.
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Emerging paradigms of β-arrestin-dependent seven Transmembrane receptor signaling.
Trends in biochemical sciences, 2011Co-Authors: Arun K Shukla, Kunhong Xiao, Robert J LefkowitzAbstract:β-Arrestins, originally discovered to desensitize activated seven Transmembrane Receptors (7TMRs; also known as G-protein-coupled Receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signaling. Recent global analyses of β-arrestin interactions and β-arrestin-dependent phosphorylation events have uncovered several previously unanticipated roles of β-arrestins in a range of cellular signaling events. These findings strongly suggest that the functional roles of β-arrestins are much broader than currently understood. Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diverse functional capabilities of β-arrestins in cellular signaling.
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Quantifying ligand bias at seven-Transmembrane Receptors.
Molecular pharmacology, 2011Co-Authors: Sudarshan Rajagopal, Seungkirl Ahn, Jonathan D. Violin, David H. Rominger, William Gowen-macdonald, Christopher M. Lam, Scott M. Dewire, Robert J LefkowitzAbstract:Seven Transmembrane Receptors (7TMRs), commonly referred to as G protein-coupled Receptors, form a large part of the "druggable" genome. 7TMRs can signal through parallel pathways simultaneously, such as through heterotrimeric G proteins from different families, or, as more recently appreciated, through the multifunctional adapters, β-arrestins. Biased agonists, which signal with different efficacies to a receptor's multiple downstream pathways, are useful tools for deconvoluting this signaling complexity. These compounds may also be of therapeutic use because they have distinct functional and therapeutic profiles from "balanced agonists." Although some methods have been proposed to identify biased ligands, no comparison of these methods applied to the same set of data has been performed. Therefore, at this time, there are no generally accepted methods to quantify the relative bias of different ligands, making studies of biased signaling difficult. Here, we use complementary computational approaches for the quantification of ligand bias and demonstrate their application to two well known drug targets, the β2 adrenergic and angiotensin II type 1A Receptors. The strategy outlined here allows a quantification of ligand bias and the identification of weakly biased compounds. This general method should aid in deciphering complex signaling pathways and may be useful for the development of novel biased therapeutic ligands as drugs.
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Teaching old Receptors new tricks: biasing seven-Transmembrane Receptors
Nature reviews. Drug discovery, 2010Co-Authors: Sudarshan Rajagopal, Keshava Rajagopal, Robert J LefkowitzAbstract:Seven-Transmembrane Receptors (7TMRs; also known as G protein-coupled Receptors) are the largest class of Receptors in the human genome and are common targets for therapeutics. Originally identified as mediators of 7TMR desensitization, beta-arrestins (arrestin 2 and arrestin 3) are now recognized as true adaptor proteins that transduce signals to multiple effector pathways. Signalling that is mediated by beta-arrestins has distinct biochemical and functional consequences from those mediated by G proteins, and several biased ligands and Receptors have been identified that preferentially signal through either G protein- or beta-arrestin-mediated pathways. These ligands are not only useful tools for investigating the biochemistry of 7TMR signalling, they also have the potential to be developed into new classes of therapeutics.
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β-Arrestin-dependent signaling and trafficking of 7-Transmembrane Receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Sudha K Shenoy, William E. Miller, Arun K Shukla, Seungkirl Ahn, Aalok S. Modi, Kunhong Xiao, Magali Berthouze, Keith D. Wilkinson, Robert J LefkowitzAbstract:Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-Transmembrane Receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds beta-arrestin2 and leads to the deubiquitination of beta-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the beta(2)AR, previously shown to form loose complexes with beta-arrestin ("class A") promote a beta-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight beta-arrestin complexes ("class B"), promotes a distinct beta-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-beta-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated Receptors to downstream effectors.
Sudha K Shenoy - One of the best experts on this subject based on the ideXlab platform.
