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

Tang, W, Strachan, RT, Lefkowitz, RJ, and Rockman, HA. "Allosteric modulation of β-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch." The Journal of Biological Chemistry 289, no. 41 (October 2014): 28271-28283.

PMID
25170081
Full Text

Shukla, AK, Westfield, GH, Xiao, K, Reis, RI, Huang, L-Y, Tripathi-Shukla, P, Qian, J, Li, S, Blanc, A, Oleskie, AN, Dosey, AM, Su, M, Liang, C-R, Gu, L-L, Shan, J-M, Chen, X, Hanna, R, Choi, M, Yao, XJ, Klink, BU, Kahsai, AW, Sidhu, SS, Koide, S, Penczek, PA, Kossiakoff, AA, Woods, VL, Kobilka, BK, Skiniotis, G, and Lefkowitz, RJ. "Visualization of arrestin recruitment by a G-protein-coupled receptor." Nature 512, no. 7513 (August 2014): 218-222.

PMID
25043026
Full Text

Strachan, RT, Sun, J-P, Rominger, DH, Violin, JD, Ahn, S, Rojas Bie Thomsen, A, Zhu, X, Kleist, A, Costa, T, and Lefkowitz, RJ. "Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR)." The Journal of Biological Chemistry 289, no. 20 (May 2014): 14211-14224.

PMID
24668815
Full Text

Wisler, JW, Xiao, K, Thomsen, ARB, and Lefkowitz, RJ. "Recent developments in biased agonism." Current Opinion in Cell Biology 27 (April 2014): 18-24. (Review)

PMID
24680426
Full Text

Staus, DP, Wingler, LM, Strachan, RT, Rasmussen, SGF, Pardon, E, Ahn, S, Steyaert, J, Kobilka, BK, and Lefkowitz, RJ. "Regulation of β2-adrenergic receptor function by conformationally selective single-domain intrabodies." Molecular Pharmacology 85, no. 3 (March 2014): 472-481.

PMID
24319111
Full Text

Simard, E, Kovacs, JJ, Miller, WE, Kim, J, Grandbois, M, and Lefkowitz, RJ. "beta-Arrestin Regulation of Myosin Light Chain Phosphorylation Promotes AT1aR-mediated Cell Contraction and Migration." PLOS ONE 8, no. 11 (November 8, 2013).

PMID
24255721
Full Text

Simard, E, Kovacs, JJ, Miller, WE, Kim, J, Grandbois, M, and Lefkowitz, RJ. "β-arrestin regulation of myosin light chain phosphorylation promotes AT1aR-mediated cell contraction and migration." Plos One 8, no. 11 (November 8, 2013).

Full Text

Aristotelous, T, Ahn, S, Shukla, AK, Gawron, S, Sassano, MF, Kahsai, AW, Wingler, LM, Zhu, X, Tripathi-Shukla, P, Huang, X-P, Riley, J, Besnard, J, Read, KD, Roth, BL, Gilbert, IH, Hopkins, AL, Lefkowitz, RJ, and Navratilova, I. "Discovery of β2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor." Acs Medicinal Chemistry Letters 4, no. 10 (October 2013): 1005-1010.

PMID
24454993
Full Text

Lefkowitz, RJ. "A brief history of G-protein coupled receptors (Nobel Lecture)." Angewandte Chemie (International Ed. in English) 52, no. 25 (June 2013): 6366-6378.

PMID
23650015
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 (May 2013): 137-141.

PMID
23604254
Full Text

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