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

  • M.D., Columbia University, 1966

Publications

Rajagopal, S, Kovacs, J, Badea, C, Johnson, GA, Rockman, HA, Piantadosi, CA, and Lefkowitz, RJ. "BETA-ARRESTINS REGULATE SIGNALING BY BONE MORPHOGENETIC PROTEIN TYPE II RECEPTOR IN PULMONARY ARTERIAL HYPERTENSION." JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 57, no. 14 (April 5, 2011): E2046-E2046.

Full Text

Lovgren, AK, Kovacs, JJ, Xie, T, Potts, EN, Li, Y, Foster, WM, Liang, J, Meltzer, EB, Jiang, D, Lefkowitz, RJ, and Noble, PW. "β-arrestin deficiency protects against pulmonary fibrosis in mice and prevents fibroblast invasion of extracellular matrix." Sci Transl Med 3, no. 74 (March 16, 2011): 74ra23-.

PMID
21411739
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Whalen, EJ, Rajagopal, S, and Lefkowitz, RJ. "Therapeutic potential of β-arrestin- and G protein-biased agonists." Trends Mol Med 17, no. 3 (March 2011): 126-139. (Review)

PMID
21183406
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Shukla, AK, Kim, J, Ahn, S, Xiao, K, Shenoy, SK, Liedtke, W, and Lefkowitz, RJ. "Arresting a transient receptor potential (TRP) channel: beta-arrestin 1 mediates ubiquitination and functional down-regulation of TRPV4." J Biol Chem 285, no. 39 (September 24, 2010): 30115-30125.

PMID
20650893
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Xiao, K, Sun, J, Kim, J, Rajagopal, S, Zhai, B, Villén, J, Haas, W, Kovacs, JJ, Shukla, AK, Hara, MR, Hernandez, M, Lachmann, A, Zhao, S, Lin, Y, Cheng, Y, Mizuno, K, Ma'ayan, A, Gygi, SP, and Lefkowitz, RJ. "Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven transmembrane receptor (7TMR)." Proc Natl Acad Sci U S A 107, no. 34 (August 24, 2010): 15299-15304.

PMID
20686112
Full Text

Maudsley, S, Liao, S, Yuan, L, Lefkowitz, RJ, Luttrell, LM, and Gesty-Palmer, D. "The Unique Efficacy Profile of a beta-Arrestin Pathway-Selective Parathyroid Hormone Receptor Agonist Revealed by Metabolic Pathways Analysis." June 2010.

Scholars@Duke

Rajagopal, S, Rajagopal, K, and Lefkowitz, RJ. "Teaching old receptors new tricks: biasing seven-transmembrane receptors." Nat Rev Drug Discov 9, no. 5 (May 2010): 373-386. (Review)

PMID
20431569
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Rajagopal, S, Kim, J, Ahn, S, Craig, S, Lam, CM, Gerard, NP, Gerard, C, and Lefkowitz, RJ. "Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7." Proc Natl Acad Sci U S A 107, no. 2 (January 12, 2010): 628-632.

PMID
20018651
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Kenakin, T, Agnati, LF, Caron, M, Fredholm, B, Guidoli, D, Kobilka, B, Lefkowitz, RW, Lohse, M, Woods, A, and Fuxe, K. "International workshop at the nobel forum, karolinska institutet on g protein-coupled receptors: Finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached." Journal of Receptors and Signal Transduction 30, no. 5 (2010): 284-286.

PMID
20858022
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Chen, M, Philipp, M, Wang, J, Premont, RT, Garrison, TR, Caron, MG, Lefkowitz, RJ, and Chen, W. "G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway." J Biol Chem 284, no. 50 (December 11, 2009): 35040-35048.

PMID
19801552
Full Text

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