Manning Lab

The Manning lab is delineating the molecular wiring and functions of a signal transduction network that senses and responds to nutrients and other growth stimuli, is aberrantly regulated in a diverse set of human diseases, and plays an evolutionarily conserved role in aging.  In normal cells, the PI3K-mTOR signaling network is exquisitely regulated by both cell intrinsic signals, in the form of nutrients and cellular stress, and exogenous signals from secreted growth factors, cytokines, and hormones. The Manning lab has found that these physiological signals are sensed in an integrated manner that assures that the pathway is spatially and temporally activated only under optimal local and systemic nutrient conditions. Several projects in the lab are aimed at defining regulatory mechanisms involving the TSC protein complex, which is a central, signal-integrating node within this vast network.  Furthermore, negative feedback mechanisms are prevalent within the network and have a profound influence on the intensity and duration of signal propagation, as well as the response of the network to pharmacological interventions.  The importance of a mechanistic understanding of this regulation is underscored by the fact that aberrant signaling within the network is a common feature of pathological states, including cancer, type-2 diabetes, and obesity.

In studies initiated through a variety of unbiased omics approaches, the Manning lab has found that the primary function of the PI3K-mTOR network is to control cellular metabolism.  The network serves to link growth signals to mechanisms controlling the key anabolic processes that underlie growth. Activation of mTOR complex 1 (mTORC1) in response to nutrients and other growth signals promotes the conversion of nutrients into biomass through downstream transcriptional and post-translational effects on major metabolic enzymes, such as those influencing protein, lipid and nucleotide synthesis.  Through these molecular mechanisms, the network controls cell and tissue growth, as well as integrated systemic metabolism.  The lab is particularly interested in cancer metabolism and how the common dysregulation of PI3K and mTORC1 in human tumors alters the metabolism of tumor cells and distinguishes them from their cells of origin.

The Manning lab is defining the mechanisms and consequences of PI3K-mTOR network dysfunction in a variety of pathological states.  One such setting is the neurological and tumor syndrome tuberous sclerosis complex (TSC), as well as the related proliferative lung disorder lymphangioleiomyomatosis (LAM).  TSC and LAM are caused by inactivating mutations in TSC1 or TSC2, which are tumor suppressors that form a protein complex (the TSC complex) that is a central negative regulator of mTORC1.  In addition to serving as the key link between growth factor signaling and mTORC1 activation, the TSC complex is also a shared downstream target of the most common oncogenic signaling pathways, including PI3K and RAS, resulting in aberrant regulation of the TSC complex and activation of mTORC1 in the majority of sporadic cancers.  Through mechanisms that are currently unknown, exquisite control of signaling through the PI3K-mTOR network is also perturbed by nutrient excess and obesity, as well as over the course of organismal aging. In a context-dependent manner, these signaling defects can contribute to metabolic reprogramming in cancer cells and the development of insulin resistance and metabolic dysfunction underlying type-2 diabetes.  These are areas of active investigation in the lab.