R J Lefkowitz

Duke University, Durham, North Carolina, United States

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Publications (817)6740.58 Total impact

  • Wei Tang, Ryan T Strachan, Robert J Lefkowitz, Howard A Rockman
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    ABSTRACT: It has recently been appreciated that the angiotensin-II type-1 receptor (AT1R), a prototypic member of the G protein-coupled receptor (GPCR) superfamily, also functions as a mechanosensor. Specifically, mechanical stretch activates the AT1R to promote downstream signaling mediated exclusively by the multifunctional scaffold protein, β-arrestin, in a manner consistent with previously identified β-arrestin-biased ligands. However, the ligand-independent mechanism by which mechanical stretch promotes β-arrestin-biased signaling remains unknown. Implicit in the concept of biased agonism (i.e., the ability of an agonist to activate a subset of receptor-mediated signaling pathways) is the notion that distinct active conformations of the receptor mediate differential activation of signaling pathways. Here we determined if mechanical stretch stabilizes distinct β-arrestin-activating conformations of the AT1R by using β-arrestin2-biased agonists as conformational probes in pharmacological and biophysical assays. When tested at cells expressing the AT1R fused to β-arrestin (AT1R-β-arrestin2), we found that osmotic stretch increased the binding affinity and potency of the β-arrestin-biased agonist TRV120023, with no effect on the balanced agonist AngII. In addition, the effect of osmotic stretch on ERK activation was markedly augmented in cells expressing the AT1R-β-arrestin2 fusion compared to the wild type AT1R, and completely blocked in cells expressing the AT1R-Gq fusion. Biophysical experiments with an intramolecular BRET β-arrestin2 biosensor revealed that osmotic stretch and TRV120023 activate AT1Rs to stabilize β-arrestin2 active conformations which differ from those stabilized by the AT1R activated by angiotensin II. Together, these data support a novel ligand-independent mechanism whereby mechanical stretch allosterically stabilizes specific β-arrestin-biased active conformations of the AT1R and have important implications for understanding pathophysiological AT1R signaling.
    Journal of Biological Chemistry 08/2014; · 4.65 Impact Factor
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    ABSTRACT: G-protein-coupled receptors (GPCRs) are critically regulated by b-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling 1–5 . A recent surge of structural data on a number of GPCRs, including the b 2 adrenergic receptor (b 2 AR)–G-protein complex, has provided novel insights into the structural basis of receptor activation 6–11 . However, complement-ary information has been lacking on the recruitment of b-arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor–b-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human b 2 AR–b-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative-stain electron microscopy and to character-ize the interactions between b 2 AR and b-arrestin 1 using hydrogen– deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three-dimensional reconstructions reveal bimodal binding of b-arrestin 1 to the b 2 AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of b-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of b-arrestin 1 when coupled to the b 2 AR. A molecular model of the b 2 AR– b-arrestin signalling complex was made by docking activated b-arrestin 1 and b 2 AR crystal structures into the electron microscopy map den-sities with constraints provided by HDX-MS and crosslinking, al-lowing us to obtain valuable insights into the overall architecture of a receptor–arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins. To facilitate the isolation of a stable b 2 AR–b-arrestin complex, we used a modified b 2 AR construct with its C terminus replaced by that of the arginine vasopressin type 2 receptor (AVPR 2). This chimaeric re-ceptor (b 2 V 2 R) maintains pharmacological properties identical to the b 2 AR, but it binds b-arrestins with higher affinity compared to wild-type b 2 AR 12 . We co-expressed b 2 V 2 R, b-arrestin 1 (1–393) and GRK2 CAAX (GRK2 with a membrane-tethering prenylation signal) in insect cells followed by agonist stimulation and affinity purification through the Flag-tagged receptor (Fig. 1a) However, since the isolation