Research in the Manning lab is focused on signal transduction pathways underlying complex human diseases, including tumor syndromes, cancer, and metabolic diseases.
Much of the research in our lab is focused on gaining a detailed molecular understanding of a highly integrated signaling network merging on the mammalian target of rapamycin (mTOR). The protein kinase mTOR functions within mTOR complex 1 (mTORC1), which can sense cellular growth conditions in the form of secreted growth factors and mitogens and environmental factors such as nutrients and stress. Projects in the laboratory are geared toward defining how mTORC1 senses and integrates such a diverse set of signals. An understanding of the upstream signaling pathways converging on mTORC1 is important, because it is dysregulated and implicated in a huge array of complex diseases, including most cancers and genetic tumor syndromes, childhood and aging-related neurological disorders, autoimmune diseases, and metabolic diseases.
In order to gain insight into the role of mTORC1 in these seemingly distinct clinical settings, projects are designed to uncover the cell intrinsic and tissue-specific downstream functions of mTORC1. Using cell biology and mouse genetics, in combination with biochemical, genomic, proteomic, and metabolomic approaches, we are gaining critical insights into the physiological consequences of mTORC1 activation. Recent studies have demonstrated a central role for mTORC1 in inducing specific metabolic pathways to meet the bioenergetic and anabolic needs of the cell.
Tumor Syndromes and Cancer
The signaling network lying upstream of mTORC1 converges on a G protein switch involving the tuberous sclerosis complex (TSC) tumor suppressors (TSC1 and TSC2) and the Ras-related small G protein Rheb. A complex between TSC1 and TSC2 is regulated by multi-site phosphorylation and acts as a point of integration for a diverse array of cellular signals. When active, the TSC1-TSC2 complex acts as a GTPase activating protein (GAP) for Rheb, thereby turning Rheb off by stimulating its intrinsic GTPase activity. In the presence of growth factors and nutrients, this complex is turned off, allowing the GTP-bound active version of Rheb to accumulate and turn on mTORC1.
The TSC-Rheb-mTORC1 circuit is misregulated in genetic tumor syndromes and in the majority of sporadic cancers. There are many oncogenes and tumor suppressors comprising the pathways upstream of the TSC1-TSC2 complex, and aberrant activation of mTORC1 is a shared downstream consequence of a variety of genetic lesions that contribute to tumorigenesis. Due to the frequent activation of mTORC1 in human cancers, specific inhibitors, such as rapamcyin, are being tested in a number of clinical trials. One goal of our research is to delineate the full effects of mTORC1 activation and inhibition in cells and tumors. Our research has revealed key metabolic and stress response pathways stimulated by elevated mTORC1 activity. These studies are critical to our ability to predict and interpret clinical outcomes from targeting this pathway and are revealing novel therapeutic opportunities.
Tuberous sclerosis complex (TSC) is a tumor syndrome that affects approximately 1 in 6000 individuals, most often in early childhood, and is characterized by the occurrence of benign tumors, called hamartomas, affecting a variety of organ systems including the brain, skin, kidney, lung, and heart. The clinical manifestions of TSC are multifaceted and include neurological disorders (e.g., epilepsy, autism, and mental retardation), skin lesions, lymphangioleiomyomatosis (LAM), and the failure of affected organs. The disease is caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. In addition, TSC2 mutations are found in sporadic cases of LAM, which is a proliferative and destructive lung disorder that only affects women. We are studying cell and mouse models of TSC and LAM in order to define signaling defects underlying the pathological consequences of TSC gene disruption, with a focus on delineating therapeutic strategies.
The TSC-Rheb-mTORC1 pathway is a key downstream branch of insulin signaling that drives tissue-specific anabolic processes. Recent studies have found that states of obesity and nutrient excess lead to elevated mTORC1 signaling in insulin-responsive tissues, such as skeletal muscle, adipose, and liver. While the mechanism of this aberrant activation of mTORC1 is poorly understood, it has been linked to the development of insulin resistance, which underlies type-2 diabetes. Several projects in the lab are aimed at understanding how this pathway is regulated by nutritional status, how perturbations in mammalian glucose and lipid homeostasis affect this regulation, and how mTORC1 signaling contributes to the pathophysiology of metabolic diseases. Genetic and pharmacological approaches in both cell and mouse models are being used to address these areas.