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  1. Article ; Online: An interview with Robert J. Lefkowitz.

    Lefkowitz, Robert J

    Trends in pharmacological sciences

    2012  Volume 33, Issue 2, Page(s) 51–52

    MeSH term(s) Biomedical Research/history ; History, 20th Century ; History, 21st Century ; Receptors, G-Protein-Coupled/history
    Chemical Substances Receptors, G-Protein-Coupled
    Language English
    Publishing date 2012-03-08
    Publishing country England
    Document type Historical Article ; Interview
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2011.10.009
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  2. Article: An interview with Professor Robert J. Lefkowitz, M.D. Interview by Vicki Glaser.

    Lefkowitz, Robert J

    Assay and drug development technologies

    2003  Volume 1, Issue 2, Page(s) 233–238

    Abstract: Robert J. Lefkowitz, M.D., is James B. Duke Professor of Medicine and Professor of Biochemistry ... since 1976. Dr. Lefkowitz received a Bachelor's degree from Columbia College and an M.D. degree from Columbia ...

    Abstract Robert J. Lefkowitz, M.D., is James B. Duke Professor of Medicine and Professor of Biochemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz received a Bachelor's degree from Columbia College and an M.D. degree from Columbia University College of Physicians and Surgeons. After serving an internship and one year of general medical residency at the College of Physicians and Surgeons, he served as a Clinical and Research Associate with Drs. Jesse Roth and Ira Pastan at the National Institutes of Health. He then completed his medical residency and research and clinical training in cardiovascular disease at the Massachusetts General Hospital, Boston. During this time, he continued his research in the laboratories of Dr. Edgar Haber and was a teaching fellow at Harvard Medical School. On completing his training, he was appointed Associate Professor of Medicine and Assistant Professor of Biochemistry at the Duke University Medical Center.
    MeSH term(s) Drug Industry ; Humans ; Male ; Receptors, G-Protein-Coupled/drug effects ; Receptors, G-Protein-Coupled/physiology ; Research ; Teaching
    Chemical Substances Receptors, G-Protein-Coupled
    Language English
    Publishing date 2003-04
    Publishing country United States
    Document type Interview ; Portraits
    ISSN 1540-658X
    ISSN 1540-658X
    DOI 10.1089/15406580360545044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    2005 A 2339: Show issues

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  3. Article ; Online: Focus on the research journey. An interview with Robert J. Lefkowitz, MD, scientist, mentor, and recipient of the 2007 National Medal of Science by Elaine Musgrave.

    Lefkowitz, Robert J

    Clinical and translational science

    2010  Volume 2, Issue 1, Page(s) 4–5

    MeSH term(s) Awards and Prizes ; Biomedical Research/history ; History, 20th Century ; History, 21st Century ; Humans ; Mentors ; Translational Medical Research ; United States
    Language English
    Publishing date 2010-04-21
    Publishing country United States
    Document type Biography ; Historical Article ; Interview ; Portrait
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/j.1752-8062.2008.00081.x
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  4. Article ; Online: G protein-coupled receptors: from radioligand binding to cellular signaling.

    Rockman, Howard A / Lefkowitz, Robert J

    The Journal of clinical investigation

    2024  Volume 134, Issue 5

    Abstract: Radioligand binding techniques facilitated the identification and study of G-protein coupled receptors that now represent the largest class of targets for therapeutic drugs. ...

    Abstract Radioligand binding techniques facilitated the identification and study of G-protein coupled receptors that now represent the largest class of targets for therapeutic drugs.
    MeSH term(s) Radioligand Assay/methods ; Receptors, G-Protein-Coupled/metabolism
    Chemical Substances Receptors, G-Protein-Coupled
    Language English
    Publishing date 2024-03-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI178109
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  5. Article ; Online: Marc G. Caron (1946-2022).

    Lefkowitz, Robert J / Amara, Susan G

    Nature neuroscience

    2022  Volume 25, Issue 9, Page(s) 1120

    Language English
    Publishing date 2022-08-01
    Publishing country United States
    Document type Editorial
    ZDB-ID 1420596-8
    ISSN 1546-1726 ; 1097-6256
    ISSN (online) 1546-1726
    ISSN 1097-6256
    DOI 10.1038/s41593-022-01145-y
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  6. Article ; Online: Signaling at the endosome: cryo-EM structure of a GPCR-G protein-beta-arrestin megacomplex.