of a stable complex was still not feasible (Fig. 1b, lanes 1 and 2), we explored en-hancing its stability by adding Fab30, an antibody fragment we previously reported that selectively recognizes and stabilizes the active confor-mation of b-arrestin 1 (ref. 13). Indeed, incubation of Fab30 with pre-formed complex in the membrane resulted in a robust purification of the b 2 V 2 R–b-arrestin-1 complex (Fig. 1b, lanes 5 and 6), whereas a non-specific Fab (referred to as Fab1) did not support complex stabilization (Fig. 1b, lanes 3 and 4). Complex isolation was only possible in res-ponse to an agonist (BI-167107) and not an inverse agonist (ICI-118551) (Fig. 1b, lanes 5 and 6). Furthermore, the efficiency of complex purification using this approach directly mirrors the pharmacological efficacy of the ligand used to stimulate the cells (Fig. 1c). While stimulation of cells with inverse agonists does not yield detectable co-purification of b-arrestin 1, agonists robustly stabilize the complex and partial ago-nists yield co-purification of b-arrestin 1 at moderate levels. Moreover, the efficiency of complex formation also corresponds to the ligand occu-pancy of the receptor as reflected by the increasing amount of b-arrestin 1 co-purification with increasing agonist concentrations (Extended Data Fig. 1a, b). The direct correlation of ligand efficacy and occupancy with purification efficiency reflects the fact that this approach yields a com-plex that depends on both activated receptor conformation and recep-tor phosphorylation. The purified b 2 V 2 R–b-arrestin-1–Fab30 complex also exhibited a robust interaction with the purified clathrin terminal domain compared to b-arrestin 1 alone, suggesting that b-arrestin 1 in this complex is in a physiologically relevant and functional conforma-tion (Extended Data Fig. 2)
    Nature 06/2014; · 38.60 Impact Factor
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    ABSTRACT: The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an 'active' conformation. In the past decade, however, it has been appreciated that ligands can induce distinct 'active' receptor conformations with unique downstream functional signaling profiles. Building on the initial recognition of the existence of such 'biased ligands', recent years have witnessed significant developments in several areas of GPCR biology. These include increased understanding of structural and biophysical mechanisms underlying biased agonism, improvements in characterization and quantification of ligand efficacy, as well as clinical development of these novel ligands. Here we review recent major developments in these areas over the past several years.
    Current opinion in cell biology 04/2014; 27C:18-24. · 14.15 Impact Factor
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    ABSTRACT: The concept of biased agonism arises from the recognition that the ability of an agonist to induce a receptor-mediated response (i.e., efficacy) can differ across the multiple signal transduction pathways (e.g., G protein and β-arrestin (βarr)) emanating from a single GPCR. Despite the therapeutic promise of biased agonism, the molecular mechanism(s) whereby biased agonists selectively engage signaling pathways remain elusive. This is due, in large part, to the challenges associated with quantifying ligand efficacy in cells. To address this, we developed a cell-free approach to directly quantify the transducer-specific molecular efficacies of balanced and biased ligands for the angiotensin II type 1 receptor (AT1R), a prototypic GPCR. Specifically, we defined efficacy in allosteric terms, equating shifts in ligand affinity (i.e., KLo/KHi) at AT1R-Gq and AT1R-βarr2 fusion proteins with their respective molecular efficacies for activating Gq and βarr2. Consistent with ternary complex model predictions, transducer-specific molecular efficacies were strongly correlated with cellular efficacies for activating Gq and βarr2. Subsequent comparisons across transducers revealed that biased AT1R agonists possess biased molecular efficacies which were in strong agreement with the signaling bias observed in cellular assays. These findings not only represent the first measurements of the thermodynamic driving forces underlying differences in ligand efficacy between transducers, but also support a molecular mechanism whereby divergent transducer-specific molecular efficacies generate biased agonism at a GPCR.