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g protein coupled receptor kinase 5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7 Transmembrane Receptors
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Lisheng Zhang, Sudha K Shenoy, Alexander C Fanaroff, Xinjiang Cai, Krishn Sharma, Leigh Brian, Sabrina T Exum, Karsten Peppel, Neil J FreedmanAbstract:Objective—G protein–coupled receptor kinase-5 (GRK5) is a widely expressed Ser/Thr kinase that regulates several atherogenic Receptors and may activate or inhibit nuclear factor-κB (NF-κB). This study sought to determine whether and by what mechanisms GRK5 affects atherosclerosis. Methods and Results—Grk5−/−/Apoe−/− mice developed 50% greater aortic atherosclerosis than Apoe−/− mice and demonstrated greater proliferation of macrophages and smooth muscle cells (SMCs) in atherosclerotic lesions. In Apoe−/− mice, carotid interposition grafts from Grk5−/− mice demonstrated greater upregulation of cell adhesion molecules than grafts from wild-type mice and, subsequently, more atherosclerosis. By comparing Grk5−/− with wild-type cells, we found that GRK5 desensitized 2 key atherogenic receptor tyrosine kinases: the platelet-derived growth factor receptor-β in SMCs, by augmenting ubiquitination/degradation; and the colony-stimulating factor-1 receptor (CSF-1R) in macrophages, by reducing CSF-1-induced tyrosyl ph...
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β-Arrestin-dependent signaling and trafficking of 7-Transmembrane Receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Sudha K Shenoy, William E. Miller, Arun K Shukla, Seungkirl Ahn, Aalok S. Modi, Kunhong Xiao, Magali Berthouze, Keith D. Wilkinson, Robert J LefkowitzAbstract:Beta-arrestins are multifunctional adaptors that mediate the desensitization, internalization, and some signaling functions of seven-Transmembrane Receptors (7TMRs). Agonist-stimulated ubiquitination of beta-arrestin2 mediated by the E3 ubiquitin ligase Mdm2 is critical for rapid beta(2)-adrenergic receptor (beta(2)AR) internalization. We now report the discovery that the deubiquitinating enzyme ubiquitin-specific protease 33 (USP33) binds beta-arrestin2 and leads to the deubiquitination of beta-arrestins. USP33 and Mdm2 function reciprocally and favor respectively the stability or lability of the receptor beta-arrestin complex, thus regulating the longevity and subcellular localization of receptor signalosomes. Receptors such as the beta(2)AR, previously shown to form loose complexes with beta-arrestin ("class A") promote a beta-arrestin conformation conducive for binding to the deubiquitinase, whereas the vasopressin V2R, which forms tight beta-arrestin complexes ("class B"), promotes a distinct beta-arrestin conformation that favors dissociation of the enzyme. Thus, USP33-beta-arrestin interaction is a key regulatory step in 7TMR trafficking and signal transmission from the activated Receptors to downstream effectors.
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Distinct conformational changes in β-arrestin report biased agonism at seven-Transmembrane Receptors
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Arun K Shukla, Sudha K Shenoy, Jonathan D. Violin, Erin J. Whalen, Diane Gesty-palmer, Robert J LefkowitzAbstract:β-arrestins critically regulate G protein-coupled Receptors (GPCRs), also known as seven-Transmembrane Receptors (7TMRs), both by inhibiting classical G protein signaling and by initiating distinct β-arrestin-mediated signaling. The recent discovery of β-arrestin-biased ligands and receptor mutants has allowed characterization of these independent “G protein-mediated” and “β-arrestin-mediated” signaling mechanisms of 7TMRs. However, the molecular mechanisms underlying the dual functions of β-arrestins remain unclear. Here, using an intramolecular BRET (bioluminescence resonance energy transfer)-based biosensor of β-arrestin 2 and a combination of biased ligands and/or biased mutants of three different 7TMRs, we provide evidence that β-arrestin can adopt multiple “active” conformations. Surprisingly, phosphorylation-deficient mutants of the Receptors are also capable of directing similar conformational changes in β-arrestin as is the wild-type receptor. This indicates that distinct receptor conformations induced and/or stabilized by different ligands can promote distinct and functionally specific conformations in β-arrestin even in the absence of receptor phosphorylation. Our data thus highlight another interesting aspect of 7TMR signaling—i.e., functionally specific receptor conformations can be translated to downstream effectors such as β-arrestins, thereby governing their functional specificity.