    Nguyen, Anthony H / Lefkowitz, Robert J

    The FEBS journal

    2021  Volume 288, Issue 8, Page(s) 2562–2569

    Abstract: G protein-coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to ... ...

    Abstract G protein-coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to and activates G proteins through the receptor intracellular core. To attenuate G protein signaling, the GPCR is phosphorylated at its C-terminal tail and/or relevant intracellular loops, allowing for the recruitment of β-arrestins (βarrs). βarrs then couple to the receptor intracellular core in order to mediate receptor desensitization and internalization. However, our laboratory and others have observed that some GPCRs are capable of continuously signaling through G protein even after internalization. This mode of sustained signaling stands in contrast with our previous understanding of GPCR signaling, and its molecular mechanism is still not well understood. Recently, we have solved the structure of a GPCR-G protein-βarr megacomplex by cryo-electron microscopy. This 'megaplex' structure illustrates the independent and simultaneous coupling of a G protein to the receptor intracellular core, and binding of a βarr to a phosphorylated receptor C-terminal tail, with all three components maintaining their respective canonically active conformations. The structure provides evidence for the ability of a GPCR to activate G protein even while being bound to and internalized by βarr. It also reveals that the binding of G protein and βarr to the same GPCR is not mutually exclusive, and raises a number of future questions to be answered regarding the mechanism of sustained signaling.
    MeSH term(s) Arrestins/genetics ; Arrestins/ultrastructure ; Cryoelectron Microscopy ; Endocytosis/genetics ; Endosomes/genetics ; Endosomes/ultrastructure ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/ultrastructure ; Humans ; Molecular Conformation ; Phosphorylation ; Protein Binding/genetics ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/ultrastructure ; Signal Transduction/genetics ; beta-Arrestins/genetics
    Chemical Substances Arrestins ; Receptors, G-Protein-Coupled ; beta-Arrestins ; GTP-Binding Proteins (EC 3.6.1.-)
    Language English
    Publishing date 2021-03-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.15773
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  7. Article ; Online: A Serendipitous Scientist.

    Lefkowitz, Robert J

    Annual review of pharmacology and toxicology

    2017  Volume 58, Page(s) 17–32

    Abstract: Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who ... ...

    Abstract Growing up in a middle-class Jewish home in the Bronx, I had only one professional goal: to become a physician. However, as with most of my Vietnam-era MD colleagues, I found my residency training interrupted by the Doctor Draft in 1968. Some of us who were academically inclined fulfilled this obligation by serving in the US Public Health Service as commissioned officers stationed at the National Institutes of Health. This experience would eventually change the entire trajectory of my career. Here I describe how, over a period of years, I transitioned from the life of a physician to that of a physician-scientist; my 50 years of work on cellular receptors; and some miscellaneous thoughts on subjects as varied as Nobel prizes, scientific lineages, mentoring, publishing, and funding.
    MeSH term(s) Biomedical Research ; Career Choice ; Humans ; Medical Laboratory Personnel ; Physicians ; United States
    Language English
    Publishing date 2017-07-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 196587-6
    ISSN 1545-4304 ; 0362-1642
    ISSN (online) 1545-4304
    ISSN 0362-1642
    DOI 10.1146/annurev-pharmtox-010617-053149
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  8. Article ; Online: Conformational Basis of G Protein-Coupled Receptor Signaling Versatility.

    Wingler, Laura M / Lefkowitz, Robert J

    Trends in cell biology

    2020  Volume 30, Issue 9, Page(s) 736–747

    Abstract: G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate ...

