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. "Focus on the research journey. An interview with Robert J. Lefkowitz, MD, scientist, mentor, and recipient of the 2007 National Medal of Science by Elaine Musgrave." Clinical and translational science 2, no. 1 (2009): 4-5.

PMID
20443860
Full Text

Tarrant, TK, Rampersad, RR, Esserman, D, Rothlein, LR, Liu, P, Premont, RT, Lefkowitz, RJ, Lee, DM, and Patel, DD. "Granulocyte chemotaxis and disease expression are differentially regulated by GRK subtype in an acute inflammatory arthritis model (K/BxN)." Clin Immunol 129, no. 1 (October 2008): 115-122.

PMID
18662895
Full Text

Barak, LS, Salahpour, A, Zhang, X, Masri, B, Sotnikova, TD, Ramsey, AJ, Violin, JD, Lefkowitz, RJ, Caron, MG, and Gainetdinov, RR. "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor." Mol Pharmacol 74, no. 3 (September 2008): 585-594.

PMID
18524885
Full Text

Ozawa, K, Whalen, EJ, Nelson, CD, Mu, Y, Hess, DT, Lefkowitz, RJ, and Stamler, JS. "S-nitrosylation of beta-arrestin regulates beta-adrenergic receptor trafficking." Mol Cell 31, no. 3 (August 8, 2008): 395-405.

PMID
18691971
Full Text

Nelson, CD, Kovacs, JJ, Nobles, KN, Whalen, EJ, and Lefkowitz, RJ. "Beta-arrestin scaffolding of phosphatidylinositol 4-phosphate 5-kinase Ialpha promotes agonist-stimulated sequestration of the beta2-adrenergic receptor." J Biol Chem 283, no. 30 (July 25, 2008): 21093-21101.

PMID
18534983
Full Text

Shukla, AK, Violin, JD, Whalen, EJ, Gesty-Palmer, D, Shenoy, SK, and Lefkowitz, RJ. "Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors." Proceedings of the National Academy of Sciences of the United States of America 105, no. 29 (July 11, 2008): 9988-9993.

PMID
18621717
Full Text

Kim, J, Zhang, L, Peppel, K, Wu, J-H, Zidar, DA, Brian, L, DeWire, SM, Exum, ST, Lefkowitz, RJ, and Freedman, NJ. "Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration." Circ Res 103, no. 1 (July 3, 2008): 70-79.

PMID
18519945
Full Text

Kovacs, JJ, Whalen, EJ, Liu, R, Xiao, K, Kim, J, Chen, M, Wang, J, Chen, W, and Lefkowitz, RJ. "Beta-arrestin-mediated localization of smoothened to the primary cilium." Science 320, no. 5884 (June 27, 2008): 1777-1781.

PMID
18497258
Full Text

Shukla, AK, Sun, J-P, and Lefkowitz, RJ. "Crystallizing thinking about the beta2-adrenergic receptor." Mol Pharmacol 73, no. 5 (May 2008): 1333-1338.

PMID
18239031
Full Text

DeWire, SM, Kim, J, Whalen, EJ, Ahn, S, Chen, M, and Lefkowitz, RJ. "Beta-arrestin-mediated signaling regulates protein synthesis." J Biol Chem 283, no. 16 (April 18, 2008): 10611-10620.

PMID
18276584
Full Text

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