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Seven-Transmembrane Receptors and Ubiquitination
Circulation research, 2007Co-Authors: Sudha K ShenoyAbstract:Regulation of protein function by posttranslational modification plays an important role in many biological pathways. The most well known among such modifications is protein phosphorylation performed by highly specific protein kinases. In the past decade, however, covalent linkage of the low-molecular-weight protein ubiquitin to substrate proteins (protein ubiquitination) has proven to be yet another widely used mechanism of protein regulation playing a crucial role in virtually all aspects of cellular functions. This review highlights some of the recently discovered and provocative roles for ubiquitination in the regulation of the life cycle and signal transduction properties of 7-Transmembrane Receptors that serve to integrate many biological functions and play fundamental roles in cardiovascular homeostasis.
Joanna Jędrzejewska-szmek - One of the best experts on this subject based on the ideXlab platform.
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Molecular mechanisms underlying neuronal synaptic plasticity: systems biology meets computational neuroscience in the wilds of synaptic plasticity
Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2013Co-Authors: Kim T. Blackwell, Joanna Jędrzejewska-szmekAbstract:Interactions among signaling pathways that are activated by Transmembrane Receptors produce complex networks and emergent dynamical behaviors that are implicated in synaptic plasticity. Temporal dynamics and spatial aspects are critical determinants of cell responses such as synaptic plasticity, although the mapping between spatiotemporal activity pattern and direction of synaptic plasticity is not completely understood. Computational modeling of neuronal signaling pathways has significantly contributed to understanding signaling pathways underlying synaptic plasticity. Spatial models of signaling pathways in hippocampal neurons have revealed mechanisms underlying the spatial distribution of extracellular signal-related kinase (ERK) activation in hippocampal neurons. Other spatial models have demonstrated that the major role of anchoring proteins in striatal and hippocampal synaptic plasticity is to place molecules near their activators. Simulations of yet other models have revealed that the spatial distribution of synaptic plasticity may differ for potentiation versus depression. In general, the most significant advances have been made by interactive modeling and experiments; thus, an interdisciplinary approach should be applied to investigate critical issues in neuronal signaling pathways. These issues include identifying which Transmembrane Receptors are key for activating ERK in neurons, and the crucial targets of kinases that produce long-lasting synaptic plasticity. Although the number of computer programs for computationally efficient simulation of large reaction-diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial models remain more difficult than in single compartment models. Advances in live cell imaging coupled with further software development will continue to accelerate the development of spatial models of synaptic plasticity.
Kim T. Blackwell - One of the best experts on this subject based on the ideXlab platform.
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Molecular mechanisms underlying neuronal synaptic plasticity: systems biology meets computational neuroscience in the wilds of synaptic plasticity
Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2013Co-Authors: Kim T. Blackwell, Joanna Jędrzejewska-szmekAbstract:Interactions among signaling pathways that are activated by Transmembrane Receptors produce complex networks and emergent dynamical behaviors that are implicated in synaptic plasticity. Temporal dynamics and spatial aspects are critical determinants of cell responses such as synaptic plasticity, although the mapping between spatiotemporal activity pattern and direction of synaptic plasticity is not completely understood. Computational modeling of neuronal signaling pathways has significantly contributed to understanding signaling pathways underlying synaptic plasticity. Spatial models of signaling pathways in hippocampal neurons have revealed mechanisms underlying the spatial distribution of extracellular signal-related kinase (ERK) activation in hippocampal neurons. Other spatial models have demonstrated that the major role of anchoring proteins in striatal and hippocampal synaptic plasticity is to place molecules near their activators. Simulations of yet other models have revealed that the spatial distribution of synaptic plasticity may differ for potentiation versus depression. In general, the most significant advances have been made by interactive modeling and experiments; thus, an interdisciplinary approach should be applied to investigate critical issues in neuronal signaling pathways. These issues include identifying which Transmembrane Receptors are key for activating ERK in neurons, and the crucial targets of kinases that produce long-lasting synaptic plasticity. Although the number of computer programs for computationally efficient simulation of large reaction-diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial models remain more difficult than in single compartment models. Advances in live cell imaging coupled with further software development will continue to accelerate the development of spatial models of synaptic plasticity.