    Abstract G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate subsets of the many cellular pathways downstream of these receptors. Recently, complementary information from structural and spectroscopic approaches has made significant inroads into understanding the mechanisms of these biased ligands. The consistently emerging theme is that GPCRs are highly dynamic proteins, and ligands with varying pharmacological properties differentially modulate the equilibrium among multiple conformations. Biased signaling and other recently appreciated complexities of GPCR signaling thus appear to be a natural consequence of the conformational heterogeneity of GPCRs and GPCR-transducer complexes.
    MeSH term(s) Animals ; Biophysical Phenomena ; Humans ; Ligands ; Protein Conformation ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction
    Chemical Substances Ligands ; Receptors, G-Protein-Coupled
    Language English
    Publishing date 2020-07-02
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 30122-x
    ISSN 1879-3088 ; 0962-8924
    ISSN (online) 1879-3088
    ISSN 0962-8924
    DOI 10.1016/j.tcb.2020.06.002
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  9. Article ; Online: Alfred Goodman Gilman (1941-2015).

    Lefkowitz, Robert J

    Nature

    2016  Volume 529, Issue 7586, Page(s) 284

    MeSH term(s) Adenylyl Cyclases/chemistry ; Adenylyl Cyclases/metabolism ; Biochemistry/history ; Heterotrimeric GTP-Binding Proteins/chemistry ; Heterotrimeric GTP-Binding Proteins/history ; Heterotrimeric GTP-Binding Proteins/metabolism ; History, 20th Century ; History, 21st Century ; Nobel Prize ; Signal Transduction ; United States
    Chemical Substances Heterotrimeric GTP-Binding Proteins (EC 3.6.5.1) ; Adenylyl Cyclases (EC 4.6.1.1)
    Language English
    Publishing date 2016-01-21
    Publishing country England
    Document type Biography ; Historical Article ; Journal Article ; Portraits
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/529284a
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  10. Article ; Online: Loss of biased signaling at a G protein-coupled receptor in overexpressed systems.

    Li, Angus / Liu, Samuel / Huang, Rennica / Ahn, Seungkirl / Lefkowitz, Robert J

    PloS one

    2023  Volume 18, Issue 3, Page(s) e0283477

    Abstract: G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II ( ... ...

    Abstract G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to two classes of transducers: heterotrimeric G proteins and β-arrestins. [Sarcosine1Ile4Ile8]-angiotensin II (SII), an analog of the endogenous ligand angiotensin II (AngII) for the angiotensin II type 1 receptor (AT1R), fails to activate G protein in physiologically relevant models. Despite this, SII and several derivatives induce cellular signaling outcomes through β-arrestin-2-dependent mechanisms. However, studies reliant on exogenous AT1R overexpression indicate that SII is a partial agonist for G protein signaling and lacks β-arrestin-exclusive functional specificity. We investigated this apparent discrepancy by profiling changes in functional specificity at increasing expression levels of AT1R using a stably integrated tetracycline-titratable expression system stimulated with AngII, SII, and four other AngII analogs displaying different signaling biases. Unbiased and G protein-biased ligands activated dose-dependent calcium responses at all tested receptor concentrations. In contrast, β-arrestin-biased ligands induced dose-dependent calcium signaling only at higher AT1R overexpression levels. Using inhibitors of G proteins, we demonstrated that both Gi and Gq/11 mediated overexpression-dependent calcium signaling by β-arrestin-biased ligands. Regarding β-arrestin-mediated cellular events, the β-arrestin-biased ligand TRV026 induced receptor internalization at low physiological receptor levels insufficient for it to initiate calcium signaling. In contrast, unbiased AngII exhibited no relative preference between these outcomes under such low receptor conditions. However, with high receptor overexpression, TRV026 lost its functional selectivity. These results suggest receptor overexpression misleadingly distorts the bias of AT1R ligands and highlight the risks of using overexpressed systems to infer the signaling bias of GPCR ligands in physiologically relevant contexts.
    MeSH term(s) Humans ; Signal Transduction ; Receptors, G-Protein-Coupled/metabolism ; Angiotensin II/pharmacology ; Angiotensin II/metabolism ; Ligands ; beta-Arrestins/metabolism ; GTP-Binding Proteins/metabolism ; beta-Arrestin 1/metabolism ; Receptor, Angiotensin, Type 1/metabolism ; HEK293 Cells
    Chemical Substances Receptors, G-Protein-Coupled ; Angiotensin II (11128-99-7) ; Ligands ; beta-Arrestins ; GTP-Binding Proteins (EC 3.6.1.-) ; beta-Arrestin 1 ; Receptor, Angiotensin, Type 1
    Language English
    Publishing date 2023-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0283477
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