    Journal of Biological Chemistry 03/2014; · 4.65 Impact Factor
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    ABSTRACT: The biological activity induced by ligand binding to orthosteric or allosteric sites on a GPCR is mediated by stabilization of specific receptor conformations. In the case of the β2 adrenergic receptor, these ligands are generally small molecule agonists or antagonists. However, recently a monomeric single domain antibody (nanobody) from the Camelid family was found to allosterically bind and stabilize an active conformation of the β2 adrenergic receptor (β2AR). Here we set out to study the functional interaction of 18 related nanobodies with the β2 adrenergic receptor to investigate their roles as novel tools for studying GPCR biology. Our studies revealed several sequence related nanobody families with preferences for active (agonist occupied) or inactive (antagonist occupied) receptors. Flow cytometry analysis indicates that all nanobodies bind to epitopes displayed on the intracellular receptor surface, therefore we transiently expressed them intracellularly (intrabodies) to test their effects on β2AR-dependent signaling Conformational specificity was preserved after intrabody conversion as demonstrated by the ability for the intracellularly expressed nanobodies to selectively bind agonist or antagonist-occupied receptors. When expressed as intrabodies inhibited G-protein activation (cyclic AMP accumulation), GRK-mediated receptor phosphorylation, β-arrestin recruitment, and receptor internalization to varying extents. These functional effects were likely due to either steric blockade of downstream effector (Gs, β-arrestin, GRK) interactions or stabilization of specific receptor conformations which do not support effector coupling. Together these findings strongly implicate nanobody-derived intrabodies as novel tools to study GPCR biology.
    Molecular pharmacology 12/2013; · 4.53 Impact Factor
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    ABSTRACT: G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on cellular systems overexpressing the receptors. An alternative ligand discovery strategy is a fragment-based drug discovery, where low molecular weight compounds, known as fragments, are screened as initial starting points for optimization. However, the screening of fragment libraries usually employs biophysical screening methods, and as such, it has not been routinely applied to membrane proteins. We present here a surface plasmon resonance biosensor approach that enables, cell-free, label-free, fragment screening that directly measures fragment interactions with wild-type GPCRs. We exemplify the method by the discovery of novel, selective, high affinity antagonists of human β2 adrenoceptor.
    ACS Medicinal Chemistry Letters 10/2013; 4(10):1005-1010. · 3.31 Impact Factor
  • Robert J. Lefkowitz
    Angewandte Chemie 06/2013; 125(25).
  • Robert J Lefkowitz
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    ABSTRACT: The idea of receptors has fascinated scientists for more than a century. Today it is known that the G-protein coupled receptors (GPCRs) represent by far the largest, most versatile and most ubiquitous of the several families of plasma membrane receptors. The Nobel Prize for Chemistry 2012 was awarded for studies on GPCRs.
    Angewandte Chemie International Edition 05/2013; · 11.34 Impact Factor
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    ABSTRACT: The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of β-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate β-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The structure of the β-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in β-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of β-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on β-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.
    Nature 04/2013; · 38.60 Impact Factor
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    ABSTRACT: A prospective, large library virtual screen against an activated β2AR structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound GPCR structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug-design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a DRD2 activated model templated on the activated β2AR structure returned few hits of only marginal potency.
    ACS Chemical Biology 03/2013; · 5.44 Impact Factor
  • Robert J Lefkowitz
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    ABSTRACT: Visual arrestin and the two β-arrestins (1 and 2) were originally discovered 25-30 years ago in the context of their ability to desensitize phosphorylated G protein-coupled receptors (rhodopsin and the β2-adrenergic receptor, respectively). A fourth retinal-specific member of the family (X-arrestin) was discovered later. Over the past 10-15 years, however, it has become clear that these versatile molecules subserve a host of other roles in modulating and mediating the function of most GPCRs as well as other types of receptors. Functioning as multifunctional adaptor proteins, the β-arrestins also play prominent roles in receptor endocytosis, signaling, trafficking, and ubiquitination among others. Here, I provide a brief personal perspective on how the field has evolved since its inception and speculate on future directions.