Jeremy Nathans - One of the best experts on this subject based on the ideXlab platform.
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a family of secreted proteins contains homology to the cysteine rich ligand binding domain of frizzled Receptors
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Amir Rattner, Philip M Smallwood, Debra J Gilbert, Nancy A Jenkins, Jen Chih Hsieh, N G Copeland, Jeremy NathansAbstract:This paper describes the identification of a new family of mammalian genes that encode secreted proteins containing homology to the cysteine-rich ligand-binding domain found in the frizzled family of Transmembrane Receptors. The secreted frizzled-related proteins (sFRPs) are approximately 30 kDa in size, and each contains a putative signal sequence, a frizzled-like cysteine-rich domain, and a conserved hydrophilic carboxy-terminal domain. The sFRPs are not the products of differential splicing of the known frizzled genes. Glycosylphosphatidylinositol-anchored derivatives of sFRP-2 and sFRP-3 produced in transfected human embryonic kidney cells confer cell-surface binding by the Drosophila Wingless protein. These observations suggest that sFRPs may function in vivo to modulate Wnt signaling, or, alternatively, as novel ligands for as yet unidentified Receptors.
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a member of the frizzled protein family mediating axis induction by wnt 5a
Science, 1997Co-Authors: Jeremy Nathans, Yanshu Wang, Igor B. Dawid, Xi He, Jean Pierre Saintjeannet, Harold E VarmusAbstract:In Xenopus laevis embryos, the Wingless/Wnt-1 subclass of Wnt molecules induces axis duplication, whereas the Wnt-5A subclass does not. This difference could be explained by distinct signal transduction pathways or by a lack of one or more Wnt-5A Receptors during axis formation. Wnt-5A induced axis duplication and an ectopic Spemann organizer in the presence of hFz5, a member of the Frizzled family of seven-Transmembrane Receptors. Wnt-5A/hFz5 signaling was antagonized by glycogen synthase kinase-3 and by the amino-terminal ectodomain of hFz5. These results identify hFz5 as a receptor for Wnt-5A.
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a large family of putative Transmembrane Receptors homologous to the product of the drosophila tissue polarity gene frizzled
Journal of Biological Chemistry, 1996Co-Authors: Yanshu Wang, Jennifer P Macke, Benjamin S Abella, Katrin Andreasson, Paul F Worley, Debra J Gilbert, Neal G Copeland, Nancy A Jenkins, Jeremy NathansAbstract:Abstract In Drosophila melanogaster, the frizzled gene plays an essential role in the development of tissue polarity as assessed by the orientation of cuticular structures. Through a combination of random cDNA sequencing, degenerate polymerase chain reaction amplification, and low stringency hybridization we have identified six novel frizzled homologues from mammals, at least 11 from zebrafish, several from chicken and sea urchin, and one from Caenorhabditis elegans. The complete deduced amino acid sequences of the mammalian and nematode homologues share with the Drosophila frizzled protein a conserved amino-terminal cysteine-rich domain and seven putative Transmembrane segments. Each of the mammalian homologues is expressed in a distinctive set of tissues in the adult, and at least three are expressed during embryogenesis. As hypothesized for the Drosophila frizzled protein, the frizzled homologues are likely to act as Transmembrane Receptors for as yet unidentified ligands. These observations predict the existence of a family of signal transduction pathways that are homologous to the pathway that determines tissue polarity in Drosophila.
