October 17, 2015



Generated by John Koland, PhD

RGS6 Generated by John Koland, PhD

Molecular Biology and Signaling of RGS Proteins Cells communicate with the outside world by interactions of molecules with receptors that activate signal transduction pathways, thereby converting extracellular messages into cellular responses. Various hormones, neurotransmitters, autacoids and sensory molecules activate a family of seven- transmembrane-domain receptors that specifically couple to heterotrimeric G proteins, activating specific second messenger systems.. This signaling system is extremely common and important (e.g., the senses of vision, smell and taste all work by these mechanisms), controlling exceptionally diverse physiological and pathophysiological processes. GPCRs and their signaling components enable cells to adjust to their environment rapidly and with exquisite sensitivity and precision. More than half of known drugs target components of this indispensable signaling system in humans. The intensity and duration of G protein signaling via heterotrimeric G proteins is regulated at multiple levels. Recently, a new gene family (RGS proteins) was identified that provides new insights into how G proteins are turned off once activated by receptors. RGS proteins are key negative regulators of G protein signaling by virtue of their GTPase-activating protein (GAP) activity toward G protein subunits. Our laboratory has pioneered the idea that RGS proteins possess activities apart from or in addition to those involved in G protein signaling. Molecular cloning and characterization of new members of the RGS family in our lab revealed surprising diversity in regions not associated with their GAP activity. These and other findings, including evidence that most RGS proteins traffick to and from the nucleus, raised the intriguing possibility that RGS proteins might possess diverse functional activities. In our studies, we have characterized the role of RGS proteins in G protein signaling and determined mechanisms underlying their unique subcellular trafficking in cells, gaining new insights into structural/functional relationships of RGS proteins. We identified the structural organization of genes encoding numerous RGS proteins, revealing exceptional complexity in splicing of some RGS protein transcripts (e.g., 36 splice forms of RGS6) and facilitating gene knock-in and knock-out studies (functional genomics) to determine the role of these proteins in organisms. Our recent studies have revealed novel signaling functions of RGS proteins in the nucleus, in neuronal differentiation and development, and in DNA damage signaling responses. We identified an RGS polymorphism (gene variant) in humans associated with a significant reduction in the risk of cancer, providing the first link between RGS protein expression and cancer. These studies raise questions of considerable interest and importance concerning the role of RGS proteins in cellular regulation by mechanisms both dependent on and independent of their regulatory actions on G proteins. Some current projects include identifying novel RGS protein interaction partners, anti-sense and transgene technologies to probe physiological roles of RGS proteins, defining the role of nuclear RGS proteins and determining the mechansims regulating RGS gene expression.