    Progress in molecular biology and translational science 01/2013; 118:3-18. · 2.32 Impact Factor
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    ABSTRACT: Over the last decade, it has been established that G-protein-coupled receptors (GPCRs) signal not only through canonical G-protein-mediated mechanisms, but also through the ubiquitous cellular scaffolds β-arrestin-1 and β-arrestin-2. Previous studies have implicated β-arrestins as regulators of actin reorganization in response to GPCR stimulation while also being required for membrane protrusion events that accompany cellular motility. One of the most critical events in the active movement of cells is the cyclic phosphorylation and activation of myosin light chain (MLC), which is required for cellular contraction and movement. We have identified the myosin light chain phosphatase Targeting Subunit (MYPT-1) as a binding partner of the β-arrestins and found that β-arrestins play a role in regulating the turnover of phosphorylated myosin light chain. In response to stimulation of the angiotensin Type 1a Receptor (AT1aR), MLC phosphorylation is induced quickly and potently. We have found that β-arrestin-2 facilitates dephosphorylation of MLC, while, in a reciprocal fashion, β-arrestin 1 limits dephosphorylation of MLC. Intriguingly, loss of either β-arrestin-1 or 2 blocks phospho-MLC turnover and causes a decrease in the contraction of cells as monitored by atomic force microscopy (AFM). Furthermore, by employing the β-arrestin biased ligand [Sar(1),Ile(4),Ile(8)]-Ang, we demonstrate that AT1aR-mediated cellular motility involves a β-arrestin dependent component. This suggests that the reciprocal regulation of MLC phosphorylation status by β-arrestins-1 and 2 causes turnover in the phosphorylation status of MLC that is required for cell contractility and subsequent chemotaxic motility.
    PLoS ONE 01/2013; 8(11):e80532. · 3.53 Impact Factor
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    ABSTRACT: β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic role of β-arrestins in driving oncogenesis is not known. Here we have investigated the role of β-arrestin in hematologic malignancies and have found that although both β-arrestin1 and -2 are expressed in the hematopoietic system, loss of β-arrestin2 preferentially leads to a severe impairment in the establishment and propagation of the chronic and blast crisis phases of chronic myelogenous leukemia (CML). These defects are linked to a reduced frequency, as well as defective self-renewal capacity of the cancer stem-cell population, in mouse models and in human CML patient samples. At a molecular level, the loss of β-arrestin2 leads to a significant inhibition of β-catenin stabilization, and ectopic activation of Wnt signaling reverses the defects observed in the β-arrestin2 mutant cells. These data cumulatively show that β-arrestin2 is essential for CML disease propagation and indicate that β-arrestins and the Wnt/β-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance.
    Proceedings of the National Academy of Sciences 07/2012; 109(31):12532-7. · 9.81 Impact Factor
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    ABSTRACT: Chronic stress is known to have a profound negative impact on human health and has been suggested to influence a number of disease states. However, the mechanisms underling the deleterious effects of stress remain largely unknown. Stress is known to promote the release of epinephrine, a catecholamine stress hormone that binds to β 2-adrenergic receptors (β 2ARs) with high affinity. Our previous work has demonstrated that chronic stimulation of a β 2AR-β-arrestin-1-mediated signaling pathway by infusion of isoproterenol suppresses p53 levels and impairs genomic integrity. In this pathway, β-arrestin-1, which is activated via β 2ARs, facilitates the AKT-mediated activation of Mdm2 and functions as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, Mdm2. Here we show that chronic restraint stress in mice recapitulates the effects of isoproterenol infusion to reduce p53 levels and results in the accumulation of DNA damage in the frontal cortex of the brain, two effects that are abrogated by the β-blocker, propranolol, and by genetic deletion of β-arrestin-1. These data suggest that the β 2AR-β-arrestin-1 signaling pathway may represent an attractive therapeutic target to prevent some of the negative consequences of stress in the treatment of stress-related disorders.
    Cell cycle (Georgetown, Tex.) 01/2012; 12(2). · 5.24 Impact Factor
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    ABSTRACT: Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)-based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well-established function in the desensitization of G-protein activation, GRK2 exerts a strong negative effect on β-arrestin-dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2-dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT(1A)R, and HEK293 cells expressing other 7TMRs.
