March 7, 2013

Cullen Building Main Auditorium

MELANIE COBB, PH.D.

Dr. Melanie H. Cobb was the first to molecularly character-ize the ERK family of mitogen-activated pro-tein kinases (MAPKs). As the terminal kinase in the MAP kinase module, ERKs play critical roles in signaling pathways that regulate such diverse functions as proliferation, differen-tiation, homeostasis,

motility, apoptosis, and synaptic plasticity. Dysregulation of the ERK pathway is a common feature of many cancers. Since completing her bachelor’s degree in biological chemistry at the University of Chicago, Dr. Cobb has pursued insights into cell signaling throughout her scientific career, beginning as a graduate student in the laboratory of Dr. Garland Marshall at Washington University in St. Louis. Working with the fresh water coelenterate, Hydra attenuata, she defined peptide structure-activity relationships in the glutathione-induced feeding response. After a stint with Dr. Walter Scott at Mount Sinai School of Medicine studying hormonal regulation of sodium transport, Dr. Cobb completed her postdoctoral training at Albert Einstein College of Medicine of Yeshiva University in New York under Dr. Ora Rosen, who was noted for her work on protein kinases. There, she helped elaborate the complicated pathways triggered by insulin activation of its receptor tyrosine kinase. In 1983, Dr. Cobb joined the faculty of the UT Southwestern Medical Center, where she now holds the Jane and Bill Browning Endowed Chair in Medical Science in the Department of Pharmacology. From 2003 to 2010, Dr. Cobb served as Dean of the UT Southwestern Graduate School of Biomedical Sciences. In Ora Rosen’s laboratory, Dr. Cobb had identified a protein kinase that phosphorylated ribosomal S6 protein, a key event in the insulin-dependent activation of protein synthesis. That kinase,

however, turned out to be casein kinase I, one of several kinases that phosphorylate S6 protein, but are not bona fide intermediates in the pathway for insulin-dependent stimulation of protein synthesis. The abundance of protein kinases and their relative promiscuity in vitro highlights the inherent difficulty in defining biological signaling pathways. In her own lab, Dr. Cobb succeeded in isolating the true S6 protein kinase, showing that it could be inactivated by a protein phosphatase and, more importantly, activated by microtubule-associated protein 2 (MAP2) kinase. Because MAP2 kinase was one of the few serine-threonine protein kinases known to be phosphorylated on tyrosine residues in vivo, hence a potential direct target of the activated insulin receptor tyrosine kinase, Dr. Cobb cloned the cDNA and renamed the protein, extracellular-signal regulated kinase 1 (ERK1), or more generally mitogen-activated protein (MAP) kinase, to reflect its responsiveness to external stimuli. Rather than being a direct target of the insulin receptor tyrosine kinase, Dr. Cobb showed that MAP kinase was activated by a rare, dual specificity protein kinase, MEK (or MAP kinase kinase), which phosphorylates MAP kinase on closely linked threonine and tyrosine residues. Subsequent studies revealed the links between the MAP kinase module and the insulin receptor, as well as other cell-surface receptors. Dr. Cobb continues to advance our knowledge of signaling networks and mechanisms, with a current emphasis on the role of the MAP kinase module in pancreatic beta cell function. Dr. Cobb has received numerous honors and awards, including her election as a Fellow of the American Academy of Microbiology and as a member of the National Academy of Sciences, both in 2006.

2:00 ERKonomics in beta cells and cancer

Melanie Cobb, Ph.D.

3:10 Reception/Break

3:40 The structural basis of G protein coupled receptor signaling

Brian Kobilka, M.D.

Dr. Brian K. Kobilka, starting with the recep-tors that recognize adrenaline, laid bare the workings of a very large family of cell surface proteins, G-protein-coupled recep-tors (GPCRs), whose job it is to sense molecules in the environment and com-municate their pres-ence to the interior of the cell. GPCRs

