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

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


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 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." Science Translational Medicine 3, no. 74 (March 2011): 74ra23-null.

Full Text

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

Full Text

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 Receptor and Signal Transduction Research 30, no. 5 (October 2010): 284-286.

Full Text

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." The Journal of Biological Chemistry 285, no. 39 (September 2010): 30115-30125.

Full Text

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)." Proceedings of the National Academy of Sciences of the United States of America 107, no. 34 (August 4, 2010): 15299-15304.

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.


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

Full Text

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." Proceedings of the National Academy of Sciences of the United States of America 107, no. 2 (January 2010): 628-632.

Full Text

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." The Journal of Biological Chemistry 284, no. 50 (December 2009): 35040-35048.

Full Text