Martha Vaughan graduated from the University of Chicago with a Ph.B. and earned her M.D. from the Yale University School of Medicine. She was a research fellow in Yale’s Department of Physiological Chemistry and interned at New Haven Hospital. She joined the NHLBI in the Laboratory of Cellular Physiology. In 2012, Dr. Vaughan received the NIH Director’s Award and the Ruth L. Kirschstein Mentoring Award for exemplary performance while demonstrating significant leadership skills and mentoring ability. She has authored or co-authored more than 365 papers and book chapters. Dr. Vaughan was elected to the National Academy of Sciences in 1985.
Much of cellular signaling involves the recycling of small molecule workhorses like GTP. Many proteins rely on the hydrolysis of bound GTP to GDP to affect their targets. With a longstanding interest in cellular metabolism and signaling, Dr. Vaughan became focused on one family of these so-called GTPases, the ADP ribosylation factors (Arfs), which play an important role in intracellular vesicle trafficking. After identifying and cloning several Arf proteins in the 1990s, she began studying the proteins that bound to and activated the Arfs. Two specific proteins of interest were purified based on sensitivity to brefeldin A, a fungal metabolite that inhibits protein synthesis by interfering with the trafficking of nascent proteins from the endoplasmic reticulum through the Golgi network. These proteins, named BIG1 and BIG2, have become the nexus of Dr. Vaughan’s research efforts.
BIG1 and BIG2 accelerate the replacement of bound GDP by GTP when necessary for Arf activation. However, only a small fraction of these large 200 kilodalton protein molecules interacts with Arfs, suggesting multifunctional roles for BIG1 and BIG2. Though detailed cellular distributions and localized actions of these two proteins remain to be established, Dr. Vaughan’s research has shown BIG activities throughout the cell. In addition to the Golgi network, BIG1 was associated with nucleolar complexes that assemble ribosomes for protein synthesis, as well as sites for regulating cell polarization in directed migration, whereas BIG2 was seen in peripheral vesicles that likely represent recycling endosomes.
Most recently, Dr. Vaughan’s laboratory reported a proteomic analysis of effects of BIG2 depletion, revealing its unexpected role in the coordination of actin cytoskeleton mechanics and membrane traffic in cell migration via integrin β1. This work has led Dr. Vaughan from her early interest in cellular metabolism to the integration of energy use as it relates to particular functional pursuits, such as directed movement.
In a related research focus, Dr. Vaughan and her team are studying a protein they cloned and named ARD (Arf-domain protein), which contains its own GTPase-activating and E3-ubiquitin ligase domains, allowing for autoregulation. Dr. Vaughan and colleagues recently reported evidence of ARD1 involvement in the internalization and trafficking of cell surface receptors for growth factors and hormones. Dr. Vaughan continues her work with Arf domains and Arf-associated proteins to characterize this protein family’s increasing recognized diverse functions. These studies will help us better understand how cells (and, by extension, organisms) coordinate and fine-tune the multiple processes that enable them to thrive under different physiological conditions.