George Thomas

Bio: George Thomas is recognized for his seminal studies in the purification and cloning of S6K1 and S6K2 and for his studies in elucidating the role of these kinases in cell growth and the identification of the upstream signaling components, which control their activity. He received his BA from UC San Diego in 1969 and his PhD from UC Santa Cruz in 1975. He then moved to the Friedrich Miescher Institute for Biomedical Research (FMI) in Basel, Switzerland in 1975 as a Fellow of the European Molecular Biology Organization. In 1979 he became a Junior Group Leader at the FMI and in 1983 he was promoted to Senior Group Leader. In 1991 he was voted in as a member of EMBO and in 1995 was awarded the Max Cloëtta Prize for Medical Research. He is on the Scientific Advisory Board of Novartis Oncology and The Genetics Company. In January of this year he joined the Genome Research Institute, University of Cincinnati, as Deputy Director of Research and holds the John and Gladys Strauss Endowed Chair in Cancer Research.

Talk Title: The Nutrient Input to the mTOR/S6K1 Signaling Pathway

Abstract: During the evolution of metazoans and the rise of systemic hormonal regulation, the insulin-controlled class 1 PI3K pathway was merged with the primordial nutrient driven mammalian Target of Rapamycin (mTOR) pathway to control the growth and development of the organism. An important downstream effector of this pathway is S6 kinase 1, S6K1. Consistent with its role as both an insulin and nutrient effector, S6K1-/- mice are hypoinsulinemic and mildly glucose intolerant due to reduced cell size. However, such mice maintain normal fasting glycaemia, suggesting increased insulin sensitivity in peripheral tissues. This led to the finding that S6K1-/- mice are protected against fat accumulation induced by age or a high fat diet (HFD), due to a sharp increase in metabolic rate. Although glucose rises and circulating free fatty acids increase three-fold when S6K1-/- mice are fed a HFD they remain insulin sensitive, whereas wild type mice become insulin resistant and exhibit reduced insulin signaling in peripheral tissues as judged by decreased PKB activation. However such mice have strikingly elevated S6K1 activity. These results led to a model whereby increased S6K1 activity, either through insulin activation or nutrient satiation, functions to negatively regulate insulin signaling leading to the development of insulin resistance. In the case of insulin, this effect is mediated through a canonical signaling pathway, which is initiated by the activation of class 1 PI3K. However, how the nutrient input, such as amino acids, is integrated with that of insulin signaling pathway is unclear. Given the pathology of nutrient satiation in obesity and insulin resistance, we recently set out to address this issue. Unexpectedly, we found that a major pathway by which amino acids control S6K1 signaling is distinct from that of insulin and that instead of signaling through components of the insulin/class 1 PI3K pathway, amino acids mediate S6K1 activation through a novel signaling pathway.