    Molecular Systems Biology 01/2012; 8:590. · 11.34 Impact Factor
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    Robert J Lefkowitz
    The Journal of clinical investigation 10/2011; 121(10):4201-3. · 15.39 Impact Factor
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    ABSTRACT: Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adaptor proteins β-arrestins. Moreover, several receptor ligands with differential efficacies toward these distinct signaling pathways have been identified. However, the structural basis and mechanism underlying this 'biased agonism' remains largely unknown. Here, we develop a quantitative mass spectrometry strategy that measures specific reactivities of individual side chains to investigate dynamic conformational changes in the β(2)-adrenergic receptor occupied by nine functionally distinct ligands. Unexpectedly, only a minority of residues showed reactivity patterns consistent with classical agonism, whereas the majority showed distinct patterns of reactivity even between functionally similar ligands. These findings demonstrate, contrary to two-state models for receptor activity, that there is significant variability in receptor conformations induced by different ligands, which has significant implications for the design of new therapeutic agents.
    Nature Chemical Biology 08/2011; 7(10):692-700. · 12.95 Impact Factor
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    ABSTRACT: The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs-PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.
    Nature 08/2011; 477(7364):349-53. · 38.60 Impact Factor
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    ABSTRACT: Phosphorylation of G protein-coupled receptors (GPCRs, which are also known as seven-transmembrane spanning receptors) by GPCR kinases (GRKs) plays essential roles in the regulation of receptor function by promoting interactions of the receptors with β-arrestins. These multifunctional adaptor proteins desensitize GPCRs, by reducing receptor coupling to G proteins and facilitating receptor internalization, and mediate GPCR signaling through β-arrestin-specific pathways. Detailed mapping of the phosphorylation sites on GPCRs targeted by individual GRKs and an understanding of how these sites regulate the specific functional consequences of β-arrestin engagement may aid in the discovery of therapeutic agents targeting individual β-arrestin functions. The β(2)-adrenergic receptor (β(2)AR) has many serine and threonine residues in the carboxyl-terminal tail and the intracellular loops, which are potential sites of phosphorylation. We monitored the phosphorylation of the β(2)AR at specific sites upon stimulation with an agonist that promotes signaling by both G protein-mediated and β-arrestin-mediated pathways or with a biased ligand that promotes signaling only through β-arrestin-mediated events in the presence of the full complement of GRKs or when either GRK2 or GRK6 was depleted. We correlated the specific and distinct patterns of receptor phosphorylation by individual GRKs with the functions of β-arrestins and propose that the distinct phosphorylation patterns established by different GRKs establish a "barcode" that imparts distinct conformations to the recruited β-arrestin, thus regulating its functional activities.
    Science Signaling 08/2011; 4(185):ra51. · 7.65 Impact Factor
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    Arun K Shukla, Kunhong Xiao, Robert J Lefkowitz
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    ABSTRACT: 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.
    Trends in Biochemical Sciences 07/2011; 36(9):457-69. · 13.08 Impact Factor

Publication Stats

58k Citations
6,740.58 Total Impact Points

Institutions

  • 1996–2014
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
  • 1974–2014
    • Duke University Medical Center
      • • Department of Medicine
      • • Department of Surgery
      • • Department of Cell Biology
      • • Department of Anesthesiology
      • • Division of Hematology
      • • Department of Pathology
      • • Division of Cardiology
      Durham, North Carolina, United States
  • 2013
    • Université de Sherbrooke
      • Department of Pharmacology
      Sherbrooke, Quebec, Canada
  • 1979–2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2004
    • University of Washington Seattle
      • Department of Pharmacology
      Seattle, WA, United States
  • 2003–2004
    • The Ohio State University
      • Division of Pharmacology
      Columbus, OH, United States
    • University of Texas at Austin
      • Institute for Cellular and Molecular Biology
      Texas City, TX, United States
  • 2002
    • Emory University
      • Department of Pharmacology
      Atlanta, GA, United States
  • 1998
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 1997
    • Hohenheim University
      Stuttgart, Baden-Württemberg, Germany
  • 1996–1997
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
  • 1995
    • University of Florida
      • Department of Medicine
      Gainesville, FL, United States
  • 1994
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
  • 1993
    • Cincinnati Children's Hospital Medical Center
      • Division of Pulmonary Medicine
      Cincinnati, OH, United States
    • CUNY Graduate Center
      New York City, New York, United States
  • 1992
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 1990–1991
    • Temple University
      • Fels Institute for Cancer Research and Molecular Biology
      Philadelphia, PA, United States