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

Gesty-Palmer, D, Flannery, P, Yuan, L, Corsino, L, Spurney, R, Lefkowitz, RJ, and Luttrell, LM. "A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation." Sci Transl Med 1, no. 1 (October 7, 2009): 1ra1-.

PMID
20368153
Full Text

Kovacs, JJ, Hara, MR, Davenport, CL, Kim, J, and Lefkowitz, RJ. "Arrestin development: emerging roles for beta-arrestins in developmental signaling pathways." Dev Cell 17, no. 4 (October 2009): 443-458. (Review)

PMID
19853559
Full Text

Xie, L, Xiao, K, Whalen, EJ, Forrester, MT, Freeman, RS, Fong, G, Gygi, SP, Lefkowitz, RJ, and Stamler, JS. "Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. (Published online)" Sci Signal 2, no. 78 (July 7, 2009): ra33-.

PMID
19584355
Full Text

Zidar, DA, Violin, JD, Whalen, EJ, and Lefkowitz, RJ. "Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands." Proc Natl Acad Sci U S A 106, no. 24 (June 16, 2009): 9649-9654.

PMID
19497875
Full Text

Kim, J, Ahn, S, Rajagopal, K, and Lefkowitz, RJ. "Independent beta-arrestin2 and Gq/protein kinase Czeta pathways for ERK stimulated by angiotensin type 1A receptors in vascular smooth muscle cells converge on transactivation of the epidermal growth factor receptor." J Biol Chem 284, no. 18 (May 1, 2009): 11953-11962.

PMID
19254952
Full Text

Walters, RW, Shukla, AK, Kovacs, JJ, Violin, JD, DeWire, SM, Lam, CM, Chen, JR, Muehlbauer, MJ, Whalen, EJ, and Lefkowitz, RJ. "beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice." J Clin Invest 119, no. 5 (May 2009): 1312-1321.

PMID
19349687
Full Text

Shenoy, SK, Modi, AS, Shukla, AK, Xiao, K, Berthouze, M, Ahn, S, Wilkinson, KD, Miller, WE, and Lefkowitz, RJ. "Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2." Proc Natl Acad Sci U S A 106, no. 16 (April 21, 2009): 6650-6655.

PMID
19363159
Full Text

Walters, RW, Shukla, AK, Kovacs, JJ, Violin, JD, DeWire, SM, Lam, CM, Chen, JR, Muehlbauer, MJ, Whalen, EJ, and Lefkowitz, RJ. "Beta-arrestin1 mediates nicotinic acid induced flushing, but not its antilipolytic effect." JOURNAL OF INVESTIGATIVE DERMATOLOGY 129 (April 2009): S1-S1.

Scholars@Duke

Shukla, AK, Kim, J, Ahn, S, Xiao, K, Liedtke, W, and Lefkowitz, RJ. "[beta]-arrestin 1 mediates angiotensin II induced ubiquitination and down-regulation of TRPV4." FASEB JOURNAL 23 (April 2009).

Scholars@Duke

Ahn, S, Kim, J, Hara, MR, Ren, X-R, and Lefkowitz, RJ. "{beta}-Arrestin-2 Mediates Anti-apoptotic Signaling through Regulation of BAD Phosphorylation." J Biol Chem 284, no. 13 (March 27, 2009): 8855-8865.

PMID
19171933
Full Text

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