include not only the adrenergic receptors for the stress hormone adrenaline, but also receptors for neurotransmitters such as dopamine and serotonin, for taste and smell, and for photons of light, among many, many others. Their importance in human health is underscored by the fact that GPCRs constitute the drug targets for nearly half of all prescribed medicines. Dr. Kobilka was born in Little Falls, Minnesota, and attended the University of Minnesota, Duluth. He got his first exposure to research as an undergraduate after telling his advisor, Conrad Firling, “I’d like to try some of that stuff called research.” Dr. Kobilka demonstrated an early knack for innovation, building a tissue-culture hood from scrap plastic salvaged from his father’s bakery. After graduating with a double major in chemistry and biology, he attended Yale University, where he received his M.D. in 1981. After residency training in internal medicine at Washington University School of Medicine, Dr. Kobilka joined the laboratory of Dr. Robert Lefkowitz at Duke University, where he began his lifelong quest to decipher the inner mechanisms of signal recognition and transduction by adrenergic receptors. In 1990, Dr. Kobilka joined the faculty at Stanford University School of Medicine, where he is now Chair of the Depart-ment of Molecular and Cellular Physiology. Throughout his career, Dr. Kobilka has concen-trated on the molecular machinery that allows cells to detect elevated levels of adrenaline and convert those external signals into specific cellular

responses. As a new recruit into Dr. Lefkowitz’s lab, he accepted the task of cloning the gene for the b2-adrenergic receptor. Analysis of the gene for the receptor revealed its homology to the visual pigment rhodopsin, which at that time was the sole example of a seven-transmembrane spanning receptor—the key feature of GPCRs. They realized that there were a whole family of related receptors that look alike and function in the same way. They are now known to constitute the largest superfamily of membrane receptors, including more than 1,000 members in the human genome. With single-minded focus, Dr. Kolbilka pursued the crystal structure of the adrenergic receptor, a goal some of his colleagues thought might be impossible. Never once did he consider quitting. Instead, when funding dried up, when experiments failed, when things weren’t going well, “we’d pre-celebrate.” His mindset of “irrational optimism” finally paid off in 2011 with the publication of the structure of the b2-adrenergic receptor—a molecular masterpiece. Dr. Kobilka believes that the structure will serve as a “template for computational drug screening, using the three-dimensional structure to find new drugs that bind the receptor.” For his numerous insights into the molecular mechanisms of GPCRs, Dr. Kobilka was elected to the National Academy of Sciences in 2011. In 2012, he shared the Nobel Prize in Chemistry with his friend and mentor, Dr. Robert Lefkowitz, for their studies of G-protein-coupled receptors.

BRIAN KOBILKA, M.D.

PROGRAM

T he Verna and Marrs McLean Lecture Series was inaugurated in 1972 by Salih J. Wakil, Distinguished Service Professor and

Chairman Emeritus, in honor of an outstanding Texas family for their generous support of the department. Verna and Marrs McLean shared a philosophy of civic and humanitarian responsibility and a keen commitment to education. Although they were personally generous and supported many philanthropic causes, the McLeans believed that their greatest contribution was to set an example that encouraged others to make equally strong commitments. This tradition has been maintained by their children and grandchildren, as exemplified by the recent endowment of the Ruth McLean Bowman Bowers Professorship, which supports a new faculty member in the department, as well as the establishment of the new Ruth McLean Bowman Bowers “Excellence in Research” award.

T he Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor College of Medicine was established

to promote an essential medical science focused on the knowledge of chemical reactions in the living cell, and to provide students with sound scientific principles on which to base their clinical experience. It has since expanded to provide graduate education and research training leading to a Ph.D. degree. The research programs in the department cover a broad spectrum of basic science aimed at advancing knowledge in many areas, from protein function at an atomic level to systems biology. The diversity of research topics and the collaborative spirit of a world-class faculty provide a vibrant training environment for students and postdoctoral trainees.

The department supports the National Center for Macromolecular Imaging, which provides a resource for the structural determination of proteins and large protein complexes through cryoelectron microscopy. It has assumed a national leadership role in the scientific community through numerous collaborations and continuous innovation.

Nobel Laureates of the Verna and Marrs McLean

Lectures in Biochemistry

Paul Berg Hans Adolf Krebs

Bengt I. Samuelsson Walter Gilbert

Francis Harry Compton Crick Arthur Kornberg Salvador E. Luria

D. Carleton Gajdusek George E. Palade Sydney Brenner

J. Michael Bishop James Dewey Watson

Thomas R. Cech Aaron Klug

David Baltimore Max Ferdinand Perutz

Joseph L. Goldstein Michael S. Brown Sir Paul M. Nurse Phillip A. Sharp

Christiane Nüsslein-Volhard Richard Axel

Harold E. Varmus Leland H. Hartwell

Martin Rodbell H. Robert Horvitz Mario R. Capecchi Robert J. Lefkowitz

Peter C. Agre Eric F. Wieschaus Jack W. Szostak Roger Y. Tsien

Brian K. Kobilka

Verna and Marrs McLean loved youth and valued education. This department was named in tribute to their leadership and dedication.

Their example continues to inspire.