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

  • Resident, Medicine, Massachusetts General Hospital, 1970 - 1971
  • Resident, Medicine, Columbia University, 1967 - 1968
  • Intern, Medicine, Columbia University, 1966 - 1967
  • M.D., Columbia University, 1966

Publications

Weiss, DR, Ahn, S, Sassano, MF, Kleist, A, Zhu, X, Strachan, R, Roth, BL, Lefkowitz, RJ, and Shoichet, BK. "Conformation guides molecular efficacy in docking screens of activated β-2 adrenergic G protein coupled receptor." Acs Chemical Biology 8, no. 5 (May 2013): 1018-1026.

PMID
23485065
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Shukla, AK, Manglik, A, Kruse, A, Reis, R, Tseng, WC, Staus, DP, Hilger, D, Uysal, S, Huang, L, Peduch, M, Tripathi-Shukla, P, Koide, A, Koide, S, Weis, WI, Kossiakoff, AK, Kobilka, BK, and Lefkowitz, RJ. "Crystal structure of active Beta-arrestin1 bound to phosphorylated carboxy-terminus of a G protein-coupled receptor." April 2013.

Scholars@Duke

Hara, MR, Sachs, BD, Caron, MG, and Lefkowitz, RJ. "Pharmacological blockade of a β(2)AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model." Cell Cycle (Georgetown, Tex.) 12, no. 2 (January 2013): 219-224.

PMID
23287463
Full Text

Lefkowitz, RJ. "Arrestins come of age: a personal historical perspective." Progress in Molecular Biology and Translational Science 118 (January 2013): 3-18. (Review)

PMID
23764048
Full Text

Shukla, AK, Manglik, A, Kruse, AC, Xiao, K, Reis, RI, Tseng, W-C, Staus, DP, Hilger, D, Uysal, S, Huang, L-Y, Paduch, M, Tripathi-Shukla, P, Koide, A, Koide, S, Weis, WI, Kossiakoff, AA, Kobilka, BK, and Lefkowitz, RJ. "Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide." Nature 497, no. 7447 (2013): 137-141.

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Fereshteh, M, Ito, T, Kovacs, JJ, Zhao, C, Kwon, HY, Tornini, V, Konuma, T, Chen, M, Lefkowitz, RJ, and Reya, T. "β-Arrestin2 mediates the initiation and progression of myeloid leukemia." Proceedings of the National Academy of Sciences of the United States of America 109, no. 31 (July 5, 2012): 12532-12537.

PMID
22773819
Full Text

Heitzler, D, Durand, G, Gallay, N, Rizk, A, Ahn, S, Kim, J, Violin, JD, Dupuy, L, Gauthier, C, Piketty, V, Crépieux, P, Poupon, A, Clément, F, Fages, F, Lefkowitz, RJ, and Reiter, E. "Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling." Molecular Systems Biology 8 (June 26, 2012): 590-null.

PMID
22735336
Full Text

Reiter, E, Ahn, S, Shukla, AK, and Lefkowitz, RJ. "Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors." Annual Review of Pharmacology and Toxicology 52 (January 2012): 179-197. (Review)

PMID
21942629
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Lefkowitz, RJ, and VanHook, AM. "Science Signaling Podcast: 20 November 2012." Science Signaling 5, no. 251 (2012).

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Xiao, K, Sun, J, Kim, J, Rajagopal, S, Zhai, B, Villén, J, Haas, W, Kovacs, JJ, Shukla, AK, Hara, MR, Hernandez, M, Lachmann, A, Zhao, S, Lin, Y, Cheng, Y, Mizuno, K, Ma'ayan, A, Gygi, SP, and Lefkowitz, RJ. "Global phosphorylation analysis of β-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR) (Proceedings of the National Academy of Sciences of the United States of America (2010) 107, 34 (15299-15304) doi:10.1073/pnas.1008461107)." Proceedings of the National Academy of Sciences of the United States of America 109, no. 33 (2012): 13464--.

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