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

Ahn, S, Pani, B, Kahsai, AW, Olsen, EK, Husemoen, G, Vestergaard, M, Jin, L, Zhao, S, Wingler, LM, Rambarat, PK, Simhal, RK, Xu, TT, Sun, LD, Shim, PJ, Staus, DP, Huang, L-Y, Franch, T, Chen, X, and Lefkowitz, RJ. "Small-Molecule Positive Allosteric Modulators of the β2-Adrenoceptor Isolated from DNA-Encoded Libraries." Molecular Pharmacology 94, no. 2 (August 2018): 850-861.

PMID
29769246
Full Text

Kahsai, AW, Pani, B, and Lefkowitz, RJ. "GPCR signaling: conformational activation of arrestins." Cell Research 28, no. 8 (August 2018): 783-784.

PMID
30030517
Full Text

Wisler, JW, Rockman, HA, and Lefkowitz, RJ. "Biased G Protein-Coupled Receptor Signaling: Changing the Paradigm of Drug Discovery." Circulation 137, no. 22 (May 2018): 2315-2317.

PMID
29844068
Full Text

Smith, JS, Lefkowitz, RJ, and Rajagopal, S. "Biased signalling: from simple switches to allosteric microprocessors." Nature Reviews. Drug Discovery 17, no. 4 (April 2018): 243-260. (Review)

PMID
29302067
Full Text

Staus, DP, Wingler, LM, Choi, M, Pani, B, Manglik, A, Kruse, AC, and Lefkowitz, RJ. "Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling." Proceedings of the National Academy of Sciences of the United States of America 115, no. 15 (April 2018): 3834-3839.

PMID
29581292
Full Text

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

PMID
28715979
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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
Full Text

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
Full Text

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
Full Text

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