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

Lefkowitz, RJ. "A Serendipitous Scientist." Annual review of pharmacology and toxicology 58 (January 2018): 17-32.

PMID
28715979
Full Text

Liu, X, Ahn, S, Kahsai, AW, Meng, K-C, Latorraca, NR, Pani, B, Venkatakrishnan, AJ, Masoudi, A, Weis, WI, Dror, RO, Chen, X, Lefkowitz, RJ, and Kobilka, BK. "Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure." Nature 548, no. 7668 (August 16, 2017): 480-484.

PMID
28813418
Full Text

Cahill, TJ, Thomsen, ARB, Tarrasch, JT, Plouffe, B, Nguyen, AH, Yang, F, Huang, L-Y, Kahsai, AW, Bassoni, DL, Gavino, BJ, Lamerdin, JE, Triest, S, Shukla, AK, Berger, B, Little, J, Antar, A, Blanc, A, Qu, C-X, Chen, X, Kawakami, K, Inoue, A, Aoki, J, Steyaert, J, Sun, J-P, Bouvier, M, Skiniotis, G, and Lefkowitz, RJ. "Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis." Proceedings of the National Academy of Sciences of the United States of America 114, no. 10 (March 2017): 2562-2567.

PMID
28223524
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Stoppel, LJ, Auerbach, BD, Senter, RK, Preza, AR, Lefkowitz, RJ, and Bear, MF. "β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X." Cell reports 18, no. 12 (March 2017): 2807-2814.

PMID
28329674
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Ahn, S, Kahsai, AW, Pani, B, Wang, Q-T, Zhao, S, Wall, AL, Strachan, RT, Staus, DP, Wingler, LM, Sun, LD, Sinnaeve, J, Choi, M, Cho, T, Xu, TT, Hansen, GM, Burnett, MB, Lamerdin, JE, Bassoni, DL, Gavino, BJ, Husemoen, G, Olsen, EK, Franch, T, Costanzi, S, Chen, X, and Lefkowitz, RJ. "Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library." Proceedings of the National Academy of Sciences of the United States of America 114, no. 7 (February 2017): 1708-1713.

PMID
28130548
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Kahsai, AW, Wisler, JW, Lee, J, Ahn, S, Cahill Iii, TJ, Dennison, SM, Staus, DP, Thomsen, ARB, Anasti, KM, Pani, B, Wingler, LM, Desai, H, Bompiani, KM, Strachan, RT, Qin, X, Alam, SM, Sullenger, BA, and Lefkowitz, RJ. "Conformationally selective RNA aptamers allosterically modulate the β2-adrenoceptor." Nature chemical biology 12, no. 9 (September 2016): 709-716.

PMID
27398998
Full Text

Thomsen, ARB, Plouffe, B, Cahill, TJ, Shukla, AK, Tarrasch, JT, Dosey, AM, Kahsai, AW, Strachan, RT, Pani, B, Mahoney, JP, Huang, L, Breton, B, Heydenreich, FM, Sunahara, RK, Skiniotis, G, Bouvier, M, and Lefkowitz, RJ. "GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling." Cell 166, no. 4 (August 3, 2016): 907-919.

PMID
27499021
Full Text

Staus, DP, Strachan, RT, Manglik, A, Pani, B, Kahsai, AW, Kim, TH, Wingler, LM, Ahn, S, Chatterjee, A, Masoudi, A, Kruse, AC, Pardon, E, Steyaert, J, Weis, WI, Prosser, RS, Kobilka, BK, Costa, T, and Lefkowitz, RJ. "Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation." Nature 535, no. 7612 (July 13, 2016): 448-452.

PMID
27409812
Full Text

Lefkowitz, RJ. "Alfred Goodman Gilman (1941-2015)." Nature 529, no. 7586 (January 2016): 284-.

PMID
26791713
Full Text

Rein, LAM, Wisler, JW, Theriot, BS, Huang, L-Y, Premont, RT, and Lefkowitz, RJ. "beta-arrestin2 Is Necessary for Development of MPLW515L Mutant Primary Myelofibrosis." December 3, 2015.

Scholars@Duke

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