Robert J. Lefkowitz (born April 15, 1943, Bronx, New York, U.S.) is an American physician and molecular biologist who demonstrated the existence of receptors—molecules that receive and transmit signals for cells. His research on the structure and function of cell-surface receptors—particularly of G protein-coupled receptors (GPCRs), the largest family of signal-receiving molecules found in organisms—revolutionized scientists’ understanding of how cells respond to stimuli such as hormones and how certain types of drugs exert their actions, leading to major advances in drug development. For his groundbreaking discoveries, Lefkowitz shared the 2012 Nobel Prize for Chemistry with American physician and molecular biologist Brian K. Kobilka.
In 1959 Lefkowitz graduated from the Bronx High School of Science. He received a scholarship to study at Columbia College, Columbia University, New York, where he earned a B.A. in chemistry in 1962. Having decided at an early age that he wanted to be a physician, he remained in New York to study at the Columbia University College of Physicians and Surgeons, receiving an M.D. in 1966. Two years later, after a residency at Columbia, he took a position at the National Institute of Arthritis and Metabolic Diseases (NIAMD; later the National Institute of Diabetes and Digestive and Kidney Diseases), part of the National Institutes of Health in Maryland, where he set to work on validating the existence of receptors. His initial research focused on developing a procedure (an assay) by which radioactively labeled adrenocorticotropic hormone (ACTH) would bind specifically to the membranes of cancer cells; such an assay would facilitate the purification of receptors. By 1970 he had successfully developed the procedure and had published evidence for the existence of cell-surface receptors. That year he left NIAMD for a residency and training in cardiovascular disease at Massachusetts General Hospital in Boston. In 1972, while working in the laboratory of German American physician and researcher Edgar Haber, he published a report detailing his purification of beta-adrenergic receptor protein from heart muscle cells (cardiomyocytes) in dogs. The beta-adrenergic receptor would later become a model system for the study of GPCRs.
In 1973 Lefkowitz joined the faculty at the Duke University Medical Center in Durham, North Carolina, where he later found that adrenergic receptors transmit signals to an intracellular molecule called a G protein (guanine nucleotide-binding protein), which had been discovered earlier by American pharmacologist Alfred G. Gilman and American biochemist Martin Rodbell (Gilman and Rodbell shared the 1994 Nobel Prize for Physiology or Medicine for their independent discovery of G proteins). When activated, G proteins stimulate an enzyme known as adenylate cyclase, which converts the energy-carrying molecule ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate), a process responsible for producing physiological responses prompted by hormone-receptor binding. Lefkowitz also discovered a molecule known as beta-adrenergic receptor kinase (beta-ARK), which regulates GPCR activity.
In 1984 Kobilka joined Lefkowitz’s research group at Duke. Lefkowitz was then trying to determine the DNA sequence of the beta2-adrenergic receptor. Kobilka proceeded to piece together the DNA sequence using bacteria that had been genetically engineered to produce large quantities of genomic DNA, thereby overcoming the limitations imposed by the receptor’s restricted natural production in cells. Kobilka’s breakthrough facilitated the team’s discovery that all GPCRs possess seven domains that cross through the cell membrane; those domains were found to be fundamental to the receptors’ activity. Lefkowitz later identified a protein called beta-arrestin, which acts on beta-ARK-phosphorylated GPCRs and which explained the phenomenon of GPCR desensitization in response to repeated agonist binding.
In addition to the 2012 Nobel Prize, Lefkowitz was the recipient of several other major awards, including the 2007 Shaw Prize in Life Science and Medicine and the 2007 National Medal of Science, presented to him by U.S. Pres. George W. Bush. In 1988 Lefkowitz was elected a member of the National Academy of Sciences and the American Academy of Arts and Sciences.