Robert J. Lefkowitz, MD

Professor of Medicine
James B. Duke Professor of Medicine
Professor of Biochemistry
Professor of Pathology
Professor of Chemistry
Member of the Duke Cancer Institute
Campus mail 467 Clin & Res Labs, Durham, NC 27710
Phone (919) 684-2974
Email address lefko001@receptor-biol.duke.edu

The focus of work in this laboratory is on the elucidation of the molecular properties and regulatory mechanisms controlling the function of G protein-coupled receptors. As model systems we utilize the so called adrenergic receptors for adrenaline and related molecules. The goal is to learn the general principles of signal transduction from the outside to the inside of the cell which are involved in systems as diverse as sensory perception, neuro- transmitter and hormonal signaling. Studies are performed with isolated protein, whole cells in culture and even in vivo in whole animals.

Current projects emphasize attempts to understand regulation of the receptors and their desensitization which occurs in response to persistent stimulation. We are isolating the enzymes and proteins involved in these processes and studying their mechanisms of action in isolated protein and cellular systems as well as in whole animals. Most important are special enzymes called G protein-coupled receptor kinases which phosphorylate the receptors and lead to their desensitization which occurs when they bind a second protein called barrestin. Most recently we have been developing lines of transgenic animals in which these various proteins are either overexpressed or "knockedout" by homologous recombination. These genetically altered animal lines are helping to shed new light on the ways in which receptors are regulated. They also have suggested several novel approaches to human therapeutics.

While no clinical trials are currently in progress in our program we are experimenting with novel approaches to the treatment of congestive heart failure in animal models. Specifically we are injecting recombinant adenovirus encoding either the b-adrenergic receptors or inhibitors of the b-adrenergic receptor kinase down the coronary arteries of rabbits. The hope is that these gene products when expressed in the myocardium will markedly enhance cardiac contractility.

Dr. Lefkowitz has received a great deal of recognition for his research including election to the National Academy of Sciences and the Institute of Medicine of the National Academy of Sciences as well as the receipt of numerous awards. Most recently these have included the The Louis and Artur Lucian Award for Research in Circulatory Disease, The Fred Conrad Koch Award - The Endocrine Society, The 2001 Jessie Stevenson Kovalenko Medal - The National Academy of Sciences and The Peter Harris Distinguished Scientist Award, International Society of Heart Research. Dr. Lefkowitz writes numerous review articles in the areas of hormone and drug receptors and their regulation and is a consultant for several drug companies which specialize in drugs which may affect signal transduction processes such as Norak, Lexicon Genetics and Genentech.

Education and Training

  • M.D., Columbia University, 1966

Publications

Lefkowitz, RJ. "An interview with Robert J. Lefkowitz." Trends in pharmacological sciences 33, no. 2 (2012): 51-52.

PMID
22403833
Scholars@Duke

Lefkowitz, R, and Kobilka, B. "A signal honour." Chemistry World 9, no. 11 (2012): 46-49.

Scholars@Duke

Lefkowitz, RJ. "A tale of two callings." J Clin Invest 121, no. 10 (October 2011): 4201-4203.

PMID
21965340
Full Text

Shenoy, SK, and Lefkowitz, RJ. "β-Arrestin-mediated receptor trafficking and signal transduction." Trends Pharmacol Sci 32, no. 9 (September 2011): 521-533. (Review)

PMID
21680031
Full Text

Shukla, AK, Xiao, K, and Lefkowitz, RJ. "Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling." Trends Biochem Sci 36, no. 9 (September 2011): 457-469. (Review)

PMID
21764321
Full Text

Rajagopal, S, Ahn, S, Rominger, DH, Gowen-MacDonald, W, Lam, CM, Dewire, SM, Violin, JD, and Lefkowitz, RJ. "Quantifying ligand bias at seven-transmembrane receptors." Mol Pharmacol 80, no. 3 (September 2011): 367-377.

PMID
21610196
Full Text

Kahsai, AW, Xiao, K, Rajagopal, S, Ahn, S, Shukla, AK, Sun, J, Oas, TG, and Lefkowitz, RJ. "Multiple ligand-specific conformations of the β2-adrenergic receptor. (Published online)" Nat Chem Biol 7, no. 10 (August 21, 2011): 692-700.

PMID
21857662
Full Text

Hara, MR, Kovacs, JJ, Whalen, EJ, Rajagopal, S, Strachan, RT, Grant, W, Towers, AJ, Williams, B, Lam, CM, Xiao, K, Shenoy, SK, Gregory, SG, Ahn, S, Duckett, DR, and Lefkowitz, RJ. "A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. (Published online)" Nature 477, no. 7364 (August 21, 2011): 349-353.

PMID
21857681
Full Text

Nobles, KN, Xiao, K, Ahn, S, Shukla, AK, Lam, CM, Rajagopal, S, Strachan, RT, Huang, T-Y, Bressler, EA, Hara, MR, Shenoy, SK, Gygi, SP, and Lefkowitz, RJ. "Distinct phosphorylation sites on the β(2)-adrenergic receptor establish a barcode that encodes differential functions of β-arrestin." Sci Signal 4, no. 185 (August 9, 2011): ra51-.

PMID
21868357
Full Text

Rockman, HA, and Lefkowitz, RJ. "Introduction to the series on novel aspects of cardiovascular G-protein-coupled receptor signaling." Circ Res 109, no. 2 (July 8, 2011): 202-204.

PMID
21737815
Full Text

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