Research in the Manning laboratory is aimed at characterizing biochemical links between cell signaling networks and metabolic networks in both normal and cancer cells. The goal of this research is to reveal how signaling events propagated by growth factors, the availability of energy and nutrients, and exposure to environmental stresses are perceived and integrated to properly control cell growth and survival. Importantly, these integrated signaling networks are comprised of the oncogenes and tumor suppressors that underlie the majority of human cancers, and their altered functions in cancer cells disconnect these pathways from normal control mechanisms, leading to uncontrolled cell growth and survival. To elucidate the mechanistic basis of these regulatory networks, the laboratory uses a multi-tiered approach involving biochemistry, cell biology, genomics, proteomics, metabolomics, and animal models. We are particularly interested in pathways controlling and controlled by the products of the tumor suppressor genes, TSC1 and TSC2, mutated in the diseases tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM). Our work in this field has defined the molecular link between these tumor suppressors and control of the nutrient-sensing protein kinase mammalian target of rapamycin (mTOR) by the PI3K-Akt pathway, one of the most frequently activated oncogenic signaling pathways. Using cell and mouse models, we are delineating the contributions and therapeutic opportunities arising from the aberrant activation of this pathway across diverse cancer lineages, with a focus on its impact on tumor cell metabolism.