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

Beaulieu, J-M, Marion, S, Rodriguiz, RM, Medvedev, IO, Sotnikova, TD, Ghisi, V, Wetsel, WC, Lefkowitz, RJ, Gainetdinov, RR, and Caron, MG. "A beta-arrestin 2 signaling complex mediates lithium action on behavior." Cell 132, no. 1 (January 11, 2008): 125-136.

PMID
18191226
Full Text

Beaulieu, J-M, Marion, S, Rodriguiz, RM, Medvedev, IO, Sotnikova, TD, Ghisi, V, Wetsel, WC, Lefkowitz, RJ, Gainetdinov, RR, and Caron, MG. "A beta-arrestin 2 signaling complex mediates lithium action on Behavior." CELL 132, no. 1 (January 11, 2008): 125-136.

Full Text

Wisler, JW, DeWire, SM, Whalen, EJ, Violin, JD, Drake, MT, Ahn, S, Shenoy, SK, and Lefkowitz, RJ. "A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling." Proc Natl Acad Sci U S A 104, no. 42 (October 16, 2007): 16657-16662.

PMID
17925438
Full Text

Shenoy, SK, Barak, LS, Xiao, K, Ahn, S, Berthouze, M, Shukla, AK, Luttrell, LM, and Lefkowitz, RJ. "Ubiquitination of beta-arrestin links seven-transmembrane receptor endocytosis and ERK activation." J Biol Chem 282, no. 40 (October 5, 2007): 29549-29562.

PMID
17666399
Full Text

Wang, J, Liu, R, Bond, M, Chen, M, Singh, S, Ali-Osman, F, Lefkowitz, RJ, Diehl, AM, Lyerly, HK, Barak, L, and Chen, W. "Targeting hedgehog signaling in medulloblastoma." October 2007.

Scholars@Duke

Noma, T, Lemaire, A, Naga Prasad, SV, Barki-Harrington, L, Tilley, DG, Chen, J, Le Corvoisier, P, Violin, JD, Wei, H, Lefkowitz, RJ, and Rockman, HA. "Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection." J Clin Invest 117, no. 9 (September 2007): 2445-2458.

PMID
17786238
Full Text

Violin, JD, and Lefkowitz, RJ. "Beta-arrestin-biased ligands at seven-transmembrane receptors." Trends Pharmacol Sci 28, no. 8 (August 2007): 416-422. (Review)

PMID
17644195
Full Text

Nobles, KN, Guan, Z, Xiao, K, Oas, TG, and Lefkowitz, RJ. "The active conformation of beta-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of beta-arrestins1 and -2." J Biol Chem 282, no. 29 (July 20, 2007): 21370-21381.

PMID
17513300
Full Text

Xiao, K, McClatchy, DB, Shukla, AK, Zhao, Y, Chen, M, Shenoy, SK, Yates, JR, and Lefkowitz, RJ. "Functional specialization of beta-arrestin interactions revealed by proteomic analysis." Proc Natl Acad Sci U S A 104, no. 29 (July 17, 2007): 12011-12016.

PMID
17620599
Full Text

Whalen, EJ, Foster, MW, Matsumoto, A, Ozawa, K, Violin, JD, Que, LG, Nelson, CD, Benhar, M, Keys, JR, Rockman, HA, Koch, WJ, Daaka, Y, Lefkowitz, RJ, and Stamler, JS. "Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2." Cell 129, no. 3 (May 4, 2007): 511-522.

PMID
17482545
Full Text

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