Robert J. Lefkowitz, MD

Professor of Medicine
James B. Duke Distinguished Professor of Medicine
Professor of Biochemistry
Professor of Pathology
Professor of Chemistry
Associate of the Duke Initiative for Science & Society
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

Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win.

Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. Dr. Lefkowitz began his research career in the late 1960’s and early 1970’s when there was not a clear consensus that specific receptors for drugs and hormones even existed. His group spent 15 difficult years developing techniques for labeling the receptors with radioactive drugs and then purifying the four different receptors that were known and thought to exist for adrenaline, so called adrenergic receptors. In 1986 Dr. Lefkowitz transformed the understanding of what had by then become known as G protein coupled receptors because of the way the receptor signal for the inside of a cell through G proteins, when he and his colleagues cloned the gene for the beta2-adrenergic receptor. They immediately recognized the similarity to a molecule called rhodopsin which is essentially a light receptor in the retina. This unexpected finding established the beta receptor and rhodopsin as the first member of a new family of proteins. Because each has a peptide structure, which weaves across the cell membrane seven times, these receptors are referred to as seven transmembrane receptors. This super family is now known to be the largest, most diverse and most therapeutically accessible of all the different kinds of cellular receptors. There are almost a thousand members of this receptor family and they regulate virtually all known physiological processes in humans. They include the receptors not only to numerous hormones and neurotransmitters but for the receptors which mediate the senses of sweet and bitter taste and smell amongst many others. Dr. Lefkowitz also discovered the mechanism by which receptor signaling is turned off, a process known as desensitization. Dr. Lefkowitz work was performed at the most fundamental and basic end of the research spectrum and has had remarkable consequences for clinical medicine. Today, more than half of all prescription drug sales are of drugs that target either directly or indirectly the receptors discovered by Dr. Lefkowitz and his trainees. These include amongst many others beta blockers, angiotensin receptor blockers or ARBs and antihistamines. Over the past decade he has discovered novel mechanisms by which the receptors function which may lead to the development of an entirely new class of drugs called “biased agonists”. Several such compounds are already in advanced stages of clinical testing. Dr. Lefkowitz has received numerous honors and awards, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988, the Institute of Medicine in 1994, and the American Academy of Arts and Sciences in 1988.

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

Kenakin, Terry, Luigi F. Agnati, Marc Caron, Bertil Fredholm, Diego Guidoli, Brian Kobilka, Robert W. Lefkowitz, Martin Lohse, Amina Woods, and Kjell Fuxe. “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?” J Recept Signal Transduct Res 30, no. 5 (October 2010): 284–86. https://doi.org/10.3109/10799893.2010.512438.

PMID
20858022
Full Text

Shukla, Arun K., Jihee Kim, Seungkirl Ahn, Kunhong Xiao, Sudha K. Shenoy, Wolfgang Liedtke, and Robert J. Lefkowitz. “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): 30115–25. https://doi.org/10.1074/jbc.M110.141549.

PMID
20650893
Full Text

Xiao, Kunhong, Jinpeng Sun, Jihee Kim, Sudarshan Rajagopal, Bo Zhai, Judit Villén, Wilhelm Haas, et al. “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): 15299–304. https://doi.org/10.1073/pnas.1008461107.

PMID
20686112
Full Text

Maudsley, S., S. Liao, L. Yuan, R. J. Lefkowitz, L. M. Luttrell, and D. Gesty-Palmer. “The Unique Efficacy Profile of a beta-Arrestin Pathway-Selective Parathyroid Hormone Receptor Agonist Revealed by Metabolic Pathways Analysis.” In Endocrine Reviews, Vol. 31. ENDOCRINE SOC, 2010.

Scholars@Duke

Rajagopal, Sudarshan, Keshava Rajagopal, and Robert J. Lefkowitz. “Teaching old receptors new tricks: biasing seven-transmembrane receptors.” Nat Rev Drug Discov 9, no. 5 (May 2010): 373–86. https://doi.org/10.1038/nrd3024.

PMID
20431569
Full Text

Rajagopal, Sudarshan, Jihee Kim, Seungkirl Ahn, Stewart Craig, Christopher M. Lam, Norma P. Gerard, Craig Gerard, and Robert J. Lefkowitz. “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): 628–32. https://doi.org/10.1073/pnas.0912852107.

PMID
20018651
Full Text

Chen, Minyong, Melanie Philipp, Jiangbo Wang, Richard T. Premont, Tiffany R. Garrison, Marc G. Caron, Robert J. Lefkowitz, and Wei Chen. “G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway.” J Biol Chem 284, no. 50 (December 11, 2009): 35040–48. https://doi.org/10.1074/jbc.M109.047456.

PMID
19801552
Full Text

Patel, Chetan B., Priyesh A. Patel, Stephan G. Frangakis, Minyong Chen, Sudha K. Shenoy, Robert J. Lefkowitz, and Howard A. Rockman. “A Modified beta 1-adrenergic Receptor Demonstrates Bias Towards G Protein Receptor Kinase Phosphorylation.” In Circulation, 120:S800–801. LIPPINCOTT WILLIAMS & WILKINS, 2009.

Scholars@